Mathematical Immune Response Models

(see also
Burrascano's Guidelines and Immune Response Modeling,
Models of Immune Systems: The Use of Differential Equations)


A Medline Literature Survey
Date: March 29, 2000

Joachim Gruber

Table of Contents
(Note: only some of the papers in this file have been linked to this Table of Contents)

Faculteit der Natuurwetenschappen, Wiskunde en Informatica, Universiteit van Amsterdam, August 10, 2001.

Simulating the Immune System

Wouter Hanegraaff

4.3 Conclusions
The immune system can be seen as a parallel, information processing system that learns through examples and constantly adapts itself to new situations and possesses a distributive memory for patterns.

For theoretical immunology, immune system simulations can be used to gain more insight in how various interactions together result in immunological phenomena. The immune system as a whole is a complex special purpose system.Therefore, a model that accurately simulates the immune system is no natural solver for arbitrary problems. However, particular theories about the immune system can be used to inspire new problem solving methods.

Implementing processes of the immune system may lead to useful natural solving algorithms, but studying the general operations of the immune system may also lead to identifcation factors that have relevance in areas different than immunology.

We believe that immune system models are useful because they reveal interesting behaviour that may lead to the discovery of new problem solving techniques.

1: Kosm Biol Aviakosm Med 1991 Sep-Oct;25(5):53-6

[Study of cyclic kinetics of immunity by mathematical modeling methods].

[Article in Russian]

Smirnova OA

The mathematical model of the dynamics of humoral immune responses to soluble antigens has been developed. This is a system of nonlinear differential equations describing concentrations of RESULTS:
  1. The model reproduces cyclic kinetics of the immune reaction to slowly catabolizing antigens which is observed experimentally.
  2. Within the framework of the model we describe a potential mechanism causing the oscillatory modes of the immune response. We show that the feedback (in the control of the antibody synthesis) by antibodies is due to neutralization of the main stimulus (of the immune system, i.e., free molecules of the antigen) by circulating antibodies.
PMID: 8577146, UI: 96164137

2: Folia Microbiol (Praha) 1980;25(5):430-8

Mathematical models of antibody response.

Klein P

An antigen triggers the clonal expansion of B lymphocytes accompanied by antibody production. This paper presents and compares the basic ideas of three mathematical models of B cell differentiation and proliferation.

PMID: 6968707, UI: 81045285

3: Folia Microbiol (Praha) 1973;18(4):308-14

Cyclic kinetics and mathematical expression of the primary immune response of soluble antigen. 3. Cellular activity of antigen.

Levi MI, Durikhin KV, Basova NN

PMID: 4753343, UI: 74031655

4: J Theor Biol 1990 Feb 9;142(3):317-40

Verification of immune response optimality through cybernetic modeling.

Batt BC, Kompala DS

Department of Chemical Engineering, University of Colorado, Boulder 80309-0424.

An immune response cascade that is T cell independent begins with the stimulation of virgin lymphocytes by antigen to differentiate into large lymphocytes. These immune cells can either replicate themselves or differentiate into plasma cells or memory cells. Plasma cells produce antibody at a specific rate up to two orders of magnitude greater than large lymphocytes. However, plasma cells have short life-spans and cannot replicate. Memory cells produce only surface antibody, but in the event of a subsequent infection by the same antigen, memory cells revert rapidly to large lymphocytes. Immunologic memory is maintained throughout the organism's lifetime. Many immunologists believe that the optimal response strategy calls for large lymphocytes to replicate first, then differentiate into plasma cells and when the antigen has been nearly eliminated, they form memory cells. A mathematical model incorporating the concept of cybernetics has been developed to study the optimality of the immune response. Derived from the matching law of microeconomics, cybernetic variables control the allocation of large lymphocytes to maximize the instantaneous antibody production rate at any time during the response in order to most efficiently inactivate the antigen. A mouse is selected as the model organism and bacteria as the replicating antigen. In addition to verifying the optimal switching strategy, results showing how the immune response is affected by antigen growth rate, initial antigen concentration, and the number of antibodies required to eliminate an antigen are included.

PMID: 2338827, UI: 90250942

5: Folia Microbiol (Praha) 1973;18(4):315-8

Cyclic kinetics and mathematical expression of the primary immune response of soluble antigen. IV. Response of the organism to the injection of two substances with plasma cell activity.

Levi MI, Basova NN, Durikhin KV

PMID: 4753344, UI: 74031656

6: Vopr Pitan 1987 Nov-Dec;(6):39-42

[Mathematical modelling of perorally induced immunological tolerance].

[Article in Russian]

Sharmanov TSh, Kurmangalinova IA, Nikitin SA, Chernov GIa, Kurmangalinov SM

A mathematical model of the mechanism of development of orally induced immunologic tolerance has been suggested. The model presents a system of differential non-linear equations, and it is realized as a program in FORTRAN. The model describes primary and secondary immune responses, reflects the main features of the immune system response to antigen intake with food. The immune system model response to varying doses and frequency of the antigen intake with food has been studied. It has been established that repeated administration of small doses of the food antigen leads to a deeper tolerance due to lower stimulation of the immune system. The existence of optimal tolerogenic doses of the food antigen has been proved. Qualitative changes in the immune system response to the food antigen have been recorded in case of increased permeability of the intestinal wall.

PMID: 3439085, UI: 88146667

7: Biofizika 1976 Sep-Oct;21(5):905-9

[Mathematical model of the immune response].

[Article in Russian]

Dibrov BF, Livshits MA, Vol'kenshtein MV

A model of immune reaction is suggested, which takes into account the delay in the development of an immune response. Depending on parameter values the model describes:

It is shown that the course of the reaction essentially depends on the duration of delay. Parameters regions corresponding to different regimes are determined.

PMID: 1088081, UI: 77134981

8: Biofizika 1975 Nov-Dec;20(6):1095-8

[Mathematical model of autoimmunity].

[Article in Russian]

Smirnova OA, Stepanova NV

A mathematical model of autoimmunity is developed. This model is a system of two nonlinear differential equations, which describe the concentration dynamics of tissue cells and agressive lymphocytes. An analysis of the solutions shows that this model reproduces general behaviour of autoimmune diseases.

PMID: 1203300, UI: 76089084

9: J Math Biol 1976 Nov 25;3(3-4):325-67

Optimal strategies in immunology. I. B-cell differentiation and proliferation.

Perelson AS, Mirmirani M, Oster GF

The optimal strategy available to the immune system for responding to a non-replicating thymus-independent antigen is examined. By applying Pontryagin's maximum principle to a set of mathematical models of lymphocyte populations and their antibody production, it is found that the optimal strategy of bang-bang control appears robust. In a variety of structurely related biological models, similar behaviour is observed. The models that we consider assume that antigen triggers a population of B-lymphocytes. These triggered lymphocytes can either proliferate and secrete modest amounts of antibody or differentiate into nondividing plasma cells which secrete large amounts of antibody. For biologically reasonable parameter values it is found that for low doses of antigen, immediate differentiation into plasma cells is optimal, while for high antigen doses a proliferative state followed by differentiation is the best strategy.

PMID: 1088161, UI: 77142883

10: Biofizika 1978 Jan-Feb;23(1):143-7

[Mathematical model of the immune reaction. III. Description of the infectious process in relation to changes in the number of B-lymphocytes].

[Article in Russian]

Dibrov BF, Livshits MA, Vol'kenshtein MV

A model of humoral immune reaction which takes into account explicitely the time lags in the immune response is considered. Possible regimes are described.

PMID: 304743, UI: 78104136

11: Biofizika 1978 May-Jun;23(3):494-500

[Mathematical model of the immune response. IV. Threshold character of the infectious process].

[Article in Russian]

Dibrov BF, Livshits MA, Vol'kenshtein MV

A model of immune reaction is described which takes into account the agressive behaviour of infectious microorganisms in the macroorganism. The model allows a description of threshold relationship between the infection process and the initial dose of the antigen. According to the model depending on the parameters and initial data the following regimes are possible:

PMID: 667153, UI: 78211346

12: J Theor Biol 1991 Dec 7;153(3):371-84

A quantitative model suggests immune memory involves the colocalization of B and Th cells.

Antia R, Levin B, Williamson P

Molecular and Cellular Biology Program, University of Massachusetts, Amherst.

A prominent and essential feature of the humoral immune response of vertebrates is immunologic memory: the ability to recall previous exposure to antigen. We present a mathematical model of the growth and interactions of the major cell populations involved in the humoral immune response. Our analysis of this model predicts that the formation of a dynamic association between small numbers of antigen-specific B and Th cells, "colocalization", is sufficient to account for memory and the kinetics of the secondary response--neither specifically differentiated Th or B memory cells nor networks of antigen and anti-idiotypes are required. The colocalization hypothesis explains a number of existing experimental observations and can be tested by straightforward experiments which we describe.

PMID: 1839166, UI: 92186352

13: Folia Microbiol (Praha) 1977;22(2):117-27

Cyclic kinetics and mathematical expression of the primary immune response to soluble antigen. VII. The conveyer hypothesis and its mathematical expression.

Levi MI, Smirnova OA

The conveyer hypothesis is based on the fact that because of clone predetermination, antibody production takes place in an organism without the presence of antigen as a result of natural cell differentiation. Soluble antigen is an analogue of a specific mitogen which gives rise to reproduction mainly of cells carrying on their surface the immunoglobulin receptors to the given antigen. The mathematical model of the conveyer hypothesis takes into account the initial conditions, among them the background level of antibody-producing cells before injection of a soluble antigen, migration of precursor cells in the draining lymphoid organ, and the rate of precursor differentiation, including the rate of the change of the immunoglobulin receptor number on the cell surface. Changes of antigen concentration in blood determine the intensity of precursor proliferation. Comparison of real experiments (intraperitoneal injections of capsular antigen of Pasteurella pestis into inbred mice) with calculations done on the basis of the developed mathematical model shows a definite qualitative resemblance with the kinetics of antibody-producing cells and free antibodies as well as with the decrease of free antigen concentration in blood. In spite of some differences between model experiments and real experiments the conveyer hypothesis and its mathematical model appear suitable for describing the primary immune response of mice immunized with low doses of capsular antigen of Pasteurella pestis.

PMID: 557428, UI: 77139415

14: J Theor Biol 1992 Oct 7;158(3):329-57

A model for simulating cognate recognition and response in the immune system.

Seiden PE, Celada F

IBM T. J. Watson Research Center, Yorktown Heights, NY 10598.

We have constructed a model of the immune system that focuses on the clonotypic cell types and their interactions with other cells, and with antigens and antibodies. We carry out simulations of the humoral immune system based on a generalized cellular automaton implementation of the model. We propose using computer simulation as a tool for doing experiments in machine, in the computer, as an adjunct to the usual in vivo and in vitro techniques. These experiments would not be intended to replace the usual biological experiments since, in the foreseeable future, a complete enough computer model capable of reliably simulating the whole immune would not be possible. However a model simulating areas of interest could be used for extensively testing ideas to help in the design of the critical biological experiments. Our present model concentrates on the cellular interactions and is quite adept at testing the importance and effects of cellular interactions with other cells, antigens and antibodies. The implementation is quite general and unrestricted allowing most other immune system components to be added with relative ease when desired.

PMID: 1287364, UI: 93164693

15: Immunol Lett 1986 Nov 3;13(6):317-21

A new mathematical model of proliferation control during immune response.

Prikrylova D, Jilek M, Dolezal J

A considerable proliferation of participating cells is a characteristic feature of the immune response. This proliferation may be controlled by Interleukin 2. Assumptions on the course of the immune response under such a control are formulated, and a new mathematical model of the immune response involving regulation of the proliferation of appropriate cells is constructed.

PMID: 2946638, UI: 87055923

16: J Math Biol 1978 Mar 28;5(3):213-56

Optimal strategies in immunology. II. B memory cell production.

Perelson AS, Mirmirani M, Oster GF

After a first encounter with most antigens, the immune system responds to susequent encounters with a faster, more efficient and more strenuous antibody response. The memory of previous antigen contacts is carried by lymphocytes. Expanding on the model developed in Part 1 of this paper, we examine the optimal strategy available to the immune system for B memory cell production. We again find that the strategy should be of the bang-bang variety. The model we consider assumes that antigen triggers a subpopulation of B-lymphocytes. These triggered lymphocytes can proliferate and secrete modest amounts of antibody, or differentiate into non-dividing plasma cells which secrete large amounts of antibody, or differentiate into non-antibody secreting memory cells. Given injections of antigen at two widely spaced times we compute the strategy which minimizes a linear combination of the primary and secondary response times. We find that for all biologically reasonable parameter values the best strategies are ones in which memory cells are produced at the end of the primary response. Exerimental results which bear on the actual strategies employed are discussed.

PMID: 307043, UI: 78195744

17: Ric Clin Lab 1980 Apr-Jun;10(2):313-30

Basic strategies of the immune system in the regulation of antibody response.

Adorini L

Three major regulatory mechanisms operating in the control of antibody response have been examined: 1. antibody feedback; 2. T cell regulation (I. regulatory interactions among T cell subsets, II. H-2 linked Ir gene control of T cell function, III. regulatory role of antigenic epitopes in T cell subsets induction); 3. idiotypic network. Analysis of the results of obtained in the lysozyme system together with available data in the literature have permitted the delineation of a model of antigen-triggered events involved in the regulation of antibody response. The basic feature of the proposed model is the integration of two major specific communication systems among lymphocytes engaged in the antibody response: antigen bridge and idiotypic complementarity.

PMID: 6161409, UI: 81102765

18: Biofizika 1977 Mar-Apr;22(2):313-7

[Mathematical model of an immune response. II. Stochastic aspects].

[Article in Russian]

Dibrov BF, Livshits MA, Vol'kenshtein MV

In the mathematical model describing the development of infection and its suppression with antibodies worked out of the course of the delayed immune response a problem of complete destruction of antigen is considered. A method of calculating the probabilities of antigen destruction is advanced. The optimal cure tactics is discussed. It is shown that the highest probability of the destruction of antigene is achieved if the serum is injected in the moment of antibodies peak and when the cure with antibiotics is started at the antigen maximum.

PMID: 861270, UI: 77182260

19: J Exp Med 1981 Oct 1;154(4):1043-57

In vitro antigen-induced, antigen-specific antibody production in man. Specific and polyclonal components, kinetics, and cellular requirements.

Lane HC, Volkman DJ, Whalen G, Fauci AS

A highly specific and reproducible antigen-induced, antigen-specific culture and assay system for antibody production by human peripheral blood B lymphocytes has been developed. The system is clearly T cell and monocyte dependent and is independent of exogenous mitogens. The major factors in our ability to trigger specific antibody production with antigen alone have been the use of extremely low concentrations of antigen in vitro (doses several orders of magnitude below those inducing a peak blastogenic response), careful attention to in vitro cell density and culture vessel geometry, and appreciation of the kinetics of the circulating antigen-inducible B cell repertoire. A dichotomy and overlap between antigen-induced, antigen-specific and antigen-induced, polyclonal responses was observed in the study of doubly immunized individuals. Whereas antibody responses highly specific for the antigen in culture were observed under one set of culture conditions (flat-bottomed vessels, 1.5 x 10(6) cells), switching to another culture system (round-bottomed vessels, 5 x 10(5) cells) resulted in polyclonal responses to antigen. Despite these culture condition-related differences in the induction of antibody synthesis, the suppression of specific antibody production that occurred at high concentrations of antigen was specific only for the antigen in culture. The capability to easily and reproducibly look at truly antigen-induced, antigen specific antibody production should be a major tool in furthering the understanding of human B cell activation and immunoregulation.

PMID: 6169778, UI: 82032143

20: FASEB J 1991 Aug;5(11):2547-53

Published erratum appears in FASEB J 1991 Oct;5(13):2867

Role of B cell antigen processing and presentation in the humoral immune response.

Myers CD

Department of Microbiology and Immunology, University of Tennessee, Memphis 38163.

In the 25 years since it was first indicated that lymphocyte subpopulations must interact during the generation of a humoral immune response, there has been an explosion of data on the molecular mechanism of this interaction. It has been demonstrated that T cells recognize a processed antigen fragment presented by a major histocompatibility complex molecule on the surface of an antigen-presenting cell. The minimal peptides required for T cell recognition of several proteins have been determined, the molecular genetics of many of the cell surface molecules involved have been defined, and the three-dimensional structure of the T cell receptor and the major histocompatibility antigens have been deduced. Several cell types have been found to act as antigen-presenting cells, although the roles of these populations in vivo remain unclear. However, it is clear that there must be a physical interaction between a B cell and a T cell before the B cell can respond to a T-dependent antigen. This interaction requires processing and presentation of the antigen by the B cell. Therefore this review focuses on antigen processing and presentation by resting B cells, one of the key steps in initiation of a humoral immune response.

Publication Types: Review Review, tutorial

PMID: 1907935, UI: 91331212

21: J Theor Biol 1977 Nov 7;69(1):23-39

Mathematical model of immune processes. II. Kinetic features of antigen-antibody interrelations.

Dibrov BF, Livshits MA, Volkenstein MV

PMID: 592869, UI: 78070232

22: Hosp Pract 1977 Feb;12(2):85-99

Genetic controls and cellular interactions in antibody formation.

Katz DH

Both thymus-derived lymphocytes (T cells) and bone marrow--derived lymphocytes (B cells) play critical roles in specific antibody responses to antigens. Genetic controls of the antibody response in mammals have been found to reside largely within the major histocompatibility complex where different genes appear to code for immune response (Ir), immune suppression (Is), and cell interaction (CI) molecules.

PMID: 300071, UI: 77117555

23: J Theor Biol 1985 Jun 21;114(4):527-61

Towards a logical analysis of the immune response.

Kaufman M, Urbain J, Thomas R

We present a new way to conceive, formalize and analyse models of the immune network. The models proposed are minimal ones, based essentially on the well-established negative feedback loop between helper and suppressor T cells.

We describe the role of a logical method in the generation and analysis of the models, and the complementarity between this logical method and the more classical description by continuous differential equations. Its fit with real situations is surprisingly good for a model of this simplicity. Nevertheless, we give it as an example of what can now be done in the field rather than as a stable model.

PMID: 3875000, UI: 85266281

24: Folia Microbiol (Praha) 1975;20(3):261-3

Cyclic kinetics and mathematical expression of the primary immune response. Cyclic kinetics of antibody-forming cells following immunization with Salmonella typhi O-antigen.

Shmuter LM

The kinetics of antibody-forming cells (AFC) in the spleen of rats immunized with Salmonella typhi O-antigen was investigated. The number of nucleated cells of spleen and blood serum antibody titres in passive haemagglutination were determined in parallel. Cyclic changes in the number of antibody-forming cells were detected as three peaks on the 4th, 9th, and 13th days following immunization. The fluctuations of their number were not related to the total number of nucleated cells of spleen. The antibody titres reached their peak on the 10th day following immunization, decreased by the 14th day and rose again on the 16th day after immunization. Repeated increases of the number of AFC were probably due to the regular, not accidental, recruitment of committed precursors cells (memory cells).

PMID: 1170127, UI: 75188217

25: Arb Paul Ehrlich Inst Georg Speyer Haus Ferdinand Blum Inst Frankf A M 1974;69:35-7

[Antigen and antibody equivalent partners in the course of the humoral immune response].

[Article in German]

Gilsenbach H, Albers P

PMID: 4406415, UI: 74152217

26: Folia Microbiol (Praha) 1985;30(3):203-11

Role of antigen and antibody in the regulation of the immune response.

Moller G

The enzyme dextranase could degrade antigenic dextran in vivo even when given 6-15 d after the antigen. Dextranase injected after the antigen suppressed the immune response when given 24 but not 48 h after the antigen, indicating that the antigen must interact with the immune system for 48 h to initiate a response. Thereafter, the B cells are independent of further antigen stimulation. To show whether antibody-mediated suppression of the immune response was determinant specific FITC-conjugated SRC were applied as immunogen and antibodies were raised both against the carrier (SRC) and the FITC hapten. When these antibodies were injected 1-3 h after the immunogen they only suppressed the immune response to the corresponding determinant. Anti-carrier antibodies usually enhanced the response to the hapten. Therefore, antibody-mediated suppression of the immune response is determinant-specific and cannot be mediated in vivo to a detectable extent by the Fc part of the antibodies.

PMID: 2408979, UI: 85232498

27: J Exp Med 1976 Jun 1;143(6):1421-8

Cell interactions in the suppression of in vitro antibody responses.

Calkins CE, Orbach-Arbouys S, Stutman O, Gershon RK

Normal T and immune B lymphocytes interact in a fashion that leads to suppression of the immune response. Normal spleen cells added to cultures of primed spleen cells specifically suppressed both the IgM and IgG secondary antibody response of the primed cells to less than 30% of the response of the immune cells cultured alone. Cell crowding as a possible in vitro artifact was ruled out. The suppression was specific for the priming antigen, even when the specific and nonspecific antigens were included in the same cultures. Suppression required both normal T and immune B cells to be present in culture. We suggest that the immune population produces a signal that can induce normal T cells to become specific suppressor cells. This form of interaction may represent an important regulatory (homeostatic) mechanism in the immune system.

PMID: 58053, UI: 76192829

28: Nature 1980 Jun 26;285(5767):662-4

In vivo cyclic change in B-lymphocyte susceptibility to T-cell control.

Calderon RA, Thomas DB

The humoral response to hapten-protein conjugates is an invaluable model for dissecting the cellular elements of lymphocyte cooperation, and the Mitchison secondary adoptive transfer system provides convincing evidence of cooperation between hapten-specific B cells and carrier-specific T cells in the production of anti-hapten antibody. Recently, attention has focused on the role of suppressor T cells in the regulation of antibody production. Several workers have shown that carrier-priming may, in some instances, suppress a subsequent hapten antibody response, both in vivo and in vitro. This effect is attributed to a suppressor T-cell population, generated during the initial phase of the immune response. Gershon and co-workers have postulated that such suppressor T cells function in a feedback regulatory loop to limit the duration of an immune response. We have examined the suppressive effect of carrier immunization in a secondary anti-hapten response in vivo and demonstrate a cyclic change in susceptibility of memory B cells to T-help and suppression. Such variation presents a severe restriction to any model of feedback control by suppressor T cells.

PMID: 6446684, UI: 80232907

29: Mikrobiyol Bul 1982 Jul;16(3):217-23

[Mechanism of immune response].

[Article in Turkish]

Gulmezoglu E

The mechanism of immune response is not yet very well understood. In the formation of immune response the macrophage, B and T lymphocytes are effective. In the interaction of these cells the physical and soluble secretory factor of the macrophages and T cells induce the differentiation and proliferation of the T and B cells. The immune response genes which are found in major histocompatibility complex genes influence the formation of immune response as well.

PMID: 6820118, UI: 83166673

30: Immunology 1996 Jun;88(2):191-7

Pulmonary immune memory: localized production of antibody in the lung after antigen challenge.

Bice DE, Muggenburg BA

Inhalation Toxicology Research Institute, Albuquerque, NM 87185, USA.

In comparison to primary immune responses after lung immunization, the level of antigen-specific antibody and the number of cells producing specific antibody are significantly increased after challenging the lungs with antigen. The response of immune memory cells in the lung to an antigen challenge could be responsible for this elevated immune response. However, increased numbers of antibody-producing cells, possibly produced in the lung-associated lymph nodes, are also found in the blood after an antigen challenge. Therefore, it is possible that both the response of immune memory cells in the lung, and the recruitment of antibody-producing cells from the blood, contribute to the elevated levels of antibody in the lung after an antigen challenge. This study compared the level of antibody produced in the lung by the response of pulmonary immune memory cells with the level of antibody produced by antibody-forming cells that enter the lung from blood after an antigen challenge. This comparison was made possible by immunizing and challenging two lung lobes of dogs with two antigens. The immune responses to both antigens were then evaluated in both lung lobes after primary immunization and challenge. Data from these evaluations showed that most antibody in the lung after an antigen challenge is produced by a localized anamnestic response of pulmonary immune memory cells. A significantly lower level of antibody entered the lung from the vasculature and/or was produced by antibody-forming cells that entered the lung from blood after an antigen challenge.

PMID: 8690450, UI: 96288254

31: Folia Microbiol (Praha) 1973;18(3):237-41

Cyclic kinetics and mathematical expression of the primary immune response to soluble antigen. II. The mathematical expression of some elements of the primary immune response.

Levi MI, Durikhin KV, Basova NN, Fomenko GA, Kravtsov FE

PMID: 4723304, UI: 73231380

32: J Theor Biol 1987 Nov 21;129(2):141-62

Model analysis of the bases of multistationarity in the humoral immune response.

Kaufman M, Thomas R

Universite Libre de Bruxelles, Service de Chimie-Physique II, Belgium.

A formal analysis of the regulation of antibody production has been developed. It comprises two complementary approaches: a logical analysis in terms of discrete (boolean) variables and functions and a more classical analysis in terms of differential equations.

The model subject to this analysis is a minimal one, which takes into account a small number of well-established facts concerning lymphocyte interactions and some reasonable assumptions.

The core of the model is

The salient feature of this minimal scheme is the prediction, for given environmental and parametrical conditions, of a multiplicity of steady states.
  1. This multistationarity occurs both in the absence of antigen or for constant antigen levels.
  2. Variations in the external constraints provoke switches among the steady states which might be related to the various modes of the humoral immune response, and depend
  3. In particular, high and low dose paralysis appear to be associated with two distinct steady state branches.
PMID: 2458507, UI: 88333839

33: Immunol Rev 1990 Jun;115:11-147

The protection: the unit of humoral immunity selected by evolution.

Cohn M, Langman RE

Developmental Biology Laboratory, Salk Institute for Biological Studies, San Diego, California 92138-9216.

Publication Types: Review Review, academic

PMID: 2202659, UI: 90361316

34: Folia Microbiol (Praha) 1973;18(3):229-36

Cyclic kinetics and mathematical expression of the primary immune response to soluble antigen. I. Cyclic kinetics of immunogenesis.

Levi MI, Durikhin KV, Basova NN, Shmuter LM, Suchkov YG, Lipnitskii AV, Gerasyuk LG

PMID: 4579241, UI: 73231379

35: Artif Organs 1996 Aug;20(8):866-77

Analysis of nonlinear properties of immune network reactions.

Hirayama H, Nishimura T, Fukuyama Y

Department of Public Health, Asahikawa Medical College, Japan.

On the basis of biochemical reaction dynamics, the temporal behavior of the immune network system was analyzed theoretically to promote the analysis of quantitative changes in the reactions of immune disorders and organ substitution. The idiotype immune network reaction system was expressed by 64 nonlinear differential equations that comprised four kinds of antibodies and B-cell subpopulations. All four kinds of antibodies decreased rapidly. With the progress of the reactions, they have increased gradually. The single and double bound antibodies increased rapidly from the onset of the reaction. The single-bound antibodies did not show a definite increase after the rapid increasing phase. The antibody-antibody complex increased parallel with the double bound antibodies. The effects of rate constant expand to all the immune complexes in the network system. The double bound antibodies and antibody-antibody complexes were oscillatory functions of a given antibody. Therefore, the idiotypic immune network system must be a chaotic one. The present theoretical method is available to evaluate the total ability of immune reaction system that operates as a network system.

PMID: 8853798, UI: 97006505

36: Aust J Exp Biol Med Sci 1967 Dec;45(6):681-94

Antigens in immunity. 13. The antigen content of single antibody-forming cells early in primary and secondary immune responses.

Nossal GJ, Williams GM, Austin CM

PMID: 5582855, UI: 68157363

37: Br J Anaesth 1979 Jan;51(1):3-6

The immune system--some basic concepts.

Owen JJ

PMID: 317876, UI: 81039190

38: Immunology 1977 Apr;32(4):445-56

The properties of immune complex-forming systems. A new theoretical approach.

Steensgaard J, Liu BM, Cline GB, Moller NP

A new mathematical model for antigen-antibody interactions has been developed. The new model is based on the assumption that the formation of complexes between a bivalent antibody and a multivalent antigen is determined thermodynamically by the concentrations and valences of antigen as well as antibody, together with one association constant which is common to all mutual interactions.

Formulae have been derived for calculation of the distributions of compositionally different antigen-antibody complexes either from knowledge of equilibrium concentrations of free antigen and antibody, or from knowledge of total amounts of antigen and antibody in the system.

A computer program for these calculation is described. The model is found to yield precise predictions of the formation of soluble immune complexes, as studied by zonal centrifugation.

It is found through use of the model that 'complex formation' as such differs in binding characteristics from adsorption, especially for high concentrations of antigens and antibodies. 'Complex formation' implies that association constants estimated through a Sips plot method will vary with antibody concentration, and that certain curvatures of the lines in a Sips plot reflect inherent properties of complex-forming systems.

PMID: 608678, UI: 78128851

39: J Theor Biol 1991 Sep 21;152(2):263-70

A discrete model for immune surveillance, tumor immunity and cancer.

Chowdhury D, Sahimi M, Stauffer D

Supercomputer Center HLRZ, Julich, Germany.

In this paper we propose a model of tumor immunity in terms of discrete automata where each automaton describes the concentration of one particular type of cell involved in immune response.

  1. In contrast to the earlier models of normal immune response, there is more than one type of cell surface antigen in this model.
  2. As a consequence, the tumor can evade destruction through humoral response by changing its identity.
  3. However, the tumor can be killed by the killer cells through cell-mediated response unless protected by a high concentration of the suppressor T cells.
PMID: 1753781, UI: 92092734

40: Proc R Soc Lond B Biol Sci 1991 Aug 22;245(1313):147-50

Maturation of the humoral immune response as an optimization problem.

Agur Z, Mazor G, Meilijson I

Department of Applied Mathematics and Computer Sciences, Weizmann Institute of Science, Israel.

Efficient immune response often depends on the production of high affinity antibodies. We show analytically that the optimal strategy for a fast production of high affinity antibodies is to utilize a step-function mutation rate, i.e. a minimal mutation rate in early stages of the immune response, followed by a discontinuous switch to the maximal possible rate when the proliferating population of B-cells exceeds a threshold value. Our results are in accordance with the biological observations concerning the time of onset of the hypermutation process, and with the mutation rate during the later stages of the primary immune response. Indeed the hypermutation process plays a crucial role in responding to a prevailing pathogen at each round of immune response, and not only for coping with future infections. Moreover, as the effect of hypermutations is shown to be crucially dependent on the number of proliferating B-cells, its onset is not expected to depend on an external signal, but rather to be related to the clone's age. This suggests that the onset is host species specific, rather than pathogen specific. Another implication of the present results is that activation of hypermutations before the B-cell population has reached the critical size may impede the efficiency of the response.

Publication Types: Review Review, tutorial

PMID: 1682938, UI: 92052305

41: Proc Natl Acad Sci U S A 1982 Jun;79(12):3828-32

Enhancing antibody: a novel component of the immune response.

Nemazee DA, Sato VL

Current descriptions of the immune response identify two classes of antigenic stimuli that result in the production of specific antibody:

  1. exogenous antigens and
  2. endogenous variable-region determinants of the immune system.
  3. We expand this scheme to include a third class of antigenic stimulus--new determinants created by the binding of antibody to antigen.
This paper describes a set of monoclonal antibodies These antibodies recognize determinants on the antibody portion of the complexes that were expressed as a consequence of antigen binding. Antibodies of this general type, "enhancing antibodies," which can strengthen antibody--antigen and idiotypic-anti-idiotypic antibody interactions, may play important regulatory and effector roles in the immune response.

We suggest a model that predicts the occurrence and specificity of different classes of such antibodies and provides a conceptual framework that gives a straightforward explanation of the appearance in the immune response of rheumatoid antibodies and of antibodies that bind cooperatively to antigen.

PMID: 6179088, UI: 82247944

42: Int Rev Immunol 1988 Mar;3(1-2):47-58

The origin of "natural antibodies" and the internal activity in the immune system.

Bandeira A, Coutinho A, Martinez C, Pereira P

Departement d'Immunologie, Institut Pasteur, Paris, France.

Publication Types: Review Review, tutorial

PMID: 3073179, UI: 89235409

43: J Immunol 1986 Mar 15;136(6):2090-4

T cell activation of antigen-specific antibody responses by large B cells is MHC restricted.

Mosier DE

The activation of small, resting B cells for antibody synthesis by helper T cells has been proposed to require an MHC-restricted interaction between the T and B cells. Large, activated B lymphocytes were, in contrast, thought to be activated by an unrestricted pathway. We re-examined this issue and found that both large and small size fractionated murine B lymphocytes required an MHC-restricted interaction with helper T cells to be activated for specific antibody synthesis. Polyspecific antibody synthesis in the same cultures was not dependent upon an MHC-restricted T-B interaction for any size category of B cell. These results are interpreted as reflecting the ability of antigen-specific B cells to focus and present antigen to T cells, in contrast to B cells of random specificity, which have no effective focusing mechanism for a given experimental antigen. We found that the polyspecific response required much higher antigen concentrations than the antigen-specific response, a result consistent with the antigen-focusing hypothesis.

PMID: 2936819, UI: 86141791

44: Science 1996 Apr 5;272(5258):50-3

The instructive role of innate immunity in the acquired immune response.

Fearon DT, Locksley RM

Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, UK.

Innate immunity has been considered only to provide rapid, incomplete antimicrobial host defense until the slower, more definitive acquired immune response develops. However, innate immunity may have an additional role in determining which antigens the acquired immune system responds to and the nature of that response. Knowledge of the molecules and pathways involved may create new therapeutic options for infectious and autoimmune diseases.

Publication Types: Review Review, tutorial

PMID: 8600536, UI: 96178660

45: J Theor Biol 1998 Oct 7;194(3):341-81

The humoral immune response to Haemophilus influenzae type b: a mathematical model based on T-zone and germinal center B-cell dynamics.

Rundell A, DeCarlo R, HogenEsch H, Doerschuk P

School of Electrical and Computer Engineering, Purdue University, West Lafayette, IN 47906, USA.

Through careful mapping of the physiology of the T-zone and GC B-blast dynamics to a mathematical representation of the cell processes including

a mathematical model is constructed to capture the
  1. dominant nominal primary,
  2. late follicular, and
  3. secondary humoral response to Haemophilus influenzae Type b.
This model explicitly incorporates into a coherent framework.

This paper describes the relevant immunology, the pertinent physiological assumptions, the developed model, and the parameter identification procedure. The model parameters were found using a parameter identification procedure that capitalizes on the timing and interactions of certain dominant physiological attributes. Simulation results and validation tests indicate that the model reflects not only

  1. a nominal primary and
  2. secondary humoral immune response but also
  3. the tertiary and T-independent responses.
The model shows robustness to variations in infection dosage, bacterial growth rate (virulence of the strain), and onset-timing of the secondary response.

The utility of this model in studying the humoral immune response is demonstrated through

The model and parameter identification techniques are easily adapted to other diseases which primarily evoke a humoral immune response. Copyright 1998 Academic Press

PMID: 9778443, UI: 98453588

46: Bull Math Biol 1992 Jul;54(4):649-72

Modeling immune reactivity in secondary lymphoid organs.

Perelson AS, Weisbuch G

Theoretical Division, Los Alamos National Laboratory, NM 87545.

Models of the dynamical interactions important in generating immune reactivity have generally assumed that the immune system is a single well-stirred compartment. Here we explicitly take into account the compartmentalized nature of the immune system and show that qualitative conclusions, such as the stability of the immune steady state, depend on architectural details. We examine a simple model idiotypic network involving only two types of B cells and antibody molecules. We show, for model parameters used by De Boer et al. (1990, Chem. Eng. Sci. 45, 2375-2382), that the immune steady state is unstable in a one compartmental model but stable in a two compartment model that contains both a lymphoid organ, such as the spleen, and the circulatory system.

PMID: 1591535, UI: 92274085

47: Zh Mikrobiol Epidemiol Immunobiol 1974 Nov;(11):50-3

[Mathematical model of the cooperative interaction in an immune response].

[Article in Russian]

Smirnova OA, Stepanova NV

PMID: 4615520, UI: 75105367

48: Crit Rev Immunol 1992;11(6):337-80

Immunological functions and in vivo cell-cell interactions of T cells in the spleen.

Van den Eertwegh AJ, Boersma WJ, Claassen E

Department of Immunology and Medical Microbiology, TNO Medical Biological Laboratory, Rijswijk, The Netherlands.

The spleen is an important lymphoid organ, involved in immune responses against all types of antigen that appear in the circulation. Its complex anatomical organization, with distinct compartments containing specialized cell types, provides a microenvironment which allows different cell-cell interactions and determines the direction of developing immune responses. In this review we evaluate the vast amount of in vitro data dealing with antigen presentation, cell-cell interactions, T and B cell activation, and the immunoregulatory role of cytokines, as suggested to be involved in immune responses. As a basis for understanding of in vivo processes, these in vitro data will be related to discrete phenomena of in vivo immune responses, such as antigen localization/trapping, cell migration patterns of immunocompetent cells, cytokine production, and antibody formation in the different compartments of the spleen. Finally, we try to bring order to the sequence of events that occur in the spleen after antigenic challenge by presenting an in vivo model for T cell dependent and T cell independent immune responses.

Publication Types: Review Review, academic

PMID: 1388710, UI: 93000456

49: J Immunol 1983 Aug;131(2):725-30

Inhibitory activity of antibodies to human Ia-like determinants: comparison of intact and pepsin-digested antibodies.

Muchmore AV, Megson M, Decker JM, Knudsen P, Mann DL, Broder S

Antibodies which react with products encoded by the human DR locus precipitate a biomolecular membrane glycoprotein complex with m.w. of 29,000 and 34,000 daltons. Such antibodies are directed against HLA-DR Ia-like antigens found on human B cells and human monocytes and have been shown previously to inhibit a variety of in vitro cellular and humoral immune reactions. We have compared the in vitro effects of such antibodies on two assays of human immunity: antigen-specific proliferation and polyclonal immunoglobulin production. Intact IgG fractions of a rabbit heteroantiserum (anti-P29,34), a human MT-2 locus alloantiserum (Ia 172), and a mouse monoclonal antibody (LB 3.1) markedly inhibited in vitro immune reactivities of human mononuclear cells. Interestingly, F(ab')2 preparations of these antibodies failed to inhibit these in vitro immune responses at the concentrations tested. These data suggest that under certain conditions, Fc domains play a critical role in the inhibitory activity of antibodies to Ia-like molecules.

PMID: 6408187, UI: 83239944

50: J Immunol 1986 Jun 1;136(11):4319-27

Concomitant immunization by the fully antigenic counterparts prevents modulated tumor cells from escaping cellular immune elimination.

De Boer RJ, Michelson S, Hogeweg P

In a mathematical model of the cellular antitumor immune response, we studied the possible role of antigenic modulation as a tumor escape mechanism.

These experimental data are incorporated in a model which we have analyzed previously.

The model incorporates interactions between macrophages and T lymphocytes, which lead to cellular antitumor immune reactions (i.e., to cytotoxic macrophages). Parameters were derived from the immune resistance of DBA/2 mice to the SL2 tumor. Although all parameters were chosen deliberately to favor the modulation process (i.e., modulation proceeds fast, demodulation slowly, and the killing rate is reduced 50-fold), modulation is found to be a poor tumor escape mechanism.

We conclude that the impact of modulation as an escape mechanism remains small because modulated tumor cells do not appear until the immune system has been stimulated (immunized) by the fully antigenic tumor cells. Thus, the elimination of modulated tumor cells generally occurs merely as a side effect of the immune response which is directed primarily against the fully antigenic tumor cells.

Parameter sensitivity analysis shows that this conclusion holds true only for cellular immunity. Conversely, the parameter analysis suggests that antigenic modulation plays a deleterious role in cytotoxic antibody responses (e.g., monoclonal antibody therapy).

PMID: 2939142, UI: 86197818

51: J Lab Clin Med 1996 Jul;128(1):61-74

Mechanism and computer simulation of immune complex formation, opsonization, and clearance.

Head M, Meryhew N, Runquist O

Department of Chemistry, Hamline University, St. Paul, MN 55104, USA.

A computer simulation of immune complex formation, opsonization, and clearance has been developed (ICMODEL) that uses equations describing the kinetics of known immunologic processes and an additional pathologic process of immune complex-mediated tissue damage and antigen production. ICMODEL was used to (1) compare simulated with reported immune response kinetics, (2) evaluate the relative stability of the immune system described by the simulation, and (3) determine the conditions required to produce high immune complex levels as found in patients with immune complex-mediated disease. ICMODEL simulated primary and secondary immune responses as well as short- and long-term immunity. ICMODEL also depicted a relatively stable immune response system. Under certain conditions, however, the system could be perturbed, resulting in an unstable response. For example, when the rate constant regulating Fc gamma-mediated phagocytosis was decreased and the rate constant regulating immune complex-mediated tissue damage/antigen production was increased, immune complex concentrations oscillated with time and increased exponentially. These data suggest that ICMODEL can be used to define the specific parameters that, when perturbed, will give rise to increased immune complex concentrations. As such, this model has direct implications for studies of immune complex-mediated disease in human patients.

Publication Types: Review Review, tutorial

PMID: 8759937, UI: 96326457

52: Eur J Immunol 1975 May;5(5):350-4

A network theory of the immune system.

Richter PH

The fact that every antibody also has antigenic properties leads to the existence of a functional network of interacting antibodies and lymphocytes in the immune system. With a minimum set of assumptions about the nature of these interactions some of the principal features of the immune response such as normal primary and secondary response, low and high zone tolerance induction, and memory can be reproduced. The low zone tolerance phenomenon plays a central role in our theory, as it is the simplest nontrivial mode of response to an antigenic stimulus. It may be understood as the defeat of the stimulated lymphocyte species against their internal adversaries. The normal response and high zone tolerance induction may be characterized as low zone tolerance on a second and third level of a hierarchy of lymphocyte populations. In particular, the weakness of the primary response is explained in terms of internal struggles which lead to a final suppression of the aggressors, thereby opening the way for an unhindered secondary response.

PMID: 1234059, UI: 77025978

53: J Autoimmun 1989 Jun;2 Suppl:195-201

Molecular dissection of an antigen-specific immune response.

Berek C

Institute for Genetics, University of Cologne, FRG.

Selection defines the repertoire of the primary response, and also which cells differentiate and enter the pool of the memory cells. Whereas the primary response is drawn from the germline repertoire, the memory response consists overwhelmingly of cells which have been hypermutated and selected to express receptors of high affinity. The accumulation of somatic mutations over time indicates that the activation of the memory cell by antigen also reactivates the hypermutation mechanism. Since the frequency of somatic mutations correlates with an increase in antibody affinity, an efficient selection operates not only on the primary B cells when first stimulated by antigen, but also on the memory cells after secondary or tertiary immunization.

Publication Types: Review Review, tutorial

PMID: 2673273, UI: 89374522

54: Int J Clin Lab Res 1992;22(2):63-8

Molecular economy and antibody function: the evolution of a Protecton.

Langman RE

The humoral immune response protects against a very large array of pathogens which attempt to escape immune recognition by changing the antigens they display. When looked at from the point of two competing sets of DNA (i.e., the pathogens vs. the host), there is a vastly larger pool of mutating pathogen DNA than in, say, a mouse. The stratagems that allow a tiny fraction of the mouse's genome to effectively compete with a hugely diverse array of pathogens is analyzed in terms of how antibody functions and how the immune system avoids such pitfalls as self-recognition and destruction. This review is a more general description of a lengthy series of papers which detailed the evolution of the Protecton. Starting from the obvious, that is the concentration-dependence of antibody function, it is apparent that the functional antibody repertoire must be relatively small if a sufficient concentration of specific antibody is to be produced in time to arrest the growth of pathogens and eventually eliminate them. Thus, commonly quoted estimates of antibody repertoires in the range from greater than 10(10) to "complete" (infinite?) must be seriously in error. Other well known "facts", such as D-diversity, and B cell signaling by receptor aggregation are also shown to be lacking in biological commonsense.

Publication Types: Editorial

PMID: 1504307, UI: 92369428

55: Zentralbl Allg Pathol 1985;130(4):307-12

[Common and contradictory aspects of inflammatory reactions and pathogenic immune reactions].

[Article in German]

Geiler G

Some basic features of the reciprocal relationship between inflammation and the pathogenic immune reactions are presented. Inflammation as a non-specific defense reaction is described first followed by presentation of the fundamental mechanisms of immunity corresponding to specific defense reactions. Immune reactions may, in certain circumstances, have a pathogenic effect leading naturally to pathogenic immune reactions. The mechanisms of this process are explained in detail. Macrophages play an important connecting link between inflammation and pathogenic immune reactions. The majority of specifically triggered pathologic immune reactions produce an inflammatory picture illustrating the relationship between the two processes. Humoral reactions controlled by B-lymphocytes manifest themselves as acute inflammation; cell-mediated processes controlled by T-lymphocytes appear as chronic inflammation with granuloma formation. Granuloma formation is specific to the immune reaction rather than to a given causal agent. Inflammation and pathologic immune reactions have different origins. The process of immune reaction is initiated by a specific phase characterized by the struggle between antigen and sensitized lymphocytes. Lymphocytes and plasma cells appear in the course of prolonged inflammatory processes for reasons which are not now known.

PMID: 3879068, UI: 86125551

56: J Exp Med 1978 Sep 1;148(3):759-65

Individual antigen-specific T lymphocytes: helper function in enabling the expression of multiple antibody isotypes.

Pierce SK, Cancro MP, Klinman NR

In recent years antigen-specific T cells have been shown to be capable of mediating a number of diverse functions in collaboration with B cells in humoral immune responses. One of the more intriguing roles attributed to helper T cells is the promotion of the synthesis of multiple immunoglobulin isotypes by B cells in T-dependent antibody responses. The experiments presented in this report were carried out to determine if an individual antigen-specific T lymphocyte has the capability to enable the production of antibodies of multiple immunoglobulin heavy chain isotypes. We describe an experimental system which allows for the isolation and antigenic stimulation of individual helper T cells in a splenic environment which provides an excess of primary B cells for collaboration with isolated T lymphocytes. Employing this system we have demonstrated that an individual antigen-specific T lymphocyte, specific for the PR8 strain of influenza virus, has the capacity to enable primary B-cell PR8-specific antibody responses of more than a single immunoglobulin isotype. The implications made by these studies regarding the problem of genetic restrictions regulating T-cell-B-cell interaction is discussed.

PMID: 308985, UI: 79028699

57: Harvey Lect 1973;67:213-46

Antigen design and immune response.

Sela M

PMID: 4122974, UI: 73195694

58: Immunol Invest 1994 Jan;23(1):53-71

A speculative view of immune recognition.


Department of Chemistry, Peking University, Beijing, People's Republic of China.

Address as of 5. Nov. 2000: Nian Qing Lu, Jiangsu Family Planning Research Institute , 277 Feng Huang Xi Jie , Nanjing 210029 , PR China , nq-lu@PUBLIC1.PTT.JS.CN.

The speculation that immunologically reactive haptens must be those attached to carriers' immunodominant epitopes suggests a clearer mechanism by which the mysterious hapten-carrier phenomena are generated. This review focuses on the molecular biological nature of immune recognition of hapten-protein antigens both by the T-cell and the B-cell. T and B lymphocytes specifically recognize one determinant of the same antigen molecule in two different ways and in different circumstances.

  1. The B-cell recognizes an antigen by the preliminary antigen receptors on the cell's surface, at the time it is still intact, interiorizes it and presents the processed antigenic peptide after an antigen processing procedure.
  2. In contrast, the T-cell recognizes a hidden antigenic determinant, together with portions of the MHC on the presenting cell.
The immune memory is mainly directed to the hidden internal determinant of an antigen.

Some aspects of the clonal selection theory of antibody formation are also discussed at the modern molecular level.

Publication Types: Review Review, tutorial

PMID: 7511567, UI: 94193217

59: Science 1984 Dec 14;226(4680):1283-8

Influence of clonal selection on the expression of immunoglobulin variable region genes.

Manser T, Huang SY, Gefter ML

The humoral immune response of the mouse to certain antigens is characterized by the dominant expression of a single or limited number of related, immunoglobulin variable region (V) structures by antibody-secreting lymphocytes. Such dominance could be due to preferred expression of these V regions in the B cell population prior to the immune response or could result from the action of selective or regulatory mechanisms during the immune response. Expression of a heavy chain variable region (VH) gene segment that partially encodes a V region structure that dominates the immune response to para-azophenylarsonate (Ars) in strain A mice was examined in the B cell population of Ars nonimmune mice. This VH gene segment participates in encoding several hundred thousand different V region structures expressed in this B cell population. The immune system is therefore capable of recurrently selecting a single V region structure from such a repertoire for dominant expression by antibody-secreting lymphocytes during an immune response.

PMID: 6334361, UI: 85065773

60: Ann Immunol (Paris) 1976 Jun-Jul;127(3-4):253-60

Polyfunctional antibodies. Their biology and inheritance.

Czaja M, Richards FF, Varga JM

It seems likely that immunoglobulins have evolved from some archetypal molecule and those forms which are useful to the animal have been retained. It is this entire population of antibodies which forms the humoral immune system and in such a system, not only the properties of individual antibody combining regions, but the properties of the multiprotein system as a whole, are important for the defences of the body against pathogens. Antibody combining sites may bind a disparate set of structurally related and unrelated ligands. This multispecificity can be biologically meaningful: the same clone can be stimulated by different antigens. In this sense, cell surface immunoglobulins are multifunctional. The major biological consequence of antibody multispecificity is overlapping binding functions within subsets of the total antibody repertoire. The most significant impact of this overlap is: (1) it reduces the number of V genes necessary to code for the total number of combining sites; (2) the cross-stimulation of clones by structurally related and unrelated antigens may be instrumental in the normal maintenance of immune responsiveness and in addition, it may explain the ability to respond to unusual and less ubiquitous antigens; (3) the antigenic history of the animal may contribute to the maturation of the immune response by cross-stimulation of pre-selected clones of antigen binding cells.

Publication Types: Review

PMID: 60898, UI: 76276459

61: Prax Klin Pneumol 1979 Apr;33 Suppl 1:260-7

[Physiological and pathological aspects of the immune reactions].

[Article in German]

Nolte D

The basic principles of modern immunology are reviewed. In analogy to the nervous defence mechanism of the body the immune reactions are divided into a "specific" afferent, "unspecific" efferent and central regulatory part. The old conception of the "lock and key" relation between antigen and antibody is re-interpreted in terms of molecular chemistry. The dual aspects of the immune response is interpreted as part of an over-all network within which the humoral and cellular defence systems are organized to act in concert. Allergy is considered to be solely a special type of immune reaction; while its disease-producing effects are undisputed its physiological significance is still obscure. The immune mechanism involved in specific densitization is discussed in detail.

PMID: 111235, UI: 79223648

62: Vet Immunol Immunopathol 1991 Nov;30(1):13-7

Overview of the avian immune system.

Sharma JM

Department of Veterinary PathoBiology, College of Veterinary Medicine, University of Minnesota, St. Paul 55108.

The avian immune system operates on the same general principles as the mammalian immune system. Antigenic stimulation initiates an immune response that involves cellular cooperation most notably between macrophages, B lymphocytes and T lymphocytes. Macrophages process the antigen and present the antigen to the lymphocytes. B lymphocytes, the principal cells that mediate humoral immunity, transform into plasma cells and produce antibodies. T lymphocytes, most important for cellular immunity, differentiate into functionally diverse subpopulations. The subpopulations of avian T cells have been identified with monoclonal reagents and appear to be similar to those of mammalian T cells. Lymphokines, the soluble products secreted by immune cells, mediate the functions of these cells. Studies on avian lymphokines have lagged behind those on mammalian lymphokines because the genes coding for avian lymphokines have not been cloned. The avian lymphokines studied thus far appear to function along the same lines as the mammalian lymphokines. The immune response in birds is highly regulated and breakdown in regulation often results in immunodepression.

Publication Types: Review Review, tutorial

PMID: 1781153, UI: 92142479

63: Biofizika 1977 Mar-Apr;22(2):241-6

[Mathematical model of adaptation of the energy metabolism of a cell. Calculation of the influence of ATP on the activity and concentration of the initiator stage enzyme].

[Article in Russian]

Kaimachnikov NP, Sel'kov EE

A simple kinetic model was constructed to study the adaptation of cell energy metabolism to a varying loading. In this model the initiatory step of energy metabolism, in which the initial substrate S is activated at the expense of ATP molecule energy, is catalyzed by an oligomeric enzyme E dissociable at high ATP concentration to monomers E1. It is assumed that the steady state level of monomers E1 in the cell is maintained by constitutive synthesis of E1 molecules, which balances their continuous hydrolysis by proteases. The properties of the kinetic model were studied using a mathematical model which is a system of nonlinear differential equations describing the change with time of the total enzyme E concentration and the concentration of ATP. The main isoclines of this system can intersect in one, two or three points. The mathematical analysis shows that the kinetic model considered exhibits adaptive properties. A sharp increase of the ATPase activity in the model initiates a transient process which leads to a rise in the total enzyme E concentration and in the efficiency of energy metabolism. As a result, the concentration of ATP drops only slightly. The establishment of a new level of the enzyme E concentration may proceed in the oscillatory fashion.

PMID: 861261, UI: 77182247

64: J Theor Biol 1990 Jul 24;145(2):207-15

A unified discrete model of immune response.

Chowdhury D, Stauffer D, Choudary PV

School of Physical Sciences, Jawaharlal Nehru University, New Delhi, India.

In this paper we propose a unified model of immune response in terms of discrete automata describing the concentrations of the cells constituting the immune network.

PMID: 2402155, UI: 90384184

65: Am J Hosp Pharm 1986 Oct;43(10):2483-93

The immune system.

Tami JA, Parr MD, Thompson JS

The components and functions of the immune system are described, and the clinical applications of agents that affect the immune system are discussed. Through both nonspecific and specific responses, the immune system recognizes and destroys or eliminates harmful foreign substances with which a host comes into contact. Nonspecific responses are usually associated with the first introduction of a foreign substance into the body and consist mainly of phagocytosis and inflammation. When the same substance, or antigen, is introduced into the body on subsequent occasions, antibodies specific for that antigen combine with the antigen and activate a complex network of specialized cells and soluble cellular secretions that eliminate the substance from the body. Certain antigens are inherited and are found on the cells and tissues of the body; these antigens play a major role in human allotransplantation, blood transfusions, and certain disease states. Recent advances in biotechnology have made it possible to alter an individual's immunologic response with such agents as azathioprine, cyclosporine, or monoclonal antibodies or to augment an individual's antitumor defenses with immunopotentiators. As the products of biotechnology are used more frequently in the hospital setting to treat or prevent disease, pharmacists will need to have a good understanding of the immune system to appreciate the functional capacity of and the problems that may exist with these agents.

Publication Types: Review

PMID: 3538863, UI: 87073479

66: Int J Hematol 1996 Jul;64(1):39-46

Suppression of humoral immunity by monoclonal antibody to CD79b, an invariant component of antigen receptors on B lymphocytes.

Nakamura T, Koyama M, Koike Y, Miyazaki K, Yoneyema A, Higashihara M, Azuma M, Kurokawa K

First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.

CD79b is an invariant component of antigen receptors on B lymphocytes. Previous data have suggested that monoclonal antibody (mAb) to CD79b would introduce negative signals into B lymphocytes and suppress humoral immunity. We tested this hypothesis in this study using in vitro assay systems, and revealed that anti-CD79b mAb effectively suppressed the antibody response to a T-cell dependent antigen. The speculated mechanisms for this immunosuppression were: (i) down-modulation of antigen receptors, (ii) inhibition of B lymphocyte differentiation, and (iii) induction of B lymphocyte unresponsiveness. Of these three, we confirmed that the first two were actually induced by anti-CD79b mAb treatment, whereas the in vitro system could not induce the unresponsiveness of B lymphocytes.

PMID: 8757966, UI: 96349698

67: Proc Natl Acad Sci U S A 1984 Sep;81(17):5537-41

Synergistic effects of antigen and soluble T-cell factors in B-lymphocyte activation.

Jelachich ML, Grusby MJ, Clark D, Tasch D, Margoliash E, Pierce SK

Supernatants from phorbol 12-myristate 13-acetate-activated cultures of the mouse EL4 thymoma, or of several mouse T-cell hybridomas stimulated either by their specific antigen or by concanavalin A, induced primary splenic B cells to proliferate and differentiate to antibody-secreting cells. This effect was not due to interleukin 2 and did not require the presence of macrophages. The antibody response was polyclonal, including antibodies specific for 2,4-dinitrophenyl and pigeon cytochrome c, present in amounts of 1% or less of the total immunoglobulin produced. The addition of either of these antigens increased the amount of the corresponding specific antibody. At very high concentrations of dinitrophenyl-hemocyanin the specific response could be depressed. These observations were taken to demonstrate that soluble T-cell factors are sufficient to activate a portion of naive B cells to antibody secretion and that under these conditions in vitro the presence of antigen merely enhances the specific response.

PMID: 6089211, UI: 84298171

68: J Theor Biol 1995 Dec 7;177(3):199-213

Natural tolerance in a simple immune network.

Calenbuhr V, Bersini H, Stewart J, Varela FJ

CREA, Ecole Polytechnique, Paris, France. Calenbuhr/

The following basic question is studied here: In the relatively stable molecular environment of a vertebrate body, can a dynamic idiotypic immune network develop a natural tolerance to endogenous components? The approach is based on stability analyses and computer simulation using a model that takes into account the dynamics of two agents of the immune system, namely B-lymphocytes and antibodies. The study investigates the behavior of simple immune networks in interaction with an antigen whose concentration is held constant as a function of the symmetry properties of the connectivity matrix of the network. Current idiotypic network models typically become unstable in the presence of this type of antigen. It is shown that idiotypic networks of a particular connectivity show tolerance towards auto-antigen without the need for ad hoc mechanisms that prevent an immune response. These tolerant network structures are characterized by aperiodic behavior in the absence of auto-antigen. When coupled to an auto-antigen, the chaotic attractor degenerates into one of several periodic ones, and at least one of them is stable. The connectivity structure needed for this behavior allows the system to adopt particular dynamic concentration patterns which do not lead to an unbounded immune response. Possible implications for the understanding of autoimmune disease and its treatment are discussed.

PMID: 8746325, UI: 96362282

69: J Immunol 1987 Jun 1;138(11):3680-3

Immunoregulation by antigen/antibody complexes. I. Specific immunosuppression induced in vivo with immune complexes formed in antibody excess.

Caulfield MJ, Shaffer D

Specific immune complexes, prepared at different ratios of antibody to antigen, were examined for their effects on the antibody response of BALB/c mice to the cell wall polysaccharide antigen (PnC) extracted from Streptococcus pneumonia R36a.

The suppression appears to be specific for the antigen (PnC), since in mice injected with TEPC-15/PnC complexes (formed in antibody excess) and challenged with PnC coupled to sheep RBC, only the response to PnC was suppressed.

PMID: 3584970, UI: 87224000

70: Annu Rev Biophys Bioeng 1983;12:117-38

Mathematical modeling in immunology.

DeLisi C

The first step in the sequence of events leading to antibody synthesis and secretion is antigen encounter by B cell receptors. The reaction leads to major membrane perturbations, including the capping and endocytosis of receptors. These events might play an important role in various aspects of the B cell response, but they are not well understood, and in any event it seems unlikely that a satisfactory explanation of response regulation to most antigens can be advanced in terms of these phenomena alone, without explicit consideration of other cell populations. Suppressor and helper T cell populations qualitatively and quantitatively regulate the response to almost all antigens. Knowledge of the antigen dose dependence of the response of these populations will undoubtedly be important for a complete understanding of major immune response phenomenology such as suppression and affinity regulation. T cell dose response patterns are currently unavailable, nor is much known of the molecular mechanisms mediating interactions among antigen responsive T cells. In order to explain why this information is important, and to connect disparate data on immunoregulation in a simple way, I introduced dose response patterns based on analogy with basophils, assumed cell interactions mediated by autoantiidiotypic antibodies, and briefly pursued the consequences. In the final section, the genetic experiments that are providing information on the molecular constraints on cell interactions were mentioned, and some of the outstanding theoretical questions were briefly discussed.

PMID: 6870214, UI: 83254703

71: J Nutr 1989 May;119(5):790-5

Antigen-specific immune response impairment in the chick as influenced by dietary vitamin A.

Friedman A, Sklan D

Department of Animal Science, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot, Israel.

The effects of a broad range of dietary vitamin A levels on antigen-specific immune responses of the chick were studied. Vitamin A deficiency and long-term excess caused impairment of the immune response as demonstrated by antigen-specific antibody production and T-lymphocyte proliferation in vitro. Immune responsiveness was correlated with both hepatic and blood vitamin A levels, and was affected prior to other physiological manifestations of hypo- or hypervitaminosis. In contrast to the effects of long-term vitamin excess, a large vitamin A bolus did not cause immune response impairment and, on the contrary, restored normal immune functions in previously vitamin A-depleted chicks. This finding implied a regulatory role for vitamin A in the immune system rather than a constitutive one.

PMID: 2786059, UI: 89257770

72: J Exp Med 1982 Sep 1;156(3):690-702

Isotype commitment in the in vivo immune responses. I. Antigen-dependent specific and polyclonal plaque-forming cell responses by B lymphocytes induced to extensive proliferation.

Bjorklund M, Coutinho A

The random recombination and deletion hypothesis for the control of isotype commitment in antibody responses was directly tested in a serial transfer system in vivo. Normal or hyperimmune spleen cells were used in weekly serial transfers with antigen into irradiated recipients until clonal senescence was observed. Antigen-specific and -nonspecific plaque-forming cells of all isotypes were determined at each transfer time. No major changes in the isotypes of specific antibodies were observed for the whole life-span of the transferred cells (9-10 wk), and no indication was obtained for the accumulation of cells transcribing the most 3' members of the C-gene cluster with sustained proliferation. Rather, the dominant isotypes were found throughout the response to be IgG1, IgG2b, and IgG2a. The results imply isotype-specific regulatory mechanisms in the control of Ig class production. These appear to operate as well in the antigen-nonspecific component of the immune response.

PMID: 6809880, UI: 82267746

73: Crit Rev Immunol 1985;5(3):201-27

Immunity and pregnancy.

Gill TJ 3d

The existence of the maternal immune response to various paternally derived antigens on the fetus and placenta is apparently paradoxical, since the immune response is generally associated with host defense. In this context, the immune response to the fetal and placental antigens may have either physiological function or be advantitious. In either event, it appears to be closely associated with the existence of the polymorphisms of the cell surface antigens, particularly those controlled by the genes in the major histocompatibility complex. The major thrust of this review will be to examine the nature of the humoral and cellular immune response to the fetus and placenta and the genetic factors influencing it. A second portion of the review will address the genetic factors influencing development, including those involved in spontaneous abortion and in the genetic control of developmental abnormalities.

Publication Types: Review

PMID: 3884273, UI: 85153316

74: J Immunol 1968 Dec;101(6):1217-22

The differential fate of soluble antigen and antigen-antibody complexes in rabbits and their effect on antibody response.

Patterson R, Suszko IM, Talbot CH

PMID: 5722460, UI: 69051420

75: Biosystems 1995;34(1-3):87-105

On the maternal transmission of immunity: a 'molecular attention' hypothesis.

Anderson RW

Department of Ecology and Evolutionary Biology, University of California, Irvine 92717, USA.

Maternally-derived antibodies can provide passive protection to their offspring. More subtle phenomena associated with maternal antibodies concern their influence in shaping the immune repertoire and priming the neonatal immune response. These phenomena suggest that maternal antibodies play a role in the education of the neonatal immune system. The educational effects are thought to be mediated by idiotypic interactions among antibodies and B cells in the context of an idiotypic network. This paper proposes that maternal antibodies trigger localized idiotypic network activity that serves to amplify and translate information concerning the molecular shapes of potential antigens. The triggering molecular signals are contained in the binding regions of the antibody molecules. These antibodies form complexes and are taken up by antigen presenting cells or retained by follicular dendritic cells and thereby incorporated into more traditional cellular immune memory mechanisms. This mechanism for maternal transmission of immunity is termed the molecular attention hypothesis and is contrasted to the dynamic memory hypothesis. Experiments are proposed that may help indicate which models are more appropriate and will further our understanding of these intriguing natural phenomena. Finally, analogies are drawn to attention in neural systems.

PMID: 7727708, UI: 95244791

76: Folia Biol (Praha) 1991;37(1):10-20

Mathematical model of antiviral immune response regulation. II. Mathematical formalization of the modelled processes. Imitation of acute course of hepatitis B.

Chuykov VV, Bazhan SI, Kulichkov VA

All-Union Research Institute of Molecular Biology, Novosibirsk Region.

The mathematical formalization of the conceptual model for antiviral immune response regulation described in the preceding report was carried out. The mathematical model is presented as a system of 30 ordinary nonlinear differential equations with delays. The algorithm for numerical integration of the mathematical model is based on Gear's methods of variable step and variable order. Initial conditions and parameters, as well as intervals of plausible values for them, were chosen for adaptation of the model for description of acute hepatitis B.

PMID: 1830011, UI: 91301285

77: J Exp Med 1976 Aug 1;144(2):568-71

Requirement for persistent extracellular antigen in cultures of antigen-binding B lymphocytes.

Pike BL, Nossal GJ

A system was established to assess the requirement for continuous presence of antigen in B-lymphocyte activation to antibody formation. Mouse spleen B lymphocytes, enriched for cells bearing anti-NIP (hapten 4-hydroxy-3-iodo-5-nitrophenylacetic acid) receptors, were pretreated briefly with NIP-POL (polymerized flagellin) antigen, washed, and added in small numbers to microcultures. The behaviour of these cells was compared with that of cells cultured in the continuous presence of antigen. Unfractionated spleen cells were studied under similar conditions. In contrast to unfractionated cells, enriched cells could not be triggered effectively by brief contact with antigen at any concentration tested. Fewer cells were activated, and clone size was smaller after brief contact with antigen than when antigen was present continuously. Furthermore, brief contact at high concentration did not cause tolerance induction.

PMID: 1085333, UI: 76263442

78: Alergia 1981 Oct;28(4):173-83

[Regulation of the immune response].

[Article in Spanish]

Conde Bonfil MC

PMID: 6800279, UI: 82133114

79: J Neuroimmunol 1988 Dec;20(2-3):269-76

Idiotypic control of the immune response.

Valderrama R, Eggers AE, Revan S, Moomjy M, Frost M, Pipia P, Di Paola M

Department of Neurology, SUNY Health Science Center, Brooklyn 11203.

Anti-idiotypic antibodies are antibodies against the antigenic determinants (idiotypes) of an antibody's antigen-binding region. Anti-idiotypes can bind near (Ab2 gamma) or away (Ab2 alpha) from the antigen-combining site or can carry the internal image of the antigen (Ab2 beta). Idiotypes and anti-idiotypes have been described in T- and B-cell systems. They have been used in basic research to purify and characterize receptors and ligands against receptors, to treat tumors, to make vaccines and to diagnose and suppress the immune response. In experimental myasthenia gravis anti-idiotypes protect animals against the disease, block idiotype binding and share idiotypic specificities.

Publication Types: Review Review, tutorial

PMID: 2461958, UI: 89067093

80: Mol Immunol 1986 Nov;23(11):1255-6

iC3b receptor and antibody formation.

Wedgwood RJ

This review discusses evidence, derived from three patients and some animal studies, on the relationship between complement, complement receptors and antibody formation. These patients (as "experiments of nature") supplemented by the animal data, confirm the importance of C3 and the iC3b receptor in the full expression of the humoral immune response. Presumably the role affects the presentation of antigen. The timing, as seen in the guinea-pig experiments, suggests that the effect is in the initial presentation of the antigen at the time of induction of the primary response and determines the nature of the secondary response to antigen several weeks later. The primary and secondary humoral immune responses appear to be a single continuum rather than two separate steps in the same process.

PMID: 2950319, UI: 87144291

81: J Theor Biol 1991 Jul 7;151(1):1-40

Mathematical model of antiviral immune response. I. Data analysis, generalized picture construction and parameters evaluation for hepatitis B.

Marchuk GI, Petrov RV, Romanyukha AA, Bocharov GA

Department of Numerical Mathematics U.S.S.R. Academy of Sciences, Moscow.

The present approach to the mathematical modelling of infectious diseases is based upon the idea that specific immune mechanisms play a leading role in development, course, and outcome of infectious disease.

The model describing the reaction of the immune system to infectious agent invasion is constructed on the bases of

The mathematical model of antiviral immune response is formulated by a system of 10 non-linear delay-differential equations.

The delayed argument terms in the right-hand part are used for the description of lymphocyte

  1. division,
  2. multiplication and
  3. differentiation
processes into effector cells. This analysis forms the bases for the solution of the parameter identification problem for the mathematical model of antiviral immune response which will be the topic of the following paper (Marchuk et al., 1991, J. theor. Biol. 15).

PMID: 1943135, UI: 92047484

82: Proc Natl Acad Sci U S A 1996 Apr 16;93(8):3357-61

Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2.

Molina H, Holers VM, Li B, Fung Y, Mariathasan S, Goellner J, Strauss-Schoenberger J, Karr RW, Chaplin DD

Department of Internal Medicine and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1- and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B- and T-cell development are overtly normal. Nevertheless, B-cell responses to low and high doses of a T-cell-dependent antigen are impaired with decreased titers of antigen-specific IgM and IgG isotypes. This defect is not complete because there is still partial activation of B lymphocytes during the primary immune response, with generation of splenic germinal centers and a detectable, although reduced, secondary antibody response. These data suggest that certain T-dependent antigens manifest an absolute dependence on complement receptors for the initiation of a normally robust immune response.

PMID: 8622941, UI: 96194973

83: J Infect Dis 1971 Jan;123(1):99-101

Experimental malaria: effects upon the immune response to different antigens.

Barker LR

PMID: 5543222, UI: 71109551

84: Nature 1995 May 25;375(6529):334-8

Antigen-induced B-cell death and elimination during germinal-centre immune responses.

Shokat KM, Goodnow CC

Howard Hughes Medical Institute, Stanford University School of Medicine, California 94305, USA.

During an immune response, hypermutation of immunoglobulin genes in B cells proliferating within germinal centres (GCs) generates variant antibodies that react with higher affinity against either foreign or self antigens. Several experiments suggest that self-reactive B cells may be censored at this stage of the immune response, but the rarity of these cells and the dynamic nature of GC reactions have prevented direct analysis. We have developed a new approach to visualize the fate of antigen-specific B cells during GC reactions by seeding an ongoing immune response with lysozyme-specific B cells from immunoglobulin-gene transgenic animals. Administration of soluble antigen at the peak of the GC response rapidly eliminates lysozyme-specific GC B cells in two waves of apoptosis, one within the GC and a second in cells that have redistributed to lymphoid zones that are rich in T cells. Elimination of these cells is inhibited by constitutive expression of the follicular lymphoma proto-oncogene bcl-2. These findings reveal censoring steps that may normally prevent affinity maturation of autoantibodies to systemic autoantigens, and might be used by pathogenic microorganisms or in clinical strategies to interfere with antibody responses.

PMID: 7753200, UI: 95272707

85: Ann Immunol (Paris) 1976 Sep-Oct;127(5):787-804

A selective theory for the epigenetic specification of the monospecific antibody production in single cell lines.

Danchin A

A new selective theory for the specification of the antibody production is presented. It is grounded on the following postulates:

  1. the antigen stimulus triggers the synthesis of antibodies having a wide variety of specificities in a given immunocompetent cell and its progeny;
  2. only these antibodies having affinity for the antigen have their synthesis stabilized, and competition between the diverse syntheses will favor the antibodies having the highest affinity; (
  3. there existes a threshold synthesis such that when the production of an antibody becomes lower than the threshold, it will go to zero.
As a consequence, one should observe, PMID: 984733, UI: 77043247

86: Zh Mikrobiol Epidemiol Immunobiol 1989 Apr;(4):60-3

[A mathematical analysis of the interconnection between the titer and avidity of antibodies].

[Article in Russian]

Ledentsova RIu, Kisliak VM

The study made by the methods of mathematical statistics (regression and dispersion analysis) and the calculation of correlative relationship have shown that the titers of antibodies and their avidity in immune rabbit sera, used as a model, are unrelated; changes in the titers and avidity of antibodies in the dynamics of immune response at different schemes of immunization have been mathematically described by means of regressive equations.

PMID: 2735171, UI: 89284822

87: Fed Proc 1976 Aug;35(10):2195-201

Clones of B lymphocytes: their natural selection and expansion.

Williamson AR, Zitron IM, McMichael AJ

The operation of clonal selection for cells of the B-lymphocyte line is discussed with regard to: 1) The clonal repertoire determined by antigen binding to B lymphocytes, which is much larger than that determined by limiting dilution cloning assays. This quantitative difference is interpreted in terms of the multiple shared specificities of each antibody molecule. 2) Multiclonal responses and initial selection by antigen of particular clones (preferential primary selection). 3) Clonal dominance. During an immune response one clone (or a small number of clones) of B cells is preferentially selected and proliferated, apparently at random, from a heterogeneous population of cells capable of responding to the given antigen. Co-dominance of two or more clones simultaneously can be obtained by mixing selected clones. Secreted antibody is seen as playing a role in the establishment of clonal dominance. A model for clonal expansion is presented. The model attempts to explain the generation of memory and antibody secreting cells within each clonal expansion in terms of the ratio of two signals, one for proliferation and one for differentiation. The delivery of these signals is proposed to involve the receptor antibody-antigen interaction for proliferation and a self-recognition site interaction for differentiation.

PMID: 1084836, UI: 76235710

88: J Math Biol 1985;22(3):353-67

A discrete mathematical model of unlabelled granulocyte kinetics. A preliminary study of feedback control.

McFarland BL, van der Vaart HR

The equations used in formulating the continuous model of granulocyte kinetics developed by O'Fallon et al. (1971) were analyzed to see if they could be altered to simulate a feedback mechanism operating on the production and development of granulocytes. After extensive study and modification of the continuous model, it was found that a discrete model based on a Leslie matrix procedure was more effective for simulating the feedback system. This discrete model was used to show experimentally, from a mathematical view point, that a feedback mechanism of some kind must be operating on the production and development of granulocytes. Further, the discrete model was subjected to preliminary tests (simultaneous and cascading feedback) to demonstrate that it has the capability of responding to feedback control.

PMID: 4067445, UI: 86061316

89: Fed Proc 1976 Jul;35(9):2061-6

Antigen-specific T-cell factor in cell cooperation and genetic control of the immune response.

Taussig MJ, Munro AJ

Cell interactions between thymus-derived (T) and bone marrow-derived (B) lymphocytes in the antibody response appear to involve soluble T-cell mediators known as 'factors.' This paper describes the properties of a T-cell factor that has specificity for the inducing antigen, a synthetic polypeptide (T, G)-A--L, and is able to replace T cells in the thymus-dependent antibody response to (T, G)-A--L. Besides antigen specificity, the main features of the molecule are that it is nonimmunoglobulin; it has a molecular weight of about 50,000; and it is a product of the I-A subregion of the H-2 complex (the mouse major histocompatibility complex). These properties suggest that the factor is closely related to the T-cell receptor, which may, by inference, also be a product of the H-2 complex. The factor cooperates well with allogeneic B cells. It can also be absorbed by bone marrow cells and B cells. Studies on the genetic control of the immune response to (T, G)-A--L using the T-cell factor indicate that two immune response genes in the H-2 complex are involved in genetic control, one expressed in T cells and the other in B cells. This two gene hypothesis has been confirmed by showing that an F1 between two low responders to (T, G)-A--L can be a high responder.

PMID: 58799, UI: 76211022

90: WMJ 1985 Sep-Oct;57(5):50-62

[Immunological recognition of antigenic determinants of proteins and peptides].

[Article in Russian]

Komissarenko SV

The data available in literature and those obtained by the author about the structure of the antigenic determinants of proteins and peptides which are identified by antibodies and different populations of immunocompetent cells are reviewed. The problems on interaction of different cells in the immune response against proteins, presentation of the immunogenic complex for identification by T-lymphocytes, structures of the antigen-identifying receptor of T-cells are discussed.

Publication Types: Review

PMID: 2414876, UI: 86045323

91: Cell Immunol 1981 May 1;60(1):234-9

Ontogeny of B-lymphocyte function. XIII. Kinetics of maturation of neonatal B lymphocytes to produce a heterogeneous antibody response to a T-independent antigen.

Lewin ML, Siskind GW

PMID: 7016343, UI: 81210256

92: J Immunol 1983 Mar;130(3):1066-70

Polyclonal activation of murine B lymphocytes by immune complexes.

Morgan EL, Weigle WO

Murine splenic B lymphocytes are stimulated by homologous immune complexes to proliferate and secrete polyclonal antibody. The use of antibody from whole serum or monoclonal antibodies to form complexes resulted in the stimulation of mouse B lymphocytes. The ratio of antibody to antigen appears to be critical for the generation of the polyclonal antibody response. Because antigen and antibody are added independently at culture initiation, the exact nature of the complex is unknown, but optimal polyclonal antibody formation occurs in slight antigen excess. Immune complex-induced polyclonal antibody production requires the presence of both macrophages and T cells, whereas B cell proliferation requires only macrophages. The role of the macrophage appears to be to cleave a low m.w. (17,000) fragment from the complex, which is responsible for lymphocyte activation.

PMID: 6600470, UI: 83110166

93: J Cell Biol 1990 Jul;111(1):55-68

The relationship between antigen concentration, antigen internalization, and antigenic complexes: modeling insights into antigen processing and presentation.

Singer DF, Linderman JJ

Department of Chemical Engineering, University of Michigan, Ann Arbor 48109.

Native antigen is processed and subsequently presented on the surface of antigen-presenting cells, an important step in the elicitation of an immune response. The early events of antigen processing and presentation include: ingestion of a native antigen, intracellular degradation to expose an antigenic peptide fragment, binding of this fragment with an MHC class II molecule, and display of this newly formed complex on the cell surface. Through the development of a mathematical model, a set of mathematical equations which describes the time-dependent appearance, disappearance, and movement of individual molecules, quantitative insight can be gained into the pathways and rate-limiting steps of antigen presentation. The credibility of the model has been verified by comparison to literature data. For example, it has been shown experimentally that macrophages require 60 min for effective antigen presentation, whereas B cells require 6-8 h. The mathematical model predicts these presentation times and identifies the difference in the cell's respective pinocytic rates and sizes as important parameters. B cells capture antigen in their environment through nonspecific fluid-phase pinocytosis as well as by binding antigen to their surface immunoglobulin, allowing receptor-mediated uptake. Uptake of antigen via receptor-mediated endocytosis has been reported to require 1,000-fold less antigen than uptake via nonspecific pinocytosis. The mathematical model clearly predicts this decrease in concentration. The model also makes quantitative predictions for the number of MHC class II-antigen complexes needed to produce T cell stimulation.

PMID: 2365735, UI: 90307798

94: J Gen Microbiol 1968 Jan;50(1):67-76

Kinetics of the immune response of rabbits to lower trypanosomatidae antigens.

Vitetta ES, Guttman HN

PMID: 5635523, UI: 68121318

95: Monatsschr Kinderheilkd 1986 Oct;134(10):716-22

[Ontogenesis of the immune system].

[Article in German]

Schneider H

A review of the current knowledge in the ontogeny of the humoral and cellular immune system is presented. Particular attention is paid to the T cell maturation in the thymus and the characterization of lymphoid cells using monoclonal antibodies.

PMID: 3491955, UI: 87089885

96: Methods Enzymol 1987;150:309-16

In vitro production of antibody in cultures of human peripheral blood lymphocytes.

Umetsu DT, Geha RS

PMID: 3323788, UI: 88121498

97: Vet Immunol Immunopathol 1986 Sep;13(1-2):51-61

IgG precipitating and non-precipitating antibodies in rabbits repeatedly injected with soluble and particulate antigens.

Margni RA, Perdigon G, Gentile T, Abatangelo C, Dokmetjian J

The immune response of precipitating antibodies and non-precipitating antibodies of high affinity (co-precipitating) of the IgG class was analyzed in rabbits repeatedly injected with egg albumin (as a soluble antigen) B. abortus-egg albumin and polymerized egg albumin (as particulate antigens). The results showed that the levels of anti-egg albumin non-precipitating antibodies induced by the soluble antigen were never higher than 10-15% of total antibodies throughout the experimental time. When particulate antigens were injected, the levels of non-precipitating antibodies increased up to 30-70% of the total antibody levels. This phenomenon is related to the way in which the antigen is available to the immune system (particle or aggregated), and is independent of the response induced by the particulate carrier. Components from the cell wall or bacterial membrane that could act as coadjuvants do not participate in this phenomenon. The results obtained seem to indicate that possibly there was a suppression of the synthesis of precipitating antibodies, and this would produce a relative increase in the non-precipitating antibodies.

PMID: 3094236, UI: 87020677

98: Folia Microbiol (Praha) 1975;20(4):354-64

Cyclic kinetics and mathematical expression of the primary immune response to soluble antigen. VI. The possibility of prediction of plasma cell reaction in the spleen of mice immunized with soluble antigen.

Levi MI, Sakayan NN, Livshits MM, Meschcheryakova IS

A mathematical expression of the accumulation of the plasma cells in the spleen of CBA mice immunized intraperitoneally is presented. The dependence of the plasma cell reaction in the spleen on the kinetics of antigen concentration in the blood was confirmed. For the transition from antigen to plasma cells, index A was proposed. The mean values of index A were used for comparison of the calculated and experimental values of the plasma cell reaction and the recorded differences were not great. In a similar way, index A was used for prediction of plasma cell accumulation in the spleen of animals, immunized with a mixture of two soluble antigens -- capsular antigen of Pasteurella pestis and complete antigen of Francisella tularensis. The calculated values of plasma cell reaction corresponded to experimental values.

PMID: 1176044, UI: 76023688

99: Int J Artif Organs 1989 Jul;12(7):471-6

A mathematical model of extracorporeal antibody removal in autoimmune disease.

Waniewski J, Prikrylova D

Institute of Biocybernetics and Biomedical Engineering PAS, Warsaw, Poland.

A mathematical model of T-B cell cooperation is adopted to describe autotolerance and autoimmunity. The model describes the development of plasma cells and T-helper cells from their precursors through activated and proliferating cells. A state of autotolerance is simulated by reducing the rate of T precursors supply (partial clonal deletion theory), while the normal rate yields a stable state of autoimmunity. During the state of autoimmunity extra-corporeal removal of autoantibody and immunosuppression are simulated. Removal of auto-antibody alone results in stimulation of the immune system and quick return to the previous state, mainly on account of activation of memory cells. Antibody overshooting is negligible. Immunosuppression leads to a slow decline in the antibody level. Synergy is clearly demonstrated between both therapies.

PMID: 2527827, UI: 89358316

100: Lab Invest 1986 Aug;55(2):126-37

Genetic aspects of cellular interactions in the immune response.

Cramer DV, Gill TJ 3d

Our understanding of the complex cellular interactions responsible for mediating effective immune responses has increased substantially in recent years. It is now clear that the genetic loci that control the interaction of the cells of the immune response encode groups of closely related cell-surface molecules. These molecules are the class I and class II antigens of the MHC, the differentiation antigens on lymphocyte subpopulations, and the receptors of various types, including the membrane immunoglobulin of B lymphocytes and the antigen receptors of T lymphocytes. Biochemical analysis of these cell surface molecules has demonstrated that they display important DNA sequence homologies. A polypeptide of approximately 110 amino acids comprises the basic building block for many of the cell surface molecules. Gradually, as a consequence of evolutionary development, the immune system has expanded its ability to respond to the external environment by an increased complexity of lymphocyte subpopulations and the surface structures that modulate their interaction. These cell surface molecules provide the structures that allow collaborative interaction of different cell types and that form the multiprotein receptor complexes involved in the recognition of, and specific response to, foreign antigens. Our future understanding of the control of the immune response will depend upon establishing the biochemical nature and the multifaceted interactions of these important molecules.

Publication Types: Review

PMID: 2426516, UI: 86283142

101: J Theor Biol 1988 Aug 22;133(4):409-28

Maturation of the immune response: a computational model.

Weinand RG, Conrad M

Department of Computer Science, Wayne State University, Detroit, Michigan 48202.

Experimental studies of the effect on antibody affinity of antigen dose and time after immunization show that average affinity increases progressively with time after immunization, and that this increase is greater at lower doses of antigen. In this paper we describe a polyclonal computer model of the immune system that yields all the essential phenomena of affinity maturation, including dose-dependency. Our main findings are (1) the dose-dependency relationship is not produced when typical assumptions regarding B-cell populations and binding reactions are employed, and (2) it is possible to reproduce this dependency by assuming two classes of lymphocytes: generalists and specialists. Generalists have a low threshold for response and produce antibody of low effectiveness, whereas specialists have a high threshold for response, and produce highly effective antibody. We make an analogy between the generalists and a pioneer species in ecological succession, and suggest how the generalists may contribute to a more effective defense against real infections.

PMID: 3249530, UI: 89260369

102: Schweiz Med Wochenschr 1989 Dec 9;119(49):1743-51

[Current concepts in the regulation of the immunologic response].

[Article in French]

de Weck AL

Institut de clinique immunologique, Inselspital, Berne.

Regulation of the immunological response occurs at several levels which reflect the increasing complexity of our defense systems and of the immune apparatus. These regulation levels could be compared to the various floors of a building which are first explored and analyzed individually. They are (a) the development and differentiation of the immune system; (b) antigen presentation and genetic predispositions for a specific immune response; (c) idiotypic regulation of the immune response; (d) isotypic regulation and genetic control of the classes of antibodies produced, in particular IgE; (e) immunological regulation through various lymphocyte subpopulations; (f) regulation of the reactivity of inflammatory cells and (g) neuroendocrine regulation of the immune system. Any one of these chapters or levels may be presented and discussed as such, and are at the present time relatively well understood. It is more difficult, however, to evaluate the vertical communications between the various levels of regulation and the relative importance of the individual regulating systems in the development of a global immune response by the organism.

Publication Types: Review Review, tutorial

PMID: 2694364, UI: 90140650

103: Nature 1988 Nov 3;336(6194):70-3

B-cell memory is short-lived in the absence of antigen.

Gray D, Skarvall H

Basel Institute for Immunology, Switzerland.

Primary encounter with antigen stimulates specific B cells not only to differentiate into cells that produce antibody at a high rate (plasma cells), but also to give rise to populations of memory cells. These cells have many characteristics that differ from virgin B cells, including their lifespan. When re-exposed to antigen, memory cells generate secondary IgG responses that are enhanced in rate, titre and affinity. At present they are considered as small resting lymphocytes which survive for long periods in a quiescent state between each antigen encounter. However, the fact that an individual may continue to make an antibody response for many months following a single injection of antigen is often overlooked. This continued antibody production is probably due to repeated stimulation of antigen-specific B cells and raises the question of whether memory B-cell clones require antigen for their maintenance. Here we show that they do, and that following transfer, in the absence of antigen, memory B-cell populations are lost from the adoptive host after 10-12 weeks.

PMID: 3263573, UI: 89040194

104: Nature 1970 Nov 21;228(273):739-44

Mathematical model of clonal selection and antibody production.

Bell GI

PMID: 5472961, UI: 71012598

105: Eur J Immunol 1995 Feb;25(2):579-86

Antigen-binding B cells and polyreactive antibodies.

Chen ZJ, Wheeler J, Notkins AL

Laboratory of Oral Medicine, National Institute of Dental Research, National Institutes of Health, Bethesda 20892.

The present experiments were initiated to see if cells capable of binding antigens could make polyreactive antibodies. Fluorescein isothiocyanate-labeled self and non-self antigens were incubated with B cells from normal individuals. Antigen-binding cells were separated from non-antigen-binding cells by flow cytometry, immortalized with Epstein-Barr virus and analyzed at the clonal level for their capacity to make polyreactive antibodies. Four to six times more cells making polyreactive antibodies were found in the B cell subset that bound antigens than in the B cell subset that did not bind antigens. The majority of the polyreactive antibodies were of the immunoglobulin (Ig)M isotype. Immunoflow cytometry revealed that cell lines making polyreactive antibodies bound a variety of antigens (e.g., insulin, IgGFc and beta-galactosidase), whereas cell lines making monoreactive antibodies bound only a single antigen. The binding of antigens to B cell lines that made polyreactive antibodies could be inhibited (range, 28%-57%) by both homogeneous and heterogeneous antigens. Both CD5+ and CD5- antigen-binding B cells made polyreactive antibodies, but the frequency was slightly higher in the CD5+ antigen-binding (85%) as compared to the CD5- antigen-binding (50%) population. Comparison of CD5+ B cells that bound antigens with CD5+ B cells that did not bind antigens showed that approximately 86% of the former, but only 15% of the latter, made polyreactive antibodies. It is concluded that cells capable of binding a variety of different antigens can make polyreactive antibodies and that antigen binding is a good marker for identifying polyreactive antibody-producing cells.

PMID: 7533091, UI: 95180323

106: J Exp Med 1967 Jul 1;126(1):81-91

Studies on the control of antibody synthesis. Interaction of antigenic competition and suppression of antibody formation by passive antibody on the immune response.

Brody NI, Walker JG, Siskind GW

PMID: 4165502, UI: 67172314

107: Eur J Immunol 1976 Mar;6(3):227-30

Cyclicity and memory in the humoral immune response of the marine toad Bufo marinus.

Azzolina LS

Bufo marinus toads immunized

PMID: 825371, UI: 77048534

108: Med Hypotheses 1985 Aug;17(4):337-50

RISH V. Application to monoclonal antibody production.

Daunter B

RISH considers that cell surface components involved in like cell identification are not involved in the structure of the plasma membrane per se and are attached to a part of their mRNA. The mRNA then acts as a template for the synthesis of DNA. Thus the component at the cell surface is attached to an RNA/DNA receptor. If there is a conformational change in the component (antigen) this will cause a distortion in its RNA/DNA receptor. This distortion is then detected by a tissue specific T lymphocyte which removes all or part of the RNA/DNA receptor from the aberrant cell and the lymphocyte then undergoes replication. During this process receptor RNA/DNA is incorporated into the daughter lymphocyte which becomes a B lymphocyte/plasma cell producing immunoglobulin. The initial tissue specific T lymphocyte becomes a dual functional helper/suppressor cell. The plasma cell after the initial immune response becomes a circulating memory B cell displaying IgM or IgD. If this cell complexes an antigen with its surface IgM or IgD a humoral immune response will be developed as previously described, but in this case the antibodies produced will be anti-idiotypic antibodies. The anti-idiotypic antibodies will regulate the production of the antibody directed against the antigen per se. The anti-idiotypic antibodies will in turn be regulated by a second anti-idiotypic antibody. In RISH five such anti-idiotypic systems may be involved in regulating the immune response to the initial non-immunoglobulin antigen. Based on the RISH anti-idiotypic mechanism a system is briefly described whereby human memory B cells, to a particular antigen, may be isolated. These B cells may then be activated to secrete immunoglobulin with autologous isolated anti-idiotypic antibodies. These activated cells may then be infected with E.B. virus to establish an immortal cell line of B cells secreting the immunoglobulin of interest.

PMID: 4046905, UI: 86013712

109: J Exp Med 1976 Nov 2;144(5):1175-87

Role of B lymphocytes in cell-mediated immunity. I. Requirement for T cells or T-cell products for antigen-induced B-cell activation.

Wahl SM, Rosenstreich DL

Although B lymphocytes can be triggered by B-cell mitogens and by certain other molecules to produce lymphokines, they do not produce lymphokines when stimulated with specific soluble protein antigens. We have investigated whether T-cell help would enable B cells to produce lymphokines when activated by antigens. Addition of small numbers of T cells to B-cell cultures resulted in significant production of a monocyte chemotactic factor. T cells could be replaced by supernates of antigen-stimulated T cells, demonstrating both that the chemotactic factor was B-cell-dervied and that T-cell help was mediated by a soluble factor. Although the T-cell factor was nonantigen specific, B-cell activation required the presence of both antigen and T-cell factor. Thus, it appears that although dependent upon T cells, B lymphocytes may play an important role in amplification of cell-mediated immune responses.

PMID: 1086881, UI: 77052875

110: J Immunol 1987 Sep 1;139(5):1609-16

Targeted antigen presentation using crosslinked antibody heteroaggregates.

Snider DP, Segal DM

We have targeted protein antigens to antigen-presenting cells in vitro by using antibody heteroaggregates containing an antibody against a protein antigen covalently crosslinked to an antibody against a target structure on the surface of the antigen-presenting cells. Antigen presentation was assessed by measurement of lymphokine released by antigen-specific T cell hybridomas. Depending on the experimental conditions, the crosslinked antibodies decreased the amount of antigen required to give a response by the hybridomas by factors of 10(2) to 10(3). Enhanced presentation occurred when antigen was targeted to MHC class I and class II molecules, surface immunoglobulin, or Fc gamma receptors on the surface of the murine B cell lymphoma-hybridoma, TA3. An enhancement of antigen presentation also occurred when antigen was targeted to surface IgD, or class I and class II MHC molecules on murine splenic B cells, and when antigen was targeted to class I and class II molecules on irradiated adherent spleen cells. No response was seen when antigen was targeted to Fc gamma R on B cells or adherent spleen cells. The ability of each crosslinked antibody to enhance presentation paralleled the total amount of each that bound to the surface of the antigen-presenting cells. Antigen presentation, mediated by crosslinked antibody, was antigen-specific and I-A restricted. The presentation of one antigen by using crosslinked antibody did not result in enhanced presentation of a second, bystander antigen. These results suggest that a novel means of stimulating immune responses may be possible in vivo, by targeting antigen to surface structures on antigen-presenting cells.

PMID: 2957430, UI: 87309765

111: J Immunol 1980 Apr;124(4):1721-6

Cellular requirements for antigen presentation in the induction of a thymus-independent antibody response in vitro.

Kirkland TN, Sieckmann DG, Longo DL, Mosier DE

The ability of various cell populations to bind and present the thymus-independent antigen TNP-Ficoll to a responding cell population was assessed. The in vitro antibody response to TNP-Ficoll depends upon the presence of B lymphocytes and plastic-adherent accessory cells, but does not require T lymphocytes. Purified B cells were the most effective population in binding and presenting TNP-Ficoll, and adherent cells did not perform this function. Antigen binding and presentation was antigen specific and could be blocked with anti-mu antibody, but not by antibodies directed against other immunoglobulin classes. Spleen cells from mice genetically unresponsive to TNP-Ficoll (CBA/N X BALB/c F1 males) were equally effective as normal spleen cells in antigen binding and presentation. We conclude that the initial events in the induction of the antibody response involves antigen binding by B cells, and that subsequent activation of the subset of B cells that can respond to TNP-Ficoll proceeds either via B cell-B cell interaction or B cell-dependent transfer of antigen to macrophage-like cells.

PMID: 6965958, UI: 80161123

112: J Theor Biol 1996 Dec 7;183(3):285-305
ÄZB Med X/905 6.1964 - 195.1998

Toxicity and neuroendocrine regulation of the immune response: a model analysis.

Muraille E, Thieffry D, Leo O, Kaufman M

Laboratoire de Physiologie Animale, Universite Libre de Bruxelles, Belgium. emura@

Various models have been proposed for the regulation of the primary immune response. Most of the models focus on the ability of the immune system to control a multiplying pathogen, and take into account the cross-regulations between different immune components.

In the present study, we integrate the immune system in the general physiology of the host and consider the interaction between the immune and neuroendocrine systems.

From a biological point of view, our model accounts for four stable regimes which can be described as
  1. "pathogen elimination/organism healthy",
  2. "pathogen elimination/ organism death",
  3. "pathogen growth/organism death" and
  4. "chronic infection".
The size of the basins of attraction of these different regimes varies as a function of some crucial parameters.

Our model allows moreover to interpret

  1. the interplay between pathogen immunogenicity and neuro-hormonal feedback,
  2. the effects of stress on immunity and
  3. the toxic shock syndrome,
in terms of transitions among the steady states.

PMID: 9015451, UI: 97167834

113: J Exp Med 1980 Mar 1;151(3):681-94

Feedback suppression of the immune response in vitro. II. IgVH-restricted antibody-dependent suppression.

Zubler RH, Benacerraf B, Germain RN

Feedback suppression of the primary humoral immune response to sheep erythrocytes (SRBC) in vitro was induced with cell-free supernate material derived from antigen-(SRBC) activated B (sIg+) cells. This soluble products bears Ig determinants and binds to the eliciting antigen (SRBC). The activity of this antibody in suppressing anti-SRBC plaque-forming cell responses is restricted to spleen cell cultures containing B cells sharing VH genes with the B cells producing the suppressive antibody. The anti-hapten (trinitrophenyl) response to derivatized SRBC is not affected by antigen-primed B cells or their products. These data are compatible with suppression being mediated by anti-antigen antibody, either (a) via blockade of different SRBC epitopes recognized by a limited set of B cell clones in each mouse strain, (b) via triggering of an anti-idiotypic response, either antibody or suppressor T cell in nature, restricted to activity in cultures containing B cells sharing VH structures with the original antibody, or (c) via interference by preformed antibody with T cell help directed at idiotype bearing B cells.

PMID: 6444664, UI: 80138941

114: J Immunol 1970 Aug;105(2):355-61

Antigen binding and the immune response. I. The early primary response to a protein antigen.

Modabber F, Sercarz E

PMID: 5433698, UI: 70253162

115: J Exp Med 1996 Apr 1;183(4):1857-64

Antibody response to a T-dependent antigen requires B cell expression of complement receptors.

Croix DA, Ahearn JM, Rosengard AM, Han S, Kelsoe G, Ma M, Carroll MC

Graduate Program in Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205-2196, USA.

Several lines of evidence indicate that antibody responses to T-dependent antigens require complement receptors expressed on either B lymphocytes or follicular dendritic cells. We have used RAG-2 deficient blastocyst complementation to create mice specifically lacking B cell complement receptors. Despite normal expression of complement receptor 1 (CR1[CD35]) and CR2 (CD21) on follicular dendritic cells, these mice have a profound defect in their capacity to mount a T-dependent antibody response. This is the first direct demonstration in vivo that B cell expression of complement receptors is required for a humoral immune response. This is the first direct demonstration in vivo that B cell expression of complement receptors is required for a humoral immune response. This suggests that CD21 and/or CD35 on B lymphocytes may be required for cellular activation, adsorptive endocytosis of antigen, recruitment to germinal centers, and/or protection from apoptosis during the humoral response to T-dependent antigens.

PMID: 8666942, UI: 96261685

116: J Exp Med 1968 Nov 1;128(5):1183-200

The effect of antigenic competition on various manifestations of humoral antibody formation and cellular immunity.

Eidinger D, Khan SA, Millar KG

PMID: 5696281, UI: 69031966

117: Biosystems 1975 Jul;7(1):101-19

Nonlinear regression methods in design of experiments and mathematical modelling. Applications to the analysis of the steady-state kinetics of glutathione reductase.

Mannervik B

A branching reaction pathway involving a ping pong and a sequential loop has been proposed for glutathione reductase (Biochem. Biophys. Res. Commun. 53 (1973) 1151). In the present investigation nonlinear regression methods have been applied in the fitting of rate equations to experimental data to test the validity of the model proposed and to discriminate between alternative mathematical models (cf. FEBS Lett. 26 (1972) 252). In the best rate law, some of the parameters were numerically redundant. Therefore, a feature-wise analysis of the rate equation was carried out by varying one substrate concentration at a time. The overall strategy used was a cyclic procedure involving: experimentation - analysis of data - modelling - design of experiments - new experimentation etc. Consideration was given to the experimental error structure and to the importance of weighting in the regression analysis. In the design of experiments for discrimination between rival models, a previously defined discrimination function was used. The results of the analysis support the branching reaction scheme proposed for glutathione reductase.

PMID: 239774, UI: 76000525

118: Soc Gen Physiol Ser 1974;29:265-81

Regulatory mechanisms in the immune response.

Benacerraf B, Katz DH, Kapp JA, Pierce CW

Publication Types: Review

PMID: 4610765, UI: 75048466

119: Anal Biochem 1991 Aug 1;196(2):319-25

Modeling of immunosensors under nonequilibrium conditions. I. Mathematic modeling of performance characteristics.

Paek SH, Schramm W

University of Michigan, Reproductive Sciences Program, Ann Arbor 48109.

Immunosensors for the detection of small analytes that use analyte-enzyme conjugates as signal generators require special attention if operated under nonequilibrium conditions. If the size of the analyte and the analyte-enzyme conjugate differ substantially, the two antigens do not diffuse at the same rate. This can cause time-dependent shifts in the sensitivity of competitive immunoassays. Therefore, immunosensors operating at short incubation times require precise timing that meets closely the specifications for which the sensors were calibrated. As an example, we have analyzed kinetic binding curves for the quantitative determination of progesterone with an immobilized monoclonal antibody and a conjugate between horseradish peroxidase and progesterone as signal generator. Mathematical paradigms have been developed to simulate the diffusion, antigen-antibody complex formation, and competitive binding processes in this analytical system. Dose-response curves obtained under nonequilibrium conditions can vary substantially from those obtained at equilibrium of antigen-antibody interaction. The degree of this variation depends on the performance characteristics of the major components of the immunosensor. The developed mathematical solutions reflect experimental results and can be used to model optimal conditions for immunosensors operating under nonequilibrium conditions. In this paper (Part I), we report on the mathematical modeling of the interaction between analyte, analyte-enzyme conjugate, and an immobilized antibody. In Part II (W. Schramm and S.-H. Paek (1991) Anal. Biochem. 196), we present experimental results and compare them with the theoretical models.

PMID: 1776681, UI: 92133745

120: Mol Immunol 1979 Jul;16(7):515-26

The specification of the immune response: a general selective model.

Danchin A

PMID: 315361, UI: 80048506

121: J Immunol 1966 Jul;97(1):34-40

A mathematical model relating circulating antibody and antibody forming cells.

Hege JS, Cole LJ

PMID: 5920458, UI: 67019960

122: Bull Math Biol 1989;51(3):359-79

Diffusion limited immunochemical sensing.

Geurts BJ

The time-dependent surface coverage of antigen-antibody complexes for a sensor in which antigens are bound to surface immobilized antibodies is determined analytically. Assuming a reversible first order reaction between the antigens and antibodies, a model is derived describing the dynamical response of the sensor. The surface coverage is related explicitly to the antigen concentration which is of special interest in experimental situations. The stationary state and short time behaviour are determined explicitly. Several illustrations of the full solution are provided.

PMID: 2730970, UI: 89274465

123: Biofizika 1975 Jan-Feb;20(1):143-6

[Mathematical modeling of the dynamics of biokinematic chains].

[Article in Russian]

Velikson VM, Chkhaidze LV

The method of mathematical modelling of the dynamics of biokinematic chains based on the application of Lagrange equations is considered. An algorythm of determining articulate moments in the matrix form. As an example of the biokinematic chain a model of man's upper extremity is considered. Correctness of the model and of the system of differential equations describing its dynamics is proved experimentally.

PMID: 1111606, UI: 75091008

124: J Immunol 1971 Jan;106(1):276-8

Specificity of tolerance to antigens the immune response to which is controlled by the PLL gene.

Selawry H, Green I, Benacerraf B

PMID: 5543719, UI: 71111471

125: Eur J Immunol 1986 Jan;16(1):69-74

2,4-Dinitrophenyl (DNP)-specific continuous B cell lines as a model system for studying B cell activation and tolerance.

Aldo-Benson M, Scheiderer L, Dwulet FE

Various model systems have been used to study isolated B cell response to receptor cross-linking and to lymphokines. Although each model is useful it is advantageous to have continuous cell lines of nonmalignant antigen-specific B lymphocytes to study antigen-induced B cell function. We further studied the characteristics of the 2,4-dinitrophenyl (DNP)-specific continuous B lymphocyte lines which we previously described (J. Exp. Med. 1983. 157:342). If the cell line lymphocytes are cultured with the antigen DNP-Ficoll without the presence of T cell factors or filler cells they do not produce an immune response above background, but the addition of supernatant from EL4 lymphoma and irradiated normal spleen filler cells results in a 7- to 10-fold increase in plaque-forming cells. The kinetics of the immune response is the same as that seen with normal B cells. Each cell line has a majority of cells which are small surface (s)IgM- lymphocytes which have cytoplasmic IgM and react with 14.8 antibody. There are also large sIgM+-bearing cells, which may be either in the resting or activated state. Some of the sIgM+ cells also bear IgD and Ia antigens but they do not bear IgG. From these studies we conclude that the continuously growing antigen-specific B cell lines can be a useful model to study B cell function.

PMID: 3485048, UI: 86136226

126: Infect Immun 1975 Jan;11(1):137-41

Immune response to hepatitis B surface antigen.

Ibrahim AB, Vyas GN, Perkins HA

A total of 69 persons were investigated for assessment of cell-mediated and humoral immunity to hepatitis B surface antigen (HBsAg). Three groups, each consisting of 20 normal persons, 20HBsAg carriers, and 20 convalescent hepatitis B patients, were studied for HBsAg, anti-HBs, and leukocyte migration inhibition with purified HBsAg. Sequential sampling if an additional group of nine acute hepatitis B patients defined the cellular and humoral immune response to HBsAg. The antigen was eliminated rapidly by mounting of cell-mediated immune response detectable for a limited period, followed by antibody response in relatively few patients moore than 3 months after clearance of circulating HBsAg.

PMID: 1116872, UI: 75114178

127: Scand J Immunol 1981 Dec;14(6):623-9

Fact and speculation on the function of immune response genes in antigen presentation.

Werdelin O

Immune responsiveness of guinea pigs to dinitrophenyl-poly-L-lysine and to the lysine rich random co-polymer of L-glutamic acid and L-lysine are both controlled by a single gene, the 'poly-L-lysine gene'. This paper reviews recent experiments which demonstrate that these two antigens specifically compete with one another for being presented to T cells by the same antigen-presenting cells. This finding is interpreted to mean that antigens to which responsiveness is controlled by the same single gene compete for the Ir gene product of antigen-presenting cells. The review discusses if the products of the immune response genes-presumable the Ia antigens-may constitute a third specific antigen recognition system. It further speculates if this idea may help to provide insight into the phenomenon of histocompatibility-restriction and into the nature of the mixed leucocyte reaction.

PMID: 6805068, UI: 82199304

128: Acta Endocrinol Suppl (Copenh) 1975;194:96-116

Kinetics of antibody formation and regulatory aspects of immunity.

Nossal GJ

This paper, which is to be read in conjunction with that of Dr. J.F.A.P. Miller earlier in this volume, addresses itself to the kinetics of antibody production and to the regulation of the immune response. It is divided into four main sections. The first examines the kinetics of antibody production to a single, strong challenge injection of antigen. The cellular events involved in the latent period and the subsequent exponential phase of antibody production are examined from the viewpoint of four key concepts: triggering, clonal expansion, IgM to IgG switch and affinity maturation. The second section examines the major regulatory influences and feedback loops in immunity. Antigen is discussed as an agent capable of causing tolerance as well as triggering. Antibody is considered an important regulator, and the mechanisms of IgM-positive feedback, IgG-negative feedback, and tolerance and blockade effects of immune complexes are outlined. Immunological memory, the opposite phenomenon to tolerance, is briefly described, as is the importance of genetic factors. The third sections looks at more complex models of the immune response, and in particular at the lessons to be learnt from tumour progression.

Publication Types: Review

PMID: 1092122, UI: 75143361

129: Rev Ig Bacteriol Virusol Parazitol Epidemiol Pneumoftiziol Bacteriol Virusol Para29 1984 Oct-Dec;29(4):303-16

[Cellular cooperation and mechanism of regulation of the immune response. II. The mechanisms of regulation and control of immune reactions].

[Article in Romanian]

Olinescu A

Publication Types: Review

PMID: 6151738, UI: 85114888

130: Vestn Akad Med Nauk SSSR 1991;(4):18-23

[Humoral cycle as a mechanism providing autoregulation of the processes of the immune system].

[Article in Russian]

Voitsekhovskii BL

The author presents a hypothesis on a possible mechanism of autoregulation of the immune response maturation in simulated influenza. A theoretical model describing a cyclic process of so-called "humoral cycle" which provides a directed selection of immunocompetent cells' clones and physiologic limitation of cytotoxic reactions. Possible features of humoral cycle function are considered in the concrete experimental examples. The author demonstrated possible mechanisms of immunological barrier violation in synthesis of big amounts of high affinity + antibodies to antigens of causative agent. Possible application of the theoretical model suggested in immunological studies is considered.

PMID: 1866980, UI: 91327696

131: WMJ 1990 Sep-Oct;62(5):83-6

[The effect of synthetic protein fragments on humoral immune response].

[Article in Russian]

Ivanova VP, Belostotskaia GB, Sorochinskaia EI, Anokhina VV, Lozhkina TK

Effect of some protein and immunopeptide synthetic fragments on the humoral immune response has been studied. Some investigated peptides are shown to influence the antibody genesis at the secondary immune response to T-dependent antigen (bovine serum albumin) in mice. The serum antibody level specific for the bovine serum albumin is measured by enzyme-linked immunosorbent assays (ELISA). Possible mechanisms of the influence of such peptide fragments on the immune system is discussed.

PMID: 2270628, UI: 91102860

132: Ann Oncol 1996 Mar;7(3):227-32

1975-1995 revised anti-cancer serological response: biological significance and clinical implications.

Canevari S, Pupa SM, Menard S

Division of Experimental Oncology E, Istituto Nazionale Tumori, Milan, Italy.

In the 1970s a considerable amount of work was carried out in an attempt to identify an anti-tumor serological response in cancer patients. These analyses have not been very informative due to the complexity and heterogeneity of the response. More recently, the availability of recombinant molecules, synthetic peptides and analytic and semi-quantitative assays has enabled a better dissection of humoral immunity. Antibodies against intracellular antigens (c-myb, c-myc, p53 and p21 ras) have been found in a significant, albeit varying, proportion of patients bearing various tumors. Association with a poor prognosis is documented for anti-p53 antibodies in breast carcinoma patients. A number of cell surface antigens, including mucins, oncoproteins and carbohydrate antigens have been found to elicit a humoral immune response and, in some instances, circulating immune complexes were observed. A protective role for or, on the other hand, masking effects of such antibodies is still controversial. An indication that a serological response can be beneficial comes from vaccination studies. A significant association between the development of an anti-tumor antigen antibody response and prolonged survival was observed following vaccination of melanoma patients with GM2 or anti-idiotypic antibodies which molecularly mimic tumor-associated antigens. It is to be hoped that in the near future the numerous ongoing immunization trials and prognostic studies demonstrate whether antibody response can exert a protective role in vivo.

Publication Types: Review Review, tutorial

PMID: 8740784, UI: 96328543

133: J Immunol 1985 Apr;134(4):2117-30

Network regulation of the immune response: modulation of suppressor lymphocytes by alternative signals including contrasuppression.

Irvine DH, Savageau MA

In the preceding paper we demonstrated that comparison of alternative designs for the immune network can be used to examine the functional significance of specified interactions in normal immune responses. In this paper we examine mathematically the functional significance of three interactions affecting the production of suppressor lymphocytes involved in regulation of normal immune responses. The interactions examined in detail are 1) antigenic stimulation of the production of suppressor lymphocytes, 2) idiotypic stimulation of the production of suppressor lymphocytes, and 3) antigenic inhibition of the production of suppressor lymphocytes (i.e., contrasuppression). The results of our analysis suggest that an immune system with only antigenic stimulation of suppressor production is less effective than a system with both antigenic and idiotypic stimulation of suppressor production on the basis of all of the criteria examined in this study. In turn, the latter system is less effective than a system with only idiotypic stimulation of suppressor production. Furthermore, a system with both idiotypic stimulation and antigenic inhibition of suppressor production can be equal or superior to a system with only idiotypic stimulation of suppressor production on the basis of the same criteria. Similar conclusions hold for the comparison of systems in which regulation by the suppressor lymphocytes of interest is exerted upon production of effector molecules rather than upon production of effector lymphocytes, and also for the comparison of systems in which interactions affecting the production of suppressor factors are of interest.

PMID: 2857746, UI: 85132635

134: Am J Otolaryngol 1985 May-Jun;6(3):148-52

Elaboration of systemic immunity following inner ear immunization.

Harris JP, Woolf NK, Ryan AF

The development of systemic humoral and cellular immunity following antigen presentation in the inner ear was compared with that seen following middle ear and peritoneal inoculation routes. Antibody developing against keyhole limpet hemocyanin was measured by a sensitive enzyme-linked immunofiltration assay, and cell-mediated immunity was measured by in vitro lymphocyte blastogenesis. The inner ear and peritoneal routes of antigen presentation resulted in a parallel rise in antibody over a 3-week period. In contrast, the middle ear route resulted in a weak, transient antibody response by 2 weeks. The acquisition of cell-mediated immunity occurred earliest (day 14) in the group receiving antigen intraperitoneally. A significant but smaller proliferative response was also seen in the group receiving antigen via the inner ear route on days 14 and 21. In contrast, the middle ear route failed to result in cell-mediated immunity. These studies indicate that the inner ear is an effective route of antigen processing which results in the acquisition of systemic humoral and cellular immunity. The development of systemic immunity, in turn, has been found to be protective of the inner ear.

PMID: 3874563, UI: 85249108

135: Adv Exp Med Biol 1985;186:369-76

Antibody responses to T-dependent antigens: contributions of dendritic cells and helper T lymphocytes.

Inaba K, Steinman RM

Dendritic cells (DC) are important accessory cells for T-dependent antibody formation. Other leukocytes -- such as macrophages and B cells -- do not independently initiate antibody responses. DC induce the two principal functions of helper T cells, i.e., direct activation of small, antigen-specific B cells, and release of B cell stimulating factors. These two helper functions can operate in tandem during the 1 degree response to hapten-carrier conjugates. Once the helper cell is sensitized in concert with DC, it interacts directly with B cells apparently in the absence of DC. These functions of helper cells all occur in discrete aggregates which contain DC and the appropriate responding lymphocytes. The DC/lymphocyte aggregates likely represent the appropriate structural unit for the study of cell-cell interactions during antibody responses.

PMID: 2931956, UI: 86022352

136: Immunol Rev 1989 Aug;110:173-85

Peripheral T cells select the B-cell repertoire in old mice.

Weksler ME, Russo C, Siskind GW

Department of Medicine, Cornell University Medical College, New York, NY 10021.

These studies have shown that the alterations in the repertoire of antibody produced by old mice is not due to an intrinsic defect in the bone marrow or in the B-lymphocyte population arising from the bone marrow but rather to a selective downregulation by auto-anti-idiotypic antibody and idiotype-anti-idiotype interactions, shifting the idiotype distribution in the peripheral B-cell population. Thus, the clonal distributions of B cells generated by bone marrow of old and young mice are very comparable. The age-related differences in antibodies expressed by young and old mice are, to a great extent, determined by the activity of a peripheral regulatory immune network. This immune cellular network operates prior to exposure to antigen, presumably on the basis of an idiotype-anti-idiotype network between T and B lymphocytes. After exposure to antigen, a network of idiotype-anti-idiotype antibody interactions also contributes to differences in the immune responses of old and young mice to foreign antigens. If the expressed repertoire of antibody reflects down-regulation of auto-anti-idiotypic antibody, comparable repertoires of B-cell clones would be expected to be recovered from old and young mice if B cells from old mice were rescued from selective peripheral downregulatory influences active in old mice. Support for this hypothesis has been obtained by generating B-cell hybridomas from young and old mice immunized with TNP bovine gamme globulin (Marcenario et al. 1989). The same number of anti-TNP hybridomas and a comparable number of IgG and high-affinity antibody-producing clones were recovered from the spleens of young and old mice. Thus, the actual B-cell clonal repertoires of young and old mice appear to be similar although the expressed repertoires of antibody-producing lymphocytes from old and young mice are very different. This conclusion has considerable impact on strategies that could be employed to reverse the senescence of humoral immunity. Strategies to counter downregulatory influences which constrain the expression of the B-cell population should be more effective than attempts to reconstitute the repertoire of B lymphocytes in aged individuals. Finally, the mechanisms underlying these age-associated shifts in the expressed humoral antibody response can be attributed to life-long interactions with self and foreign antigens. The overall shift may be described as a decreased reactivity to foreign antigens and a complementary increase in reactivity with self antigens.

Publication Types: Review Review, tutorial

PMID: 2676847, UI: 90007587

137: Mol Biother 1988;1(1):46-52

Mathematical modeling for antibody therapy in the setting of antigenic modulation.

Dillman RO, Koziol JA, Shawler DL

San Diego VA Medical Center, CA.

The in vivo efficacy of passive monoclonal antibody therapy is limited in certain systems by the process of antigenic modulation. We describe a compartmental model which addresses the kinetics of in vivo cell binding of murine monoclonal antibody T101, modulation of the T65 target antigen, serum levels of T101, and elimination of target cells. Observed data compare favorably to that predicted by the model. The model suggests that there is no rationale for administering T101 as a prolonged, continuous infusion for passive antibody therapy.

PMID: 3267371, UI: 90000658

138: Proc Natl Acad Sci U S A 1992 Feb 1;89(3):1113-7

Profound specific suppression by antigen of persistent IgM, IgG, and IgE antibody production.

Dintzis HM, Dintzis RZ

Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Ongoing, high-titer T-cell-dependent immune responses in adult mice, consisting of IgM, IgG, and IgE anti-fluorescein antibodies, can be specifically and substantially reduced (90-99%) when the mice are injected with appropriate doses of fluoresceinated dextran of defined molecular weight and hapten valence. This suppressive form of the antigen is nontoxic and specific, as responses to other antigens are unaffected. The suppression is long lasting and reduces high-affinity antibodies most markedly. Moreover, plasma cell secretion of specific antibody is virtually eliminated. This demonstrates that the reduction in antibody titer is not simply due to masking of serum antibody by the suppressive polymer. The results are discussed with reference to proposed models of B-cell and T-cell tolerance. Extension of these findings to disease-related immunogens may yield effective antigen-specific treatments of human allergy and autoimmune diseases.

PMID: 1736295, UI: 92141212

139: Int J Artif Organs 1991 Mar;14(3):186-8

Mathematical modeling of antigen and immune complex kinetics during extracorporeal removal of autoantibody.

Waniewski J, Werynski A

Institute of Biocybernetics and Biomedical Engineering PAS, Warsaw, Poland.

The extracorporeal removal of circulating auto-antibodies by repeated plasma exchange or continuous lymph drainage is modeled by single-pool kinetics. Total amounts of antigenic determinants, k-valent antibodies and immune complexes are variables of the model. Factors influencing the course of therapy are included:

This model can give useful formulae for clinical practice. The effect of treatment can be predicted from Another formula shows how the changed catabolism of antigen after antibody binding can influence the amount of immune complexes. As an example, lymph drainage in myasthenia gravis is calculated using averaged data from three patients.

PMID: 2045195, UI: 91258015

140: J Theor Biol 1996 Oct 21;182(4):513-29

Published erratum appears in J Theor Biol 1996 Nov 7;183(1):119

A model of the immune network with B-T cell co-operation. I--Prototypical structures and dynamics.

Carneiro J, Coutinho A, Faro J, Stewart J

Unite d'Immubiologie, CNRS URA 1961, Institut Pasteur, Paris, France,

Hitherto, "second generation" network models of the immune system have all been restricted to B-lymphocytes and the Ig molecules they produce. These models have not so far been able to provide a convincing mechanism for the distinction between a "Central Immune System" (CIS) composed of a connected network of lymphocyte clones which couple with "self" antigens in a tolerant mode, and a "Peripheral Immune System" (PIS) composed of clones with little or no supra-clonal organization and which produce classical immune responses when interacting with "non-self" antigens.

Here, we present a new network model which explicitly incorporates B-T cell co-operation.

In this model, B-cell activation is dependent on T-cell help, and activated T-cells are down-regulated by engagement of their TCRs by soluble Ig.

  1. We discuss the underlying biology on which we base the system of ordinary differential equations which defines the present network model.
  2. We then illustrate some basic features of the model by examining several prototypical situations with a small number of clones.
Depending on the idiotypic connectivity structure, the model exhibits two distinct modes of coupling with antigens:
  1. an "immune response" mode in which T- and B-cell clones grow exponentially; and
  2. a "tolerant" mode in which T-cell clones are controlled by inclusion of all TCRs in the repertoire of an idiotypic B-cell network.
Finally, we discuss the simplifying assumptions of the present model and argue that its range of validity is indeed the region of the state-space of the system where the discrimination between the CIS and the PIS take place.

PMID: 8944897, UI: 97100336

141: Eur J Immunol 1993 Apr;23(4):984-7

Interleukin 6 is not required for antigen-specific antibody responses by human B cells.

Costelloe KE, Smith SH, Callard RE

Cellular Immunology Unit, Institute of Child Health, London, GB.

Interleukin-6 (IL-6) is a late-acting differentiation factor for human B cells activated by polyclonal mitogens such as pokeweed mitogen (PWM) and Staphylococcus aureus Cowan strain I, but its role in specific antibody responses has not been established. We show here that IL-6 has no consistent effect on specific antibody responses by tonsillar mononuclear cells (TMC) stimulated with influenza virus. A blocking IL-6 antibody also had no effect on antibody production, suggesting that endogenous IL-6 production was not required. In control experiments, this antibody inhibited PWM-stimulated immunoglobulin secretion and proliferation of the IL-6-dependent B cell line B9. A requirement for IL-6 in responses of unfractionated TMC may have been disguised by the presence of T cells. To overcome this problem, we investigated the effect of IL-6 on specific antibody production by T-depleted B cells stimulated with antigen in the presence of IL-2, which is a T cell replacing factor (TRF) for human B cells. Specific antibody production was restored by IL-2, but not IL-6. Neither IL-6 nor anti-IL-6 antibody had any consistent effect on specific antibody production by purified B cells stimulated with antigen and TRF. These experiments show that IL-6 does not have a significant role in antigen (influenza virus)-specific antibody responses by human B lymphocytes.

PMID: 8458386, UI: 93209305

142: J Immunol 1982 May;128(5):2367-72

Activation and immunoregulation of antigen-specific human b lymphocyte responses: multifaceted role of the monocyte.

Gerrard TL, Fauci AS

The multifaceted role of the monocyte in the induction and modulation of antigen-specific antibody responses by human B cells was delineated. Monocytes were absolutely required for the induction of specific antibody responses to both TT and KLH in an antigen-induced in vitro assay. Monocytes were also required for the PWM induction of specific antibody in immunized subjects. Pulsing monocytes with specific antigen or with PWM consistently stimulated proliferation of T cells in absence of added antigen and could also stimulate specific antibody synthesis although less consistently. Stimulation of specific antibody responses with antigen required fewer numbers of monocytes than did stimulation of specific antibody responses with PWM. Polyclonal antibody synthesis induced by PWM was also dependent on monocytes. However, polyclonal antibody synthesis induced by supraoptimal concentrations of antigen was usually optimal in the absence of monocytes and was actually suppressed when increased numbers of monocytes were added to monocyte-depleted cultures. Monocyte supernatants could not replace the absolute requirements for monocytes in the induction of specific antibody synthesis. However, monocyte supernatants could profoundly modulate the antigen-specific as well as the polyclonal Ig response of lymphocytes to either antigen or PWM stimulation in a manner closely resembling monocytes themselves. Thus, we demonstrated that monocytes and their products play a critical role in the activation and immunoregulation of antigen-specific antibody responses of human B cells.

PMID: 6174632, UI: 82143816

143: Eur J Immunol 1980 Aug;10(8):641-6

Mechanisms of antigen-induced blockade of immune response and cyclophosphamide-promoted tolerance to Salmonella typhi Vi antigen.

Prigozhina TB, Fontalin LN

Blockade of the immune response, caused by a high dose of Salmonella typhi Vi antigen (200 microgram i.v.) and cyclophosphamide (CY)-induced tolerance to Vi antigen, were analyzed. The results of the study show that blockade of the immune response cannot be attributed to masking of the response resulting from neutralization of antibodies by the excess of non-cell-bound antigen. A high dose of Vi-antigen induced triggering and proliferation of specific B precursors but reversibly suppressed synthesis or secretion of antibody by plaque-forming cells. A single injection of CY (200 mg/kg i.p.) 2 days after a high dose of Vi antigen markedly prolonged the antigen-induced state of unresponsiveness. CY-induced tolerance to Vi antigen is due to elimination or long-term inactivation of specific B precursors. Dissimilarities in the characteristics of immune response blockade and CY-induced tolerance are discussed as well as their possible implications for the mode of action of CY.

PMID: 6156850, UI: 80246217

144: J Exp Med 1993 Oct 1;178(4):1459-63

Suppressive effect of antibody on processing of T cell epitopes.

Watts C, Lanzavecchia A

Department of Biochemistry, University of Dundee, United Kingdom.

Immunoglobulins drive efficient antigen capture by antigen presenting cells for processing and presentation on class II MHC-molecules. High affinity antibody/antigen interactions are stable at endosomal/lysosomal pH thus altering the substrate for antigen processing. We show that this can result in strong suppression of presentation of some T cell epitopes. This effect was observed when the antibody specificity was a B cell surface Ig, or formed part of an immune complex. In the latter case the presence of the suppressing antibody boosts presentation of other T cell epitopes through enhanced uptake into Fc receptor bearing cells. The influence of bound antibodies on the outcome of antigen processing may influence with T cell epitopes dominate T cell responses and may change the focus of the response with time.

PMID: 7690836, UI: 93389411

145: J Immunol 1981 Aug;127(2):514-7

Primary in vitro anti-KLH antibody formation by peripheral blood lymphocytes in man: detection with a radioimmunoassay.

Morimoto C, Reinherz EL, Schlossman SF

In the present report, a primary in vitro human antibody response to KLH was investigated. Peripheral blood lymphocytes were incubated with antigen for 5 days and then cultured in the absence of KLH for 4 additional days. Maximal anti-KLH antibody production, as measured by radioimmunoassay, occurred at a cell density of 1 X 10(6) and at an antigen concentration of 5 micrograms per culture. The antibody produced was shown to be predominantly of the IgM isotype and specific for KLH antigen in several binding assays. Moreover, no antibody was generated in the absence of T lymphocytes. This in vitro antibody-forming system should be of considerable use in the analysis of the cellular requirements for antibody production and the genetic control of the immune response in man.

PMID: 6166673, UI: 81240777

146: Proc Natl Acad Sci U S A 1981 Apr;78(4):2528-31

Antigen-induced in vitro antibody production in humans: a model for B cell activation and immunoregulation.

Volkman DJ, Lane HC, Fauci AS

The precise events associated with B cell activation in humans are a subject of intense investigation. It has been difficult to develop an in vitro model of antigen-specific triggering of antibody synthesis by human peripheral blood mononuclear cells that is independent of exogenous mitogens. In the present study a sensitive and reproducible culture system and enzyme-linked immunosorbent assay have been established wherein antigen alone is used to trigger antigen-specific antibody synthesis by mononuclear cells from subjects immunized to keyhole limpet hemocyanin (KLH). The in vitro antigen-induced anti-KLH response is comparable in magnitude to that induced by pokeweed mitogen, is predominantly IgM in isotype, and is accompanied by a simultaneous increase in polyclonal antibody production. Anti-KLH responses were seen at in vitro KLH concentrations as low as 0.05 microgram/ml. However, concentrations of KLH greater than 5 microgram/ml resulted in profound suppression of the anti-LHL response while continuing to trigger large amounts of total polyclonal immunoglobulin synthesis. This suppression by high concentrations of antigen was also observed in pokeweed mitogen-driven anti-KLH production. These observations are consistent with previous results from the mouse model showing a close association between antigen-specific and polyclonal responses and the phenomenon of antigen-induced, antigen-specific suppression. Thus, an in vitro model of antigen induction of antigen-specific antibody synthesis in human peripheral blood mononuclear cells has been demontrated and should prove useful in exploring the mechanism of human B cell activation and immunoregulation.

PMID: 6972539, UI: 81223913

147: Birth Defects Orig Artic Ser 1983;19(3):289-94

The human fetus and newborn: development of the immune response.

Hayward AR

Maturation of the immune system starts early in fetal life. Lymphocytes of the B series develop in the liver by 9 weeks' gestation and are present in the blood and spleen by 12 weeks. T lymphocytes start to leave the thymus from about 14 weeks' gestation and subsequently cells with helper and suppressor phenotypes are present in the spleen. The relative lack of development of secondary lymphoid tissues in healthy fetuses most probably reflects the lack of antigen stimulus. Newborn plasma contains adult levels of IgG which is acquired across the placenta from the mother. The small amounts of IgM (less than 20 mg/dL) which are normally present in healthy newborns have been reported to include antibody with specificity for maternal lymphocytes. IgA synthesis normally starts in the secretory immune system, about 2-3 weeks after birth. Poor antibody responses by newborns following immunization, especially with bacterial capsular polysaccharides, suggest that newborn immune responses are immature as compared with adults. The susceptibility of newborns to severe HSV and VZV supports this view. In vitro correlates of this immaturity include 1) deficiency of the response by newborn B cells to polyclonal activators, and 2) a lack of T cells which proliferate in HSV- or VZV-stimulated cultures. These characteristics more likely result from a lack of prior antigen stimulation and resulting clonal expansion than from intrinsic lymphocyte suppression. Antigen handling by newborn monocytes, in contrast, appears to be mature by the time of birth.

PMID: 6606446, UI: 84080780

148: Surv Immunol Res 1983;2(1):78-87

Internal images of antigens within the immune network.

Augustin AA, Sim GK, Bona CA

The variable regions of antibody molecules react with each other via specific recognition of clonally distributed antigenic determinants, known under the general term of idiotypes. The totality of such interactions determines a special behavior of the immune system, as a whole, and its ability to regulate immune responses has been analyzed by the 'immune network theory' of Jerne [5]. In light of this theory, a particular property of idiotypes appears to be of special interest: as revealed by recent experiments, frequently idiotype-like determinants represent internal images of antigens. These internal images can be topochemical copies of nominal non-self antigenic determinants, of various functional non-lymphoid receptors, or of transplantation antigens. In this article, we present a view according to which internal images are essential structures which mediate cellular interactions leading to the selection and conservation of the immune repertoire of T and B lymphocytes. Our opinion is exposed in the context of experimental data obtained in several laboratories, including ours.

Publication Types: Review

PMID: 6359324, UI: 84072366

149: Folia Microbiol (Praha) 1985;30(3):302-11

The X----Y----Z scheme after 23 years.

Jilek M, Prikrylova D

Mathematical modelling of the course of the immune response is undoubtedly one of the most progressive and most promising areas of modern immunology. Mathematical models (along with computer programs) can be taken as "the only means of thoroughly testing and examining a large and intricate theory" (Partridge et al. 1984). The first phase of construction of mathematical models is the formulation of assumptions based on the knowledge of the facts to be modelled (manifested usually in a scheme of the presumed course of the modelled process). The first mathematical models of immune response were based on the hypothesis of a two-stage differentiation of cells participating in the humoral response, published in Prague 23 years ago (Sercarz and Coons 1962; Sterzl 1962) and illustrated by the X----Y----Z scheme. Many contemporary mathematical models still stem from this scheme which undoubtedly fits the fundamental data concerning the immune system.

PMID: 4040052, UI: 85232510

150: J Thorac Cardiovasc Surg 1987 Dec;94(6):802-11

Immunoregulation: the key to transplantation and autoimmunity.

Nossal GJ

Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.

Immune responses depend on a unique set of recognition structures, namely, antibody molecules embedded in the B cell membrane for antibody formation and alpha-beta chain heterodimers of the T cell receptor for cellular immune receptors. These structures are coded for by genes, which undergo rearrangements during the differentiation of B- and T-lymphocytes known as somatic translocations. The end result of this process is the creation of separate repertoires of B and T cells, each single cell displaying a unique receptor. Antigen acts by selecting preexisting antigen-reactive cells for division and further differentiation. Accessory cells such as macrophages are essential for the initiation of most immune responses. Different subsets of T-lymphocytes play a vital regulatory role, not only in controlling cell-mediated immunity as such, but also in guiding B cell function. Understanding the roles of accessory cells, regulatory T cells, and the molecules on their surface is essential for understanding immunoregulation. At present, immunosuppression in organ transplantation and therapy of autoimmune diseases are largely nonspecific and empirical. As the rules of the interactive immunoproliferative cascade are progressively unraveled, more targeted immune manipulation will become possible, and some future avenues of this sort are described.

PMID: 3682850, UI: 88064314

151: Cancer Immunol Immunother 1986;23(3):159-64

A survey of some formal models in tumor immunology.

Dullens HF, Van der Tol MW, De Weger RA, Den Otter W

Computer technology has acquired an important role in structuring a variety of biological systems. The availability of modern powerful computers has stimulated the development of good and accurate models of biological systems. Biological systems, such as the immune response against cancer, are complex and it is difficult to experimentally control all the interacting elements constituting the immune response of a host to cancer. Complex biosystems do not always behave or act as expected during experimental investigation. In these cases computer models can be helpful in understanding the behavior of such complex systems. The purpose of this review is to consider the use of mathematical models to study the immune response against cancer. The logic and design of some operable models relevant for tumor immunology will be discussed. Special attention is given to the conceptualization of a model based upon a new hypothesis of tumor rejection presented by De Weger et al. [10]. Technical details concerning the mathematical aspects, differential equations, details on hardware and software package etc. are not included in this survey. These details are contained to in the original papers.

PMID: 3491679, UI: 87078138

152: Infect Immun 1995 Sep;63(9):3241-4

Cytokines as adjuvants for vaccines: antigen-specific responses differ from polyclonal responses.

Taylor CE

Division of Microbiology & Infectious Diseases, National Institute of Allergy and Infectious Diseases, Rockville, Maryland 20892-7630, USA.

The use of cytokines in the administration of vaccines has a unique value in obtaining the appropriate immune response and in ensuring a protective outcome. Earlier studies indicating that cytokines can influence the generation of a particular antibody isotype may represent an oversimplification of a more complex problem. Several studies discussed in this review show that the effect of a given cytokine on the immune response depends on whether one examines the antigen-specific response or the polyclonal response (i.e., total serum immunoglobulins). Further, a balanced regulation of immune responsiveness is important in maintaining homeostasis of the immune system. Consequently, for any vaccine that uses cytokines to boost the response, due consideration must be given to these important variables.

Publication Types: Review Review, tutorial

PMID: 7543878, UI: 95369869

153: Proc Natl Acad Sci U S A 1975 Mar;72(3):888-91

Cyclic AMP and immune responses: changes in the splenic level of cyclic AMP during the response of mice to antigen.

Plescia OJ, Yamamoto I, Shimamura T

Intravenous injection of sheep erythrocytes into normal immunologically competent C57BL/6J mice results in significant and characteristic changes in the splenic level of 3':5'-cAMP with initiation of the immune response and proliferation of antibody-forming cells. The level increases 2- to 3-fold initially, peaks at 2 min, and returns to base level in an hour. Between 2 and 5 days there is a decrease, followed by a peak when the rate of proliferation of antibody-forming cells is maximal. Changes in splenic level of cAMP are thus transitory and biphasic, and they occur only in response to foreign substances that are immunogenic, such as heterologous erythrocytes, and not to antigenically inert carbon particles. They are also dependent upon the dose of immunogen. Moreover, the double-stranded hybrid of polyadenylate and polyuridylate, which acts synergistically with antigen in stimulating endogenous cAMP, is immuno-enhancing if given with sheep erythrocytes when the cAMP level is increasing, and immunosuppresive if given when cAMP is decreasing. These data provide direct evidence for a role of cAMP as a mediator in the activation and proliferation of immunocytes stimulated by antigen. With knowledge of the transitory and biphasic nature of the cAMP response induced by antigen, one can avoid indiscriminate use of drugs that modify the level of endogenous cAMP and instead employ them rationally in controlling the immune response, enhancing or suppressing it as desired.

PMID: 165492, UI: 75158240

154: J Clin Invest 1984 Oct;74(4):1204-13

In vitro antigen-induced antibody responses to hepatitis B surface antigen in man. Kinetic and cellular requirements.

Cupps TR, Gerin JL, Purcell RH, Goldsmith PK, Fauci AS

In this report we define the parameters of the human immune response after immunization with hepatitis B vaccine. 2 wk after booster immunization, there is significant spontaneous secretion of antibody to hepatitis B surface antigen (anti-HBs IgG), which is not further augmented by stimulation with antigen or pokeweed mitogen (PWM). By 4 wk there is little spontaneous secretion of specific antibody, and low doses of antigen or PWM produce significant increases in the amount of anti-HBs IgG produced. By 8 wk the peripheral blood mononuclear cells are refractory to stimulation by antigen, but anti-HBs IgG is produced in response to PWM. 0.5 yr or more after the last immunization, some individuals will manifest an antigen-induced specific antibody response. This induction of anti-HBs IgG by hepatitis B surface antigen (HBsAg) is monocyte- and T cell-dependent. Note that there is a dichotomy in the T cell response to HBsAg. The specific antibody response is clearly T cell dependent, but no in vitro T cell proliferative response to HBsAG could be demonstrated in the immunized individuals. Although the precise reason for the absent proliferative response to HBsAg despite well-established humoral immunity has not been determined, there was no evidence to suggest nonspecific suppression by HBsAg or the presence of an adherent suppressor cell population. The ability to evaluate antigen-induced, antigen-specific responses to HBsAg will be useful in defining the unique interaction between the human immune response and this clinically important viral agent.

PMID: 6332826, UI: 85007436

155: J Exp Med 1981 Nov 1;154(5):1694-702

In vivo effects of antibodies to immune response gene products. I. Haplotype-specific suppression of humoral immune responses with a monoclonal anti-I-A.

Rosenbaum JT, Adelman NE, McDevitt HO

Immune response (Ir) gene products control immunologic function at several critical sites. We administered in vivo a monoclonal antibody reactive with I-Ak to F1 mice with the genotype H-2k/b. These treated mnice made a markedly reduced antibody response to antigen (H,G)-A--L, under the control of I-Ak, but not to antigen (T,G)-A--L, under the control of I-Ab. This relative specificity was lost if the antigen was given in complete Freund's adjuvant rather than aqueous solution. The monoclonal antibody reduced the antibody titer in an ongoing, secondary response as well. Several potential mechanisms can be postulated for this effect. This haplotypic specificity might ultimately be relevant to human disease.

PMID: 6795305, UI: 82054654

156: Neoplasma 1977;24(3):303-10

Some data concerning immune processes in concomitant tumor immunity experimental models. Comparative in vivo and in vitro investigations II. In vitro experiments.

Donovan G, Popp I, Badea E, Bologa L

The humoral and cellular immune status of C57BL/6 male mice and "R" male rats bearing MC-induced sarcomas were investigated in vitro, using 51Cr-releasing and mixed hemadsorption assays. Analysis was performed on mice subjected to concomitant tumor immunity (CTI) model experiments or bearing primary tumors of different sizes, that was done also in rats. Chromatographic fractions, assumed to contain tumor specific antigens, antibodies or antigen-antibody complexes were identified by their absorption capacity upon specially prepared syngeneic immune sera. Free antibody and antigen-antibody complexes, accompanied with a weak cell mediated immunity (CMI) were correlated with efficient CTI in 2--3% TW/TBW tumor bearers. Homoral immunity (HI) showed sometimes an important increase after challenge administration. High levels of free antigen and antigen-antibody complexes, lack of antibodies and CMI were correlated with CTI absence in huge tumor bearers, representing 30--37% of total body weight. Conditions determining variability of results reported by different authors and the possible mechanisms by which serum immune factor may impair the tumor bearer's immune status are discussed.

PMID: 895940, UI: 77255238

157: Int J Sports Med 1991 Jun;12 Suppl 1:S2-4

The immune system: cells and molecules for the integration of self and non-self.

Eichmann K

Max-Planck-Institute for Immunobiology, Freiburg, Germany.

In a reductionist view, the immune system consists of 4 cell types, 3 diverse receptor systems and 10 to 15 soluble mediators including lymphokines and antibody molecules. Using these elements, the immune system generates 3 different effector mechanisms: Activated macrophages for the killing of intracellular microorganisms, cytotoxic T cells for the killing of virus-infected cells, and antibodies for the neutralization of soluble and cell-associated antigens of various types. While it is already very difficult to derive reliable results form reductionists experiments, such as studying immune responses in culture systems, it is infinitely more complicated to study the influence of physical exercise on the immune system.

PMID: 1894393, UI: 91373017

158: Zh Mikrobiol Epidemiol Immunobiol 1990 Jun;(6):79-84

[A method for the experimental determination of the intensity of immunity from a series of different antigen doses].

[Article in Russian]

Kachevskii NV

A new immunological regularity has been discovered mathematically; proceeding from this regularity, a simple index characterizing the immune responsiveness of animals has been proposed and a new (universal) method for the determination of the intensity of immunity has been developed and checked according to experimental data.

PMID: 2220225, UI: 91021683

159: Chronobiologia 1978 Jan-Mar;5(1):56-65

A simulation study of oscillating glycolysis: a comparison between a model and experiments.

Richter O, Vohmann HJ, Betz A

Glycolysis is the best known biochemical oscillator and suitable for the exploration of the basic features of biological rhythms on a biochemical and mathematical level. Because of our detailed knowledge of its component structure (enzyme kinetics, metabolite pattern) glycolysis can be described by a set of coupled nonlinear differential equations of first order with respect to time, whose individual terms consist of enzyme velocities assuming a steady state hypothesis for the enzymatic forms. Due to the feedback control of PFK by the adenylates the system is able to oscillate. The outcomes of a simplified model, containing only the basic elements of glycolysis, show good agreements with experimental results.

PMID: 688850, UI: 79003063

160: J Reticuloendothel Soc 1980 Dec;28(Suppl):61s-71s

Role of environmental antigens in the ontogeny of the secretory immune response.

Cebra JJ, Gearhart PJ, Halsey JF, Hurwitz JL, Shahin RD

Publication Types: Review

PMID: 6777492, UI: 81072112

161: J Pharm Sci 1975 Aug;64(8):1325-8

Pharmacokinetic model for a primary antibody response.

Cammarata A, Smith J, Willett NP

Antigen distribution and clearance studied in vivo may be viewed as a pharmacokinetic problem complicated by the intervention of the immune response. A model characterizing the clearance of the simple antigen phiX174 from the bloodstream of various experimental animals, as well as the subsequent serum antibody response, was developed. The present model is the simplest of the possible models and no doubt will have to be modified when considering more complex antigens, additional distribution modes, and differences in antibody reactivity. For the primary (IgM) immune response, however, early events in the immunological response can be adequately accounted for in a consistent and quantitative manner.

PMID: 1151705, UI: 75213632

162: Anal Biochem 1991 Aug 1;196(2):326-36

Modeling of immunosensors under nonequilibrium conditions. II. Experimental determination of performance characteristics.

Schramm W, Paek SH

University of Michigan, Reproductive Sciences Program, Ann Arbor 48109.

In an attempt to optimize immunosensors operating with an immobilized antibody as binding protein and an analyte-enzyme conjugate as signal generator that is significantly larger in molecular size than the analyte, in a previous communication (Part I) (S.-H. Paek and W. Schramm (1991) Anal. Biochem. 196) we developed mathematical models for the prediction of performance characteristics. These models are compared in this contribution with experimentally obtained results. As an example, a monoclonal antibody to the steroid hormone progesterone has been used as binding protein, an 125I-progesterone derivative, and a progesterone-horseradish peroxidase derivative as tracers for signal generation. A minimum of parameters needs to be experimentally determined to calculate the performance: the amount of immobilized antibody, the diffusion coefficient of antigens, the thickness of the penetration layer, and the on- and off-rates for binding of the antigen to the antibody. We have described simple methods to obtain these data for the labeled antigen and for the unlabeled analyte that does not provide a signal per se. Kinetic binding curves for antigen-antibody complex formation obtained with the mathematical models correlated well with experimentally obtained results for antigens of different sizes. Although equilibrium of the antigen-antibody complex for the enzyme-labeled analyte conjugate requires about 4 h in the absence of free analyte, dose-response curves can be obtained after 5 min and the relative position of these curves does not change significantly after 30 min. Using a total volume of 200 microliters for the analytical procedure in microtiter wells, agitation as a means to accelerate convective diffusion during an incubation period of 30 min is not necessary with the analyte-enzyme conjugate. However, immunosensors using large analyte-enzyme conjugates as signal generators for the detection of small analytes require strict control of the incubation time if operated within short periods of time (less than 30 min).

PMID: 1776682, UI: 92133746

163: Am J Reprod Immunol 1989 Aug;20(4):140-6

Present status of tumor immunology in clinical gynecology.

Barber HR

Department of Ob/Gyn, Lenox Hill Hospital, New York, NY 10021.

The function of the immune system is to protect the body from damage caused by invading microorganisms, that is, bacteria, viruses, fungi, and parasites. The humoral mechanism functions through plasma cells producing antibodies that control bacterial infections. Viruses, fungi and parasites are controlled through the thymus dependent T lymphocytes. It is now clear that cancers also invoke immunologic reactions in their hosts. Cancer cells, like bacteria and viruses have their own characteristic antigens. An antigen is defined as a substance, usually a protein or polysaccharide, that the body recognizes as foreign, and to whose presence it reacts by forming antibodies. Antigenic differences represent the first known qualitative distinction between cancer cells and their normal counterparts. These qualitative differences between normal and cancer cells had escaped other methods of investigation, but were revealed by immunological techniques that take advantage of the extraordinary power of discrimination of the immune defense mechanism itself. This mechanism is capable of distinguishing even minute differences between protein molecules, probably one different amino acid in a chain of several thousand. Burnet's clonal selection theory has become the central dogma of immunology. It can be summarized by saying that lymphocytes have been destined from time immemorial to identify a specific antigen. When the lymphocyte encounters that antigen it becomes a sensitized lymphocyte, and on contact with similar antigens again produces an immune response including the production of very potent pharmacologic agents called lymphokines. Immunodeficiency diseases are identified by increased frequency of infections in patients. The impaired immunity decreases the patient's protection against developing a malignancy. Autoimmunity is the reaction of the immune system against the body's own tissue.

Publication Types: Review Review literature

PMID: 2696480, UI: 90166224

164: Arch Ophthalmol 1970 Feb;83(2):131

Local immunity.

Kaufman HE

PMID: 5411521, UI: 70086903

165: Antibiot Khimioter 1989 Jul;34(7):526-30

[Multifactor analysis of parameters of immunity under the combined action of doxycycline and a low molecular weight immunomodulator of microbial origin].

[Article in Russian]

Nikitin AV, Fomina IP, Ivanitskaia LP, Fishman VM, Bodunkova LE

The effect of doxycycline combination with a low molecular immunomodulator of microbial origin on the primary immune response to the vaccine EV antigens was studied in multifactor experiments. Mathematical processing of the data provided construction of polynomial statistic models of the second order describing increased delayed type hypersensitivity (IDTH) and the antibody titer. Analysis of the quasimonofactor models revealed different character of regulation of the cellular and humoral response. Nomograms were plotted for precise quantitative estimation of the dose-time parameters of the regimens for combined use of the antibiotic and immunomodulator providing the required levels of IDTH and the antibody titer.

PMID: 2818085, UI: 90055497

166: Birth Defects Orig Artic Ser 1975;11(1):549-57

Developmental immunity in the piglet.

Kim YB

Germfree colostrum-deprived piglets are immunologically "virgin" and extremely susceptible to microbial infection due to lack of passive maternal immunity. They are, however, highly immunologically competent as determined by their excellent immune response to various antigenic stimulation. The results suggest that antigen is the sole inducer of specific antibody formation and support the hypothesis that the initial step in the "true" primary immune response involves priming of multipotential uncommitted immunocompetent cells ("virgin" X cells) to committed monopotent cells (Y cells), and that Y cells proliferate and differentiate into antibody-forming cells (Z cells).

PMID: 1096995, UI: 75206108

167: Clin Microbiol Rev 1990 Apr;3(2):132-52

Immunoserology of infectious diseases.

James K

Central DuPage Hospital, Winfield, Illinois 60190.

The immune response to microorganisms not only participates in the elimination of unwanted organisms from the body, but also assists in diagnosis of infectious diseases.

  1. The nonspecific immune response is the first line of defense, assisting the body until the specific immune response can be mobilized to provide protective mechanisms.
  2. The specific immune response involves humoral or cell-mediated immunity or both, dependent on the nature of the organism and its site of sequestration.
A variety of test systems have been developed to identify the causative organisms of infectious diseases. Test systems used in immunoserology have classically included methods of detecting antigen-antibody reactions which range from complement fixation to immunoassay methods. Relevant test systems for detecting antigens and antibodies are described. With numerous test systems available to detect antigens and antibodies, there can be confusion regarding selection of the appropriate system for each application. Publication Types: Review Review, academic

PMID: 2187592, UI: 90254579

168: Vrach Delo 1989 Nov;(11):83-6

[The role of immunological disorders in the infertile marriage].

[Article in Russian]

Vovk IB, Ivaniuta LI, Chernyshov VP, Galanina IK

The authors used modern immunological methods to investigate regulatory subpopulations of T-lymphocytes in 300 married couples. It was established that disorders of the immune status in females with infertility may develop according to two immune mechanisms--due to development of isoimmune response to ovocyte antigens. Development of antispermatic immunity is related to changes in the T- and B-system of immunity without involvement of the regulatory C-lymphocyte subpopulations while the C-suppressor deficit may be one of the links in the disorders of the immunological status leading to the development of antibodies to own ovarian antigens. Appearance of immunological disorders in the process of treatment of infertility is the reason for their correction.

PMID: 2609594, UI: 90118074

169: Front Biosci 1998 Mar 16;3:d338-7

Mathematical modeling of immunological reactions.

Morel PA

Department of Medicine, University of Pittsburgh and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213

[Record supplied by publisher]

The immune system is a highly regulated, complex and integrated system which has evolved to provide the organism with substantial defenses against pathogenic organisms. Over the last several decades there has been an explosion of experimental data in this area, and new techniques in molecular and cellular biology have been crucial in deepening our understanding of immune processes. Most of these new techniques have allowed the isolation of the process or cell under study so that the results can be readily interpretable. At the present time, however, there is an emerging need to understand the system as it functions as a whole and the language of mathematics is the one best suited for this purpose.

This review, written from the perspective of an experimental immunologist, describes some of the recent advances in the development of mathematical models of the immune system. Particular emphasis is placed on the rapidly growing field of modeling in HIV infection and T cell activation. Immunology as a whole will benefit from the introduction of the language of mathematics in much the same way as neuroscience has done in the last decade.

PMID: 9495835

170: J Immunol 1975 Jul;115(1):106-11

Long-lasting in vitro immune response to a distinct antigenic determinant of a bacterial protein. Cyclic changes of antibody titer and affinity.

Macario AJ, Conway de Macario E

Long-lasting (60 days or more) antibody responses in vitro by rabbit lymph node fragments to a distinct determinant of Escherichia coli beta-D-galactosidase were obtained by supplementing culture medium with fetal calf and horse serum. Antibodies released in the supernatant were removed every 3rd to 5th day together with the spent medium, without pooling to minimize intermixing of molecules synthesized far apart in time. Antibody titer, association constant, and heterogeneity index were measured in medium samples collected throughout the response in order to draw profiles of their changes under conditions whereby a limited number of clones synthesize antibodies in a closed system without connection to antigen depots, central lymphoid organs, and circulating cell and antibody pools.

It was found that antibody affinity changes cyclically and that such cycles may be repeated.

  1. Cycles are composed of an ascendant limb with a gradual increase in affinity and a parallel diminution of heterogeneity.
  2. A descendant limb follows with the opposite modifications.
High affinity antibodies predominate at the peak of the cycles, whereas low affinity molecules take over at the end of the cycles until the next ascendant limb begins; these persist after the last cycle has waned.

PMID: 50342, UI: 75212186

171: J Theor Biol 1991 Dec 21;153(4):477-98

Morphogenesis in shape-space. Elementary meta-dynamics in a model of the immune network.

Stewart J, Varela FJ

Unite d'Immunobiologie, Institut Pasteur, Paris, France.

A unique feature of the immune system is that it possesses meta-dynamics: the process governing the removal of certain clones from the active population and the recruitment of new clones from the pool of lymphocytes freshly produced by the bone marrow.

In this paper, we present a computer model which focuses on those aspects of the system that characteristically derive from the meta-dynamics as such. We observe that when a region of shape-space is densely populated, there is an emergence of dynamically quasi-stable configurations. Moreover, when the system develops in the presence of permanent self-antigens, the latter are systematically incorporated into such coherent configurations.

We conclude that the meta-dynamics of the biological immune system may be such that it gives rise to the emergence of a connected, self-sustaining network that we call the Central Immune System: a coherent self-identity which incorporates the molecules of the somatic self and, more generally, reflects the history of its own development.

PMID: 1806750, UI: 92219810

172: Science 1996 Jan 19;271(5247):348-50

C3d of complement as a molecular adjuvant: bridging innate and acquired immunity.

Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT

Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge School of Medicine, UK.

An optimal immune response should differentiate between harmful and innocuous antigens. Primitive systems of innate immunity, such as the complement system, may play a role in this distinction. When activated, the C3 component of complement attaches to potential antigens on microorganisms. To determine whether this alters acquired immune recognition, mice were immunized with a recombinant model antigen, hen egg lysozyme (HEL), fused to murine C3d. HEL bearing two and three copies of C3d was 1000- and 10,000-fold more immunogenic, respectively, than HEL alone. Thus, C3d is a molecular adjuvant of innate immunity that profoundly influences an acquired immune response.

PMID: 8553069, UI: 96144683

173: Ann N Y Acad Sci 1994 Apr 15;712:1-12

Development of an immune system.

Marchalonis JJ, Schluter SF

Department of Microbiology and Immunology, University of Arizona, College of Medicine, Tucson 85724.

Minimally, an immune response is an induced cellular and/or humoral defense mechanism specific for the challenging agent. The system is a cognitive one inasmuch as a second stimulus with the same antigen can specifically induce either an enhanced response (memory) or diminished response (tolerance). The cells responsible for the initial antigen-specific recognition in higher vertebrates are clonally restricted T and B lymphocytes. Accessory cells are necessary for the processing and presentation of antigen, and physiologic mediators (cytokines) are essential for proliferation, interaction, and regulation of the system. Although it now appears that the recombination mechanisms essential for the anticipatory immune response occurred late in the deuterostome stream leading to vertebrates, molecules required for cell adhesion and regulation are widely spread in phylogeny. Their emergence must have preceded the divergence between ancestral protostomes and deuterostomes. Genetic mechanisms underlying the generation of diversity in the light and heavy chains of antibodies of mammals may be quite distinct in primitive vertebrates, particularly elasmobranchs, the ancestors of which diverged from those of mammals more than 400 million years ago. Despite this, clonal selection of antigen receptors of lymphocytes is most probably universal within the vertebrates. There is no need to force induced recognition in protostomes (e.g. insects) or lower deuterostomes (e.g. echinoderms) into mammalian models of immunity.

Publication Types: Review Review, academic

PMID: 8192324, UI: 94249862

174: Riv Eur Sci Med Farmacol 1989 Apr;11(2):99-104

[Methods for studying feedback. Proposal for a mathematical reference model].

[Article in Italian]

Gavelli MS, Guarini G

Attention is drawn to the relationship between informatic and biological models in the study of problems of human physiology and physiopathology. The biomathematical principles are analyzed, to which reference must be made for the elaboration of the expert systems, necessary in evaluating biological feed-back in particular.

PMID: 2799005, UI: 90018645

175: Cancer 1975 Dec;36(6 Suppl):2469-71

The immunology of large bowel carcinoma in a rat model.

Sjogren HO, Steele G Jr

A rat large bowel carcinoma model has been established with close similarities to the immunological features of the corresponding human neoplasms as far as those are presently known:

  1. common antigens with tissue-type specificity,
  2. expression of immunogenic gut-specific embryonal antigens,
  3. cell-mediated immunity present in tumor bearers, whose sera are capable of blocking the lymphocyte effect specifically, and
  4. rapid disappearance of the serum blocking activity after tumor excision.
It is suggested that this model is therefore particularly suitable for further detailed analysis of the potential function in vivo of tissue-type specific antigens. In addition, this model appears to be applicable to correlating alterations in immune status with tumor course after various modes of intervention such as chemotherapy and immunotherapy alone, or in combination with surgery.

PMID: 1212664, UI: 76116026

176: Immunol Cell Biol 1997 Dec;75(6):523-7

Dependence of the adaptive immune response on innate immunity: some questions answered but new paradoxes emerge.

Parish CR, O'Neill ER

Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory.

Recently a new model of vertebrate immunity has been gaining popularity. In this new model it is hypothesized that activation of innate immunity is a prerequisite for an adaptive immune response to an antigen. Following activation the innate system induces key costimulator molecules on APC, which are essential for antigen-driven clonal expansion of T and B cells. The model largely explains the need for adjuvants in the induction of adaptive immunity, provides a possible mechanism for the immune system to perceive the biological nature of a pathogen and thereby produce the most effective immune response, and transfers much of the onus of self-non-self discrimination from the adaptive to the innate immune system. In the present article we highlight two paradoxes raised by the new model. First, by linking adaptive immunity to innate recognition the immune system is unable to take full advantage of the genetic diversity of T and B cell antigen receptors. Thus, the ability of the immune system to combat a pathogen is totally dependent on the efficiency of recognition by the innate system and, therefore, the germ-line mutation rate of the genes involved in the innate response. Second, if signals from the innate system induce costimulatory molecules on APC, then one would expect the accidental clonal expansion of many autoreactive T and B cells. We suggest that one means of resolving the first paradox is to propose that the major reason for the evolution of adaptive immunity was to provide, via immunological memory, resistance to reinfection, rather than simply to combat the primary infection by the pathogen. In the case of autoreactivity we suggest that autodestruction is prevented by immune responses being tightly regulated at the effector T cell level. Finally, we argue that the two paradoxes, rather than undermining the new model of immunity, highlight our lack of understanding of key elements of the vertebrate immune system.

PMID: 9492188, UI: 98151152

177: Curr Opin Immunol 1998 Jun;10(3):252-8

Long-lived plasma cells: a mechanism for maintaining persistent antibody production.

Slifka MK, Ahmed R

Scripps Research Institute, Department of Neuropharmacology, La Jolla, CA 92122, USA.

Current models suggest that continuous antigenic stimulation of memory B cells is required to maintain long-term antibody production. In view of recent developments concerning plasma cell longevity, a new model is described that incorporates the important role of long-lived plasma cells in sustaining persistent antibody responses.

Publication Types: Review Review, tutorial

PMID: 9638360, UI: 98302216

178: Immunol Rev 1989 Aug;110:89-103

Establishment and functional implications of B-cell connectivity.

Holmberg D, Andersson A, Carlsson L, Forsgren S

Institute for Applied Cell and Molecular Biology, University of Umea, Sweden.

We have discussed some aspects of the structure of the normal immune system, particularly the B-cell compartment. We have argued: that a basic property of the natural antibody repertoire is constituted by high degrees of connectivity within the immune system as well as between the system and other components of the organism; that the complementarities constituting this connectivity are based on self-self interactions, high degrees of degeneracy or somatically selected interactions and that these properties are conserved through evolution, to ensure self-reference; that by evolutionary selection, antibody V-genes encoding such structural properties are ensured to be expressed early in ontogeny. The set of highly connected cells will be kept through ontogeny and form the basis for a compartment of naturally-activated lymphocytes making up 10-15% of the total lymphocyte population. As suggested before, this pool of connected cells may be responsible for maintenance of normal network dynamics and prevention of autoaggression.

Publication Types: Review Review, tutorial

PMID: 2676850, UI: 90007591

179: Vet Parasitol 1993 Feb;46(1-4):63-79

Regulation of immunity to Ostertagia ostertagi.

Klesius PH

USDA, ARS, Animal Parasite Research Laboratory, Auburn, AL 36830-0952.

Knowledge of bovine immune response to ostertagiasis is important to understanding the mechanisms of innate and acquired immunity to this economically important helminth parasite that infects cattle worldwide. Infection causes both antibody and cellular immune responses. Evidence shows that Ostertagia possesses excretory-secretory (ES) molecules that may regulate immune cell responses that affect acquired immunity and pathophysiological changes to infection. Ostertagia can down-regulate antibody and cellular immune responses. One of these ES regulatory molecules is a lectin that causes eosinophil chemotaxis. In addition to its antigenicity, this regulatory molecule serves as a means of communication between the parasite and cells of the host immune system. It is suggested that, lacking this type of communication, Ostertagia infection may not be readily recognized by the host immune cells. A hypothesis is proposed for the mechanisms of acquired immunity to Type I ostertagiasis. Regulatory molecules of Ostertagia ES are suggested as suitable vaccine candidates.

Publication Types: Review Review, tutorial

PMID: 8484225, UI: 93248695

180: Adv Exp Med Biol 1987;216B:901-9

Inter-relationship between mucosal and systemic immunity determining the balance between damage and defense in the bovine gut in response to environmental antigens.

Porter P, Powell JR, Barratt ME

Department of Immunology, Unilever Research Laboratory, Sharnbrook, Beds, Bedford, England.

At weaning, the complex interactions of macromolecular components embracing maternally derived antibodies and antigens of microbial and dietary origin, grossly influence the immune response, directing it towards protective or damaging reactions in the intestinal mucosa. In young calves, passively acquired maternal antibody surprisingly enhances the systemic IgG1 mediated type III hypersensitivity reactions to dietary antigen. Furthermore, unresponsiveness to orally administered protein antigen in the young calf fails to develop. Additionally, antigens from gram negative bacteria can influence the development of IgE mediated hypersensitivity reactions. In the normal deleterious gut reactions to protein antigens from the lumen, IgE responses infrequently occur, and are transient. However, these can be reinforced by simultaneous challenge with protein and microbial antigen. These observations bring some new perspectives on health and nutrition of young farm animals at weaning.

PMID: 3425468, UI: 88103001

181: Anat Rec 1976 Jan;184(1):49-71

Cellular mechanisms involved in cyclic stroma renewal of the uterus. III. Cells of the immune response.

Padykula HA

The principal cell types associated with the humoral immune response (monocyte-macrophages, lymphocytes, and plasma cells) are numerous in the endometrial stroma of the uterus during the first four postpartum days in two types of mammals, the marsupial North America opossum and the eutherian albino rat. This transietn cellular differentiation coincides with the physiologic period of rapid uterine regression which includes massive reduction in the amount of extracellular stromal material. In addition, heterophils and eosinophils, cell types also known to be associated with phagocytic and immunologic activity, appear in the stroma during the first two postpartum days; their presence may, however, be associated more directly with the postpartum estrus that occurs on day 1 postpartum than with endometrial regression. Thus, the five cell types, which are known in pathologic conditions to be components present in the inflammatory response to a foreign antigen, are conspicuously present in the normal regressing endometrium. Furthermore, there is ample ultrastructural evidence of frequent macrophagic-lymphocytic interaction, transformation of lymphocytes, and active secretion by plasma cells during this early postpartum period. An hypothesis has been derived by uniting this new description of endometrial stromal cell differentiation with the existing literature on uterine collagenase activity, an important feature of postpartum regression (reviews of Gross, '74; Harris and Krane, '74). It is based on the assumption that during regression the extracellular action of neutral collagenase (and possibly other extracellular proteases) release new antigenic sites in proteins located in the ground substance. In the case of collagenase, these transient antigenic sites would arise at the locus of enzymic cleavage as well as from the subsequent denaturation of the fragments of the collagen molecule. This endogenous antigenic stimulus would be strong and temporary, and would lead to the cellular manifestations of the transient humoral immunologic response which are evident in the regressing stroma of these two mammals. This humoral immune reaction may be one of the regulatory mechanisms involved in the cyclic renewal of the extracellular compartment of the uterine stroma.

PMID: 1252014, UI: 76134445

182: Infect Immun 1988 Apr;56(4):823-30

Antibody synthesis specific for nonoral antigens in inflamed gingiva.

Mallison SM 3d, Szakal AK, Ranney RR, Tew JG

Department of Microbiology and Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.

In vitro experimentation indicates that periodontitis-associated bacteria contain potent polyclonal B-cell activators (PBA). We reasoned that if PBA were operative in vivo, plasma cells specific for nonoral antigens should be present in the inflamed gingival tissues, which are characterized by a plasma cell infiltrate. To test this, rabbits with experimental periodontitis were immunized in the hind legs with the histochemically detectable antigen horseradish peroxidase (HRP) or glucose oxidase (GO). At various times after secondary immunization, inflamed gingival tissue was removed, sectioned, and treated histochemically to reveal plasma cells that specifically bound HRP or GO. Remarkably, by 9 days after secondary immunization, hundreds of HRP- or GO-binding plasma cells were found in the inflamed gingival tissue of immunized rabbits. The presence of these plasma cells, observed 7 to 10 days after booster immunization, was further substantiated by the presence of large amounts of locally produced HRP- or GO-specific antibody in gingival crevicular fluid. By 1 month after secondary immunization, the number of antigen-binding plasma cells had decreased dramatically, but a small number of antigen-specific plasma cells were detected for as long as 9 months after secondary immunization. The large number of HRP- or GO-specific plasma cells observed 9 days after immunization led us to see whether recently stimulated cells were more susceptible to PBA. Peripheral blood lymphocytes (PBL) were obtained at different times after booster immunization and cultured in the presence or absence of a PBA from Fusobacterium nucleatum. At 7 days after immunization, PBL spontaneously differentiated into antibody-forming cells in culture, and this process was enhanced by PBA. In contrast, PBL taken months after immunization produced little antibody in culture, and enhancement by PBA was difficult to detect. Compared with resting B cells, the recently stimulated B cells clearly differentiated more readily into antibody-forming cells. In conclusion, antibody synthesis specific for nonoral antigens did occur in inflamed gingival tissue, and a number of mechanisms, including PBA, probably contributed to this phenomenon.

PMID: 3257940, UI: 88153061

183: J Theor Biol 1997 Feb 21;184(4):405-21

Further studies on the problem of immune network modelling.

Faro J, Carneiro J, Velasco S

Departamento de Fisica Aplicada, Universidad de Salamanca, Spain.

In a previous work we have analysed a family of antibody and B-cell network models (basic AB models) of the immune system. This analysis focused principally on the physiological interpretation of their parameters. Our approach consisted in building a detailed and general mathematical model (referred to as the GIB model) and then simplifying it formally to a version (named the RIB model) that belongs to the family of AB models, but which is more general than the basic AB models. From that study it was clear that some of the assumptions necessary to simplify the GIB model into the RIB one, as well as to recover the basic AB models from the RIB one, are quite unrealistic from a physiological point of view. All this raised the issue of the reliability, or even the heuristic value, of theoretical studies based on current network models for experimental immunologists. One approach to clarify this issue is to ask whether the unrealism of the assumptions implicit in the RIB and AB models entails qualitatively different behaviours between them compared to the GIB one. We initiate here such a work by performing a comparative study of a two-clone system of the AB and RIB models, and a variant of the GIB model in which the different molecular compartments were merged into a single one (labelled IGB model). Because all those models rely critically on certain B-cell activation functions, which constitute the core of an implicit model of individual B-cell reactivity or "local rules", we focused the present numerical study, to a great extent, on two parameters determining those activation functions (Hill coefficient and thresholds). Our results indicate that: (1) the RIB and IGB models display in general a much larger diversity of steady states than the AB models; (2) only under a very restricted parameter regime did all studied models behave similarly; (3) the parameter regime under which the AB and IGB models, but not the RIB one, behave similarly is still rather restricted through not as much as in (2); and (4) even relatively small quantitative changes (within reasonable values) in the postulated "local rules" can induce very large quantitative changes in the behaviour of the AB and RIB models but not the IGB model. In the light of the present results, we discuss the need of postulating a set of "local rules" solidly based on experimental evidence as a necessary condition for the reliability of current network models.

PMID: 9082072, UI: 97226930

184: J Math Biol 1994;33(2):111-37

Immune networks modeled by replicator equations.

Stadler PF, Schuster P, Perelson AS

Institut fur Theoretische Chemie, Universitat Wien, Austria.

In order to evaluate the role of idiotypic networks in the operation of the immune system a number of mathematical models have been formulated. Here we examine a class of B-cell models in which cell proliferation is governed by a non-negative, unimodal, symmetric response function f (h), where the field h summarizes the effect of the network on a single clone.

185: Kosm Biol Aviakosm Med 1989 Jan-Feb;23(1):41-5

[Mathematical modeling of cyclic kinetics of hematopoiesis].

[Article in Russian]

Smirnova OA

Mathematical models of the time course of formation of platelets, erythrocytes, granulocytes and lymph cells of mammals have been developed. They are systems of nonlinear differential equations where concentrations of mature blood cells and their bone marrow precursors are the variables.

The models

  1. represent the main stages in the development of the various types of blood cells and
  2. allow for specific formation of red and white blood cells.
Verification with the aid of have shown that the models reproduce all dynamic variations of the hemopoietic system, including stable fluctuations of concentrations of the various types of blood cells and their precursors (limiting cycles). Calculated parameters of stable fluctuations are in good agreement with experimental data. Within the framework of the models the origination of limiting cycles is described and their interpretation is given.

These models can be used to simulate monthly biologic rhythms inherent in the various types of hemopoiesis as well as to analyze flight biomedical data and to discriminate space flight effects on hemopoiesis.

PMID: 2709750, UI: 89217726

186: Crit Rev Ther Drug Carrier Syst 1985;1(4):311-74

Immunological problems of polymer-bound drugs.

Rihova B, Riha I

For the application of polymer-bound drugs (especially in combination with the targeting antibodies), it is essential to know more about the immunogenicity and possible hazards from immune reactions induced by their repeated application. The immune reaction depends on many factors (including structure of antigen, dose of antigen, schedule and way of the application, genetic background of the immunized, i.e., receiving organism) and could be weakened or eliminated by a choice of suitable factors. Problems connected with the immune reaction of the humoral and cellular type (B and T cell involvement) against different polymers and polymer-bound drugs and possible consequences for their clinical use will be discussed.

Publication Types: Review

PMID: 2420476, UI: 86161721

187: Biosensors 1987-88;3(1):1-15

Direct immunochemical sensing: basic chemical principles and fundamental limitations.

Eddowes MJ

Sensors Department, THORN EMI Central Research Laboratories, Hayes, Middlesex, Great Britain.

Models describing the binding of antigens to surface immobilised antibodies have been developed. These models are applied to the assessment of the likely analytical utility of direct immunochemical sensors employing immobilised antibody layers. Fundamental limitations to the device response arising from the equilibrium and kinetic characteristics of the binding reaction and from mass transport constraints imply that measurement over the micromolar to nanomolar concentration range may be practical.

PMID: 3675654, UI: 88049829

188: C R Acad Sci III 1999 May;322(5):363-73

[Short-term dynamics of intertidal microphytobenthos biomass. Mathematical model].

[Article in French]

Guarini JM, Gros P, Blanchard GF, Bacher C

CNRS-Ifremer, Centre de recherche en ecologie marine et aquaculture de L'Houmeau, France.

We formulate a deterministic mathematical model to describe the dynamics of the microphytobenthos of intertidal mudflats. It is 'minimal' because it only takes into account the essential processes governing the functioning of the system: the autotrophic production, the active upward and downward migrations of epipelic microalgae, the saturation of the mud surface by a biofilm of diatoms and the global net loss rates of biomass. According to the photic environment of the benthic diatoms inhabiting intertidal mudflats, and to their migration rhythm, the model is composed of two sub-systems of ordinary differential equations; they describe the simultaneous evolution of the biomass 'S' concentrated in the mud surface biofilm--the photic layer--and of the biomass 'F' diluted in the topmost centimetre of the mud--the aphotic layer. Qualitatively, the model solutions agree fairly well with the in situ observed dynamics of the S + F biomass. The study of the mathematical properties of the model, under some simplifying assumptions, shows the convergence of solutions to a stable cyclic equilibrium, whatever the frequencies of the physical synchronizers of the production. The sensitivity analysis reveals the necessity of a better knowledge of the processes of biomass losses, which so far are uncertain, and may further vary in space and time.

PMID: 10340108, UI: 99271467

189: Bull Math Biol 1993 Nov;55(6):1091-131

A Cayley tree immune network model with antibody dynamics.

Anderson RW, Neumann AU, Perelson AS

Theoretical Biology and Biophysics, Los Alamos National Laboratory, NM 87545.

A Cayley tree model of idiotypic networks that includes both B cell and antibody dynamics is formulated and analysed. As in models with B cells only, localized states exist in the network with limited numbers of activated clones surrounded by virgin or near-virgin clones. The existence and stability of these localized network states are explored as a function of model parameters. As in previous models that have included antibody, the stability of immune and tolerant localized states are shown to depend on the ratio of antibody to B cell lifetimes as well as the rate of antibody complex removal.

As model parameters are varied, localized steady-states can break down via two routes:

  1. dynamically, into chaotic attractors, or
  2. structurally into percolation attractors.
For a given set of parameters percolation and chaotic attractors can coexist with localized attractors, and thus there do not exist clear cut boundaries in parameter space that separate regions of localized attractors from regions of percolation and chaotic attractors.

Stable limit cycles, which are frequent in the two-clone antibody B cell (AB) model, are only observed in highly connected networks. Also found in highly connected networks are localized chaotic attractors. As in experiments by Lundkvist et al. (1989. Proc. natn. Acad. Sci. U.S.A. 86, 5074-5078), injection of Ab1 antibodies into a system operating in the chaotic regime can cause a cessation of fluctuations of Ab1 and Ab2 antibodies, a phenomenon already observed in the two-clone AB model. Interestingly, chaotic fluctuations continue at higher levels of the tree, a phenomenon observed by Lundkvist et al. but not accounted for previously.

PMID: 8281129, UI: 94108374

190: Cesk Patol 1977 May;13(1-2):44-51

[Development of arrangement and degradation of the system of rough endoplasmic reticulum in antibody-producing plasma cells].

[Article in Czech]

Hajdu I, Hofman J

During the immune response of the cells of murine omentum to horseradish peroxidase which had been administered intraperitoneally together together with endotoxin or endotoxoid acting as an adjuvans the plasma cells showed several different patterns of the rough endoplasmic reticulum [RER] system. Irregular to bizarre RER structures occurred plasma cells during the initial phase of the immune reaction only, whereas the plasma cells found at later stages had characteristic highly organized RER systems. The irregular "atypical" RER patterns have been regarded by some authorities as fully functional structures developed under the influence of a rapid differentiation of immunocompetent cells following administration of mitogens as well as due to a variously pronounced toxic influence of mitogens upon cell organelles. The possibilities of RER system degradation and the fate of antibodies which had not been discharged by the plasma cells has been discussed.

PMID: 597922, UI: 78082428

191: J Immunol 1981 Jun;126(6):2443-9

A kinetic analysis of immune-mediated clearance of erythrocytes.

Meryhew NL, Runquist OA

A mathematical expression has been derived that successfully correlates the kinetic data for the immune-mediated clearance of red blood cells. The expression resulted from the solution of differential equations arising from a clearance mechanism that was, essentially, consistent with that described by Schreiber and Frank. The mathematical expression correlated data for both IgG-and IgM-mediated reactions. Four different rate constants appear in the final kinetic equation; these constants, which measure the rates of the various steps in the clearance process, were evaluated by an iterative curve-matching process. The values of the rate constants were found to be dependent upon type of sensitizing immunoglobulin, number of C1-fixing sites, and several known immune system modifiers. Correlation of the derived rate expression with the experimental data provided a critical test for the Schreiber-Frank mechanism and the values of the rate constants provided additional insights into the immune clearance process.

PMID: 7229383, UI: 81193120

192: Folia Biol (Praha) 1976;22(2):65-73

Independent cyclic fluctuations of cell surface parameters: expression of H-2 antigens, rosetting capacity and thickness of the cell coat.

Peknicova J, Haskovec C, Viklicky V, Kinkor M, Lengerova A

Cultures of a mouse X mouse cell hybrid (synchronized either by hydroxyurea or Colcemid) were tested for fluctuations during the cell cycle of several parameters characterizing the cell surface: expression of H-2 antigens, capacity of the cells to form rosettes with sheep red blood cells and thickness of the cell coat. H-2 antigenicity of cells collected at different phases of the mitotic cycle was assessed on the basis of their capacity to bind 125I-labelled antibodies as well as their sensitivity to complement dependent immune lysis. The latter parameters fluctuated more or less independently: around mitosis, their trends were even opposite and minimum antibody-binding capacity roughly coincided with maximum cytolytic sensitivity. The cyclic fluctuations of H-2 antigenicity were similar, but not identical for two antigens contributed to the cell hybrid by different parents and even the curves for two antigens of the same parental origin displayed a slight shift one from another. The frequency of cells forming large rosettes (i.e., of more than six SRBC) reached its peak roughly at the boundery of G1 and S phase. Mitotic (versus non-mitotic) cells had a significantly thicker cell coat (as visualized by ruthenium red staining and electron microscopy) and a high incidence of morphological abnormalities. The tested parameters thus seem to fluctuate independently of each other.

PMID: 1278569, UI: 76211230

193: J Theor Biol 1987 Nov 21;129(2):219-30

A mathematical model for determining minimal inhibitory concentrations (MICs) via diffusion assays.

Awerbuch TE, Lustman L

Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115.

A mathematical model is presented for the description of inhibition zones in a diffusion bioassay. In such an experiment the drug is placed at the center of a Petri dish containing a bacterial lawn in an agar gel and after a certain incubation period one observes a concentric ring around the center marking the toxic area. From the knowledge of the radius rtox of the toxic zone, the lower limit ctox at which the inhibitory response is observed can be readily calculated. This quantity is very important in evaluating the sensitivity of microorganisms to toxic substances. The mathematical model of the assay is given by a two-dimensional diffusion equation describing the changes in drug concentration due to diffusion, decay of the chemical and consumption by bacteria. The diffusion equation being mildly non-linear is solved numerically with the aid of a computer. For this purpose a numerical solver was developed as well as a "best-fit" simulation program that fits the parameters for which experimental values could not be obtained. The method was tested with N-methyl-N'-nitro-N-nitrosoguanidine and ethylmethanesulfonate and was seen to be fast, efficient, and inexpensive. In principle it could be used for routine quantitative screening for toxicity of chemicals.

PMID: 3455463, UI: 88333843

194: Ann Biol Clin (Paris) 1985;43(6):856-60

The role of porto-systemic shunts in the specific humoral immune response in patients with schistosomal hepatic fibrosis.

Helmy-Khalil S, Khalil SA, el Sawy M, Youssef M, el Kader MA, el Hallous D, el Balassy F, Souka M, el Girby A, Fahmy MH

The present study was devoted to elucidate the role of collaterals (porto-systemic shunts) in the specific humoral immune response to schistosomal soluble egg antigen (SEA) in patients with schistosomal hepatic fibrosis (SHF). Twenty five patients with SHF with collaterals, ten patients with SHF without collaterals and twenty healthy control subjects constituted the material of this study. In vivo and in vitro tests for humoral immunity to SEA included serum immunoglobulins estimation, immediate intradermal test, indirect haemagglutination test and determination of B lymphocytes count in peripheral blood. Significant differences have been observed between cases without collaterals and those with collaterals; and in the latter group before and after decongestion. These results tend to consolidate the view of the role of collaterals in schistosomal antigenemia and subsequent humoral immune response.

PMID: 3938625, UI: 86184800

195: Infect Immun 1983 Jul;41(1):399-409

Local immune response to repeated topical antigen application in the simian labial mucosa.

Nair PN, Schroeder HE

Minor salivary glands of the oral mucosa in healthy monkeys (Macaca fascicularis and Macaca mulatta) contain organized structural units suitable for recognizing and processing antigens. A previous study of M. fascicularis monkeys provided experimental evidence of retrograde access of oral antigens deep into the minor salivary glands. The present study aimed at exploring the possible immune response of simian oral mucosa to repeated topical application of a chemically defined antigenic solution at the labial and gut mucosa. Ten female M. fascicularis animals were challenged topically at the lower lip mucosa at weekly intervals for a variable period of 4 to 8 weeks with a solution consisting of horseradish peroxidase, ferritin, and special India ink. Transmission electron microscopic examination of immunohistochemically treated sections of the labial glands revealed the presence of plasma cells containing specific anti-horseradish peroxidase antibody. These cells resided in the interacinar regions. Enteric and gut priming with the same antigen in four other monkeys, bypassing the oral mucosa, failed to reveal the presence of horseradish peroxidase-positive plasma cells in the labial mucosa of any of the four animals, although in one animal such cells could be identified in a mesenteric lymph node. This is suggestive of the existence, at least in primates, of a local immune response of the oral mucosa independent of systemic involvement.

PMID: 6862630, UI: 83236918

196: Math Biosci 1990 Feb;98(1):127-42

Serological interpretation--theoretical limits to information from blocking.

Hoover DN, Wohlgemuth A

Odyssey Research Associates, Ithaca, New York 14850.

Contemporary immunogenetics uses a symbolism that tacitly assumes a one-to-one correspondence between genes, antigens, and antibody reagents that identify these. Thus a particular gene will be symbolized by an identifier, say X, and the reagent that supposedly uniquely identifies X is called anti-X. Ultimately, the precise relation between genes and antibody reagents will be determined by molecular techniques. Previous mathematical work has shown that by allowing a general relation (not constrained by symbolic conventions), alternative genetic descriptions can be found for some systems.

This work predicts that when the relation is identified for these systems by molecular means, there will be an unresolved cross-reactivity, that is, there will not be a simple one-to-one correspondence between genes and the reagents used to identify them. This will contradict the notation in which the immunogenetic systems are described. Serology will have to be reinterpreted in terms of a more general notation that will allow for cross-reactivity. The focus of a mathematical model will switch from making inferences about genes, antigens, and antibodies in some system to analyzing genetics and serology as described by the notation. This paper investigates the information theoretically available from the serological operations of blocking, absorption, and elution. We show that, except for antigens (called undetectable) that mimic combinations of other antigens (in all cells in the system), blocking can theoretically reveal the relationship between antigens and antibodies in a system.

PMID: 2134496, UI: 92199704

197: Med Klin 1978 Apr 28;73(17):615-20

[Hemagglutinins and immunoglobulins in surgical patients and blood donors].

[Article in German]

Peter H, Peter H, Werny D

In our investigations 60 patients with severe consuming surgical illness and 61 patients with tumors, especially of the bowel, have shown distinctly higher values of hemagglutinins and immunoglobulins than 60 other patients with slighter disease and 1181 healthy blood donors. Therefore we conclude that those are able to form much more humoral antibodies as supposed up to now, inspite of their severe illness. The stimulation of their immune-system may be caused by resorption of intestinal mucosa, containing compounds identical to the bloodgroup substances A and B, from ulcera and during surgery, or by resorption of similar bacterial antigens e.g. Common-Antigen. The good humoral situation of the tumor patients contrasts to their supposed insufficient cellular immune defense, not tested by us. Therefore the BCG stimulation is only necessary if an insufficient cellular immune situation is proved. X-rays and cytostatica used without severe indication, will destroy the humoral antibodies found by us.

PMID: 642863, UI: 78155894

198: Acta Biotheor 1976;25(2-3):111-29

Life cycle patterns and their genetic control: an attempt to reconcile evolutionary and mechanistic speculation.

Manning JT

A model is proposed which implicates molecular recognition systems as the major controlling factors in life cycle expression. It is envisaged that such systems are important in immune functioning and catabolic, metabolic molecule recognition at both inter- and intra-cellular level. These recognition systems have the following characteristics: 1) Specific recognition molecules (recognisers), e.g. vertebrate antibodies, invertebrate agglutinins and plant agglutinins may recognise specific substances, e.g. antigens, catabolic and metabolic molecules. 2) The range of possible recognisable substances is very wide and variable. 3) The recognisers may themselves be recognised by other recognisers. 4) Recognisers are usually produced in large amounts only on presentation of the appropriate recognisable molecule. 5) The progressive introduction of new recognisable molecules increases the recogniser interaction, this interaction causing depression of some recogniser types (immune depression) and facilitation of other types among which may be recognisers specific for self components (e.g. auto-immunity). 6) Low juvenile viability is associated with a restricted range of available recognisers, high adult viability with increasing recogniser range and some auto-immunity/immune depression, senescence with a wide range of available recognisers and extensive auto-immunity/immune depression. Life cycle patterns and their control are discussed. It is suggested control mechanisms may include: 1) Dietary restriction and in some periods complete nutritional abstinence. 2) Specific recogniser depression, genes implicated here are the various antigens (species and polymorphic) found on cell surfaces, in the serum and in various body fluids of vertebrates, e.g. ABO, MNSs, P, Rh, Le and other blood groups, the ABO and Le secretor antigens and the HL-A antigens. In addition the immune response and mixed lymphocyte culture loci are implicated. Finally life cycle control is discussed with relation to sexual selection.

PMID: 823744, UI: 77018345

199: Biomed Tech (Berl) 1992 Jul-Aug;37(7-8):162-9

[Model for immunologic testing of biomaterials].

[Article in German]

Thull R, Trautner K, Karle EJ

Lehrstuhl und Abteilung fur Experimentelle Zahnmedizin Zahn-, Mund- und Kieferklinik Universitat Wurzburg.

Corrosion products and electric fields are capable of changing proteins to antigens, thus permitting the immunological system to identify the biomaterial as foreign. The reaction between corrosion products and a macro-molecule also leads to an antigen (carrier antigen), such as conformational changes of a macro-molecule, e.g. a protein, caused by the electric field at the implant surface (modified macro-molecule antigen). While the sensitivity to corrosion and the effectiveness of galvanic elements is measurable by electrochemical methods, suitable methods of determining the field strength in the vicinity of biomaterial surfaces are still unavailable. The influence of the double layer of uncoated and coated titanium surfaces on the conformation of proteins and their conversion to antigens are investigated with polyclonal antibodies capable of identifying the unchanged protein despite adsorption to the surface. 14C-marked Bovine Serum Albumin serves as a model protein. Determination of the total number of protein molecules adsorbed is effected via the detection of the emitted electrons. The quotient of the concentration of natural proteins to the concentration of adsorbed molecules gives the biocompatibility index, which is independent of the surface area, and gives an indication of the expected biocompatibility of the material. The results of the biological tests of titanium and two coating materials on titanium were confirmed in an animal experiment. It is possible that in the future immunological tests may replace experiments in animals.

PMID: 1391602, UI: 93004270

200: Med Parazitol (Mosk) 1989 Sep-Oct;(5):29-31

[Changes in the indices of the B-immunity system in patients with intestinal nematodiases after treatment].

[Article in Russian]

Blagov NA, Baryshev MD

A decrease in the titers of antibodies to opportunistic bacteria has been observed in 100 patients suffering from ascariasis, trichocephaliasis and mixed invasion (ascariasis and trichocephaliasis). The immune suppression was higher in patients with mixed invasion. Medamine treatment enhances the suppression of antibody production. Changes in humoral immunity parameters are due to the effect of helminthic antigens and the composition of Escherichia in the large intestine of the affected subjects.

PMID: 2615705, UI: 90136328

201: J Pharm Sci 1988 Jan;77(1):39-47

A system approach to pharmacodynamics. I: Theoretical framework.

Veng-Pedersen P, Gillespie WR

College of Pharmacy, University of Iowa, Iowa City 52242.

A general theoretical framework is constructed for the relationship between a pharmacokinetic response r (e.g., systemic drug concentration or input rate), and an observed pharmacologic effect response E. The overall relationship may be described mathematically by E = omega(r) = omega p(omega b(omega r(r))) where omega is an operator that describes the overall relationship, and omega r, omega b, and omega p are operators that describe the contributions of components of the pharmacodynamic system. The kinetic basis for applying certain general mathematical properties such as linearity are discussed. The result is the introduction of various specific mathematical structures that may be applied to pharmacodynamic systems [e.g., E = phi t(r), E = phi t(psi r*r), E = phi p(psi p*phi b(r)), and E = phi p(psi p*phi b(psi r*r))].

PMID: 3346822, UI: 88155341

202: Proc Natl Acad Sci U S A 1997 Jan 21;94(2):549-52

Immunocompetence, ornamentation, and viability of male barn swallows (Hirundo rustica).

Saino N, Bolzern AM, Moller AP

Dipartimento di Biologia, Universita di Milano, Italy.

Immunocompetence (i.e., the ability to produce an immune response to pathogens) can be predicted to influence the chances that organisms have to survive and reproduce. In this study we simulated a challenge to the immune systems of male barn swallows (Hirundo rustica) by injecting them intraperitoneally with a multigenic antigen, sheep red blood cells, and we analyzed long-term survival in relation to their immunocompetence. Males were assigned to four groups that differed for the treatment of the length of the outermost tail feathers, a sexually dimorphic ornamental character that is currently under directional sexual selection. Immunocompetence was measured as change of concentration of gamma globulins relative to plasma proteins. The intensity of the immune response was independent of age. Males that showed the highest short-term response to sheep red blood cells were more likely to survive until the breeding season following that in which they had been inoculated, a pattern consistently observed within each experimental group. Males with comparatively long tails were more likely to survive than those with short tails. To our knowledge, the results of this study are the first to demonstrate that immunocompetence can predict long-term survival in a free-ranging vertebrate. Moreover, they are compatible with current models of parasite-mediated sexual selection because long-tailed males are more immunocompetent than short-tailed ones, and females, by preferring to mate with the most ornamented males, may acquire the "good genes" for high immunocompetence and, hence, for high viability of their offspring.

PMID: 9012821, UI: 97165059

Version: January 3, 2005.
Address of this page is
Homepage of this server is
Send comments to Joachim Gruber