Idiotypic Interactions Research Articles

Neonatal immunization prevents the development of a chronic autoimmune response against CD4 caused by HIV-1 gp120 in rats.

The AIDS autoimmune hypothesis suggests that suppression of the autoimmunity against CD4 T lymphocytes should positively affect the course of HIV infection. The aim of this study was to determine whether neonatal immunization can be used to prevent induction of anti-CD4 autoimmune response triggered by HIV-1. The induction of anti-CD4 lymphocytes in HIV infection proceeds via their idiotypic interactions with anti-gp120 lymphocytes; therefore, the creation of tolerance to gp120 by means of neonatal immunization with gp120 may prevent subsequent induction of anti-CD4 lymphocytes. Neonatal immunization with CD4 may also be effective, since it can increase natural tolerance to CD4 and prevent its subsequent breakdown by gp120. Thus, anti-gp120 lymphocytes and anti-CD4 lymphocytes are potential neonatal stimulation targets. To determine which of these targets can be manipulated during the neonatal period, a computer model of the immune network was used. The computer model predictions were tested in a rat model of autoimmune CD4 T lymphocytopenia induced by gp120. The in silico studies predicted that stimulating a clone against an external antigen that is in idiotype-anti-idiotype interactions with an autoclone, when stimulation is performed during the time that the dynamic behavior type of the immune network is being established, changes the autoimmune response from self-perpetuating to transient. Experimental studies confirmed the predictions of the computer model and showed that neonatal immunization with gp120 suppresses anti-CD4 autoantibody production and prevents the development of autoimmune CD4 T lymphocytopenia triggered in adult rats by gp120. Neonatal HIV-1 gp120 immunization enhances natural tolerance to CD4.

Role of disorders related to idiotypic and anti-idiotypic interactions in slowing down the achievement of negative serologic reactions in patients with early onset forms of syphilis after specific therapy

Role of disorders related to idiotypic and anti-idiotypic interactions in slowing down the achievement of negative serologic reactions in patients with early onset forms of syphilis after specific therapy

Self-tolerance and autoimmunity in a minimal model of the idiotypic network

We consider self-tolerance and its failure—autoimmunity—in a minimal mathematical model of the idiotypic network. A node in the network represents a clone of B-lymphocytes and its antibodies of the same idiotype which is encoded by a bitstring. The links between nodes represent possible interactions between clones of almost complementary idiotype. A clone survives only if the number of populated neighbored nodes is neither too small nor too large. The dynamics is driven by the influx of lymphocytes with randomly generated idiotype from the bone marrow. Previous work has revealed that the network evolves toward a highly organized modular architecture, characterized by groups of nodes which share statistical properties. The structural properties of the architecture can be described analytically, the statistical properties determined from simulations are confirmed by a modular mean-field theory. To model the presence of self we permanently occupy one or several nodes. These nodes influence their linked neighbors, the autoreactive clones, but are themselves not affected by idiotypic interactions. The architecture is very similar to the case without self, but organized such that the neighbors of self are only weakly occupied, thus providing self-tolerance. This supports the perspective that self-reactive clones, which regularly occur in healthy organisms, are controlled by anti-idiotypic clones. We discuss how perturbations, like an infection with foreign antigen, a change in the influx of new idiotypes, or the random removal of idiotypes, may lead to autoreactivity and devise protocols which cause a reconstitution of the self-tolerant state. The results could be helpful to understand network and probabilistic aspects of autoimmune disorders.

The role of idiotypic interactions in the adaptive immune system: a belief-propagation approach

In this work we use belief-propagation techniques to study the equilibrium behaviour of a minimal model for the immune system comprising interacting T and B clones. We investigate the effect of the so-called idiotypic interactions among complementary B clones on the system’s activation. Our results show that B–B interactions increase the system’s resilience to noise, making clonal activation more stable, while increasing the cross-talk between different clones. We derive analytically the noise level at which a B clone gets activated, in the absence of cross-talk, and find that this increases with the strength of idiotypic interactions and with the number of T cells sending signals to the B clones. We also derive, analytically and numerically, via population dynamics, the critical line where clonal cross-talk arises. Our approach allows us to derive the B clone size distribution, which can be experimentally measured and gives important information about the adaptive immune system response to antigens and vaccination.

A dynamical model of the adaptive immune system: effects of cells promiscuity, antigens and B–B interactions

.We analyse a minimal model for the immune response in the adaptive immune system comprising three different players: antigens, T and B cells. We assume B–T interactions to be diluted and sampled locally from heterogeneous degree distributions, which mimic B cells receptors’ promiscuity. We derive dynamical equations for the order parameters quantifying the B cells activation and study the nature and stability of the stationary solutions using linear stability analysis and Monte Carlo simulations. The system’s behaviour is studied in different scaling regimes of the number of B cells, dilution in the interactions and number of antigens. Our analysis shows that: (i) B cells activation depends on the number of receptors in such a way that cells with an insufficient number of triggered receptors cannot be activated; (ii) idiotypic (i.e. B–B) interactions enhance parallel activation of multiple clones, improving the system’s ability to fight different pathogens in parallel; (iii) the higher the fraction of antigens within the host the harder is for the system to sustain parallel signalling to B cells, crucial for the homeostatic control of cell numbers.

A Multi-word-agent Autonomous Learning Model for Regulating Word Combination Strength

Words are basic structural units of language that combine with each other to form sentences. The learning strength of combinative relations between words is of key importance in sentence structure analysis. Inspired by the analogies between words and lymphocytes, a multi-word-agent autonomous learning model based on an artificial immune system is proposed to learn word combination strength. The model is constructed via Cellular Automation, and words are modeled as B cell word agents and as antigen word agents. The language network is then simulated as an immune network. Meanwhile, Spreading Activation is employed to simulate idiotypic interactions between B cells. This research provides a completely new perspective on language and words and introduces biologically inspired processes from immune systems into the proposed model. The most significant advantage of the model is the ability of continuous learning and the concise implementation method. According to the graph-based dependency parsing method, the syntax dependency tree of a sentence can be predicted based on word combination strength in a bottom-up paradigm, from pairs of smaller structures to larger structures. Therefore, the effectiveness of the model can be verified by sentence dependency parsing. The experimental results on the Penn Chinese Treebank 5.1 indicate that our model can effectively and continuously learn word combination strength.

A complex immunological idiotypic network for maintenance of tolerance.

A complex immunological idiotypic network for maintenance of tolerance.

Rheumatoid factor in idiotypic regulation of autoimmunity

Rheumatoid factor (RF) is known to be heterogeneous, and RFs detected by various methods exhibit different characteristics. In addition to interacting with the Fc region of immunoglobulin G (IgG), certain RFs are able to recognize idiotypes of antibodies. Given the important role of idiotypic interactions in regulating autoimmunity, we hypothesize that RF is involved in regulation of lymphocyte activity against autoimmune disease-inducing antigens via idiotype-anti-idiotype interactions with these lymphocytes. RF level and the existence of idiotype-anti-idiotype interactions between RF and antibodies to autoimmunity-inducing antigens were studied in rats resistant and sensitive to collagen-induced arthritis, encephalomyelitis and atherosclerosis. RF was assayed by agglutination of tanned IgG-loaded erythrocytes. Rat resistance to autoimmune disease is associated with high RF production during the initiation of the immune response, and a low RF level during this period may be a preclinical marker of experimental autoimmune disease manifestation. RF-containing sera compete with an antigen if the RF-containing sera were obtained from rats immunized with that antigen, and they non-specifically inhibit binding of different antigen-antibody pairs. This suggests that RFs are anti-idiotypic antibodies that carry two kinds of paratopes: a particular paratope that recognizes the antigen-binding sites of antibodies, and a shared paratope that serves to recognize the recurrent idiotype on antibodies. Antigenic epitopes for the shared RF paratope can be created in the hinge region of Fc fragments of homologous IgG. RF detected by agglutination of tanned IgG-loaded erythrocytes is involved in negative idiotypic regulation of lymphocytes specific to autoimmunity-inducing antigens.

Self-Tolerance in a Minimal Model of the Idiotypic Network

We consider the problem of self-tolerance in the frame of a minimalistic model of the idiotypic network. A node of this network represents a population of B-lymphocytes of the same idiotype, which is encoded by a bit string. The links of the network connect nodes with (nearly) complementary strings. The population of a node survives if the number of occupied neighbors is not too small and not too large. There is an influx of lymphocytes with random idiotype from the bone marrow. Previous investigations have shown that this system evolves toward highly organized architectures, where the nodes can be classified into groups according to their statistical properties. The building principles of these architectures can be analytically described and the statistical results of simulations agree very well with results of a modular mean-field theory. In this paper, we present simulation results for the case that one or several nodes, playing the role of self, are permanently occupied. These self nodes influence their linked neighbors, the autoreactive clones, but are themselves not affected by idiotypic interactions. We observe that the group structure of the architecture is very similar to the case without self antigen, but organized such that the neighbors of the self are only weakly occupied, thus providing self-tolerance. We also treat this situation in mean-field theory, which give results in good agreement with data from simulation. The model supports the view that autoreactive clones, which naturally occur also in healthy organisms are controlled by anti-idiotypic interactions, and could be helpful to understand network aspects of autoimmune disorders.

Role of disorders related to idiotypic and anti-idiotypic interactions in slowing down the achievement of negative serologic reactions in patients with early onset forms of syphilis after specific therapy

Goal. To study the humoral immunity state in patients with the slowed down achievement of negative serologic reactions after the treatment of early onset forms of syphilis by means of examining the blood serum level of idiotypic and anti-idiotypic antibodies to cardiolipin and p17 Treponema Pallidum antigenic protein. Materials and methods. The study involved 324 patients (39.5% male and 60.5% female) with the slowed down achievement of negative serologic reactions. Primary (idiotypic) antibodies to cardiolipin and p17 protein were obtained using immunochromatographic assays with the help of the Bio Logik LP system. Purified antibodies were concentrated using the ultrafiltration technique with the aid of the XM-100А membrane. To obtain the rabbit antiserum to p17 Treponema Pallidum protein, chinchilla rabbits were immunized using the commercial recombinant p17 protein. To determine anti-cardiolipin idiotypic antibodies in the blood serum, the ELISa method optimized for detecting anti-cardiolipin antibodies was applied. To determine anti-cardiolipin anti-idiotypic antibodies as well as idiotypic and anti-idiotypic antibodies to p17 Treponema Pallidum protein, the standard ELISA method was applied. The following antigens were used to process the pads: F(ab)2 fragments of anti-cardiolipin antibodies (5 μg/mL), recombinant р17 T. pallidum protein (5 μg/mL) and F(ab)2 fragments of antibodies to р17 T. pallidum protein (10 μg/mL). The level of antibodies was assessed based on the absorbancy and expressed in conventional activity units using the K coefficient being the absorbancy of the serum under examination to the mean absorbancy of control serums ratio. The K value exceeding 1.5 conventional units indicated the increased level of antibodies. Results. Patients with the slowed down achievement of negative serologic reactions demonstrated a selective increase in the level of anti-idiotypic antibodies (AIAB) relative to T. pallidum antigens, cardiolipin and p17 protein, vs. first-order antibodies, which points at abnormal mutual regulation between idiotypic antibodies (IAB) and AIAB; the discovered phenomenon lays the immunochemical basis for the formation of a self-sustaining “vicious circle” contributing to the induction of high levels of antibodies to treponema antigens even when the pathogen was destroyed.

The rheumatoid factor in idiotypic regulation of autoimmunity

Event Abstract Back to Event The rheumatoid factor in idiotypic regulation of autoimmunity Liubov Beduleva1*, Igor Menshikov1 and Elena Stolyarova1 1 Udmurt State University, Russia Rheumatoid factors (RFs) were defined originally by the ability to react with Fc region of IgG and useful marker for the diagnosis of rheumatoid arthritis. Further studies showed that RFs are able to bind the Fab region of IgG, and to enter into idiotypic interactions with antibodies of different specificity. Facts about RF multiplicity and heterogeneous behavior require new look at the role of RF. Taking into account important role of idiotypic interactions in autoimmunity regulation we assumed that RFs might regulate autoimmune response through idiotypic interactions. We’ve investigated RF level in rats resistant and susceptible to arthritis, encephalomyelitis, atherosclerosis and idiotypic interactions between RFs and antibodies to antigens-inductors of autoimmunity. We revealed that in the autoimmune disease-resistant rats the increase of RF level preceded antibodies appearance to given antigens, on the contrary it was not observed in autoimmune rats. Thus resistance to induction of autoimmune diseases in rats is associated with high RF production within the initiation of immune response, and low RF level in this period may be used as a preclinical marker of autoimmunity manifestation. RF containing sera competes with antigen, if sera was obtained by this antigen immunization, and nonspecifically inhibit binding of different antigen-antibodies pairs. These facts suggest that RFs are anti-idiotypic antibodies carrying individual and shared paratopes. Individual paratope recognizes antigen-binding sites of antibodies. Shared paratope is bound to recurrent idiotype in antibodies of different specificity. Thus RFs are involved in negative idiotypic regulation of lymphocytes specific to antigens-inductors of autoimmune diseases. Acknowledgements The study was supported by the Ministry of Education and Science of Russian Federation, projects 14.B37.21.0211; 14.B37.21.0564; 14.124.13.1159-MD. Keywords: Arthritis, Encephalomyelitis, Atherosclerosis, immune network, Rheumatoid Factor Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Beduleva L, Menshikov I and Stolyarova E (2013). The rheumatoid factor in idiotypic regulation of autoimmunity. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00319 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 23 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Prof. Liubov Beduleva, Udmurt State University, Izhevsk, Russia, blv76@mail.ru Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Liubov Beduleva Igor Menshikov Elena Stolyarova Google Liubov Beduleva Igor Menshikov Elena Stolyarova Google Scholar Liubov Beduleva Igor Menshikov Elena Stolyarova PubMed Liubov Beduleva Igor Menshikov Elena Stolyarova Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

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Immunization of mice with DNA coding for the variable regions of anti-idiotypic antibody generates antigen-specific response

Understanding the mechanisms of generation and maintenance of immunological memory is crucial for rational vaccine design. A hypothesis known as relay hypothesis was earlier proposed which explains the maintenance of immunological memory through interaction of idiotypic and anti-idiotypic lymphocytes. In the present study, we have shown that immunization with rinderpest virus hemagglutinin protein specific anti-idiotypic antibody (Ab(2)v(beta)) DNAs coding for heavy and light chains generates antigen-specific antibody and T cell responses as well as Ab1 specific T cell response. We further show that boosting with the recombinant Ab(2)-vbeta proteins generates B and T cell memory response specific for antigen in anti-id DNA primed mice. This study provides experimental evidence for perpetuation of immunological memory through idiotypic network interactions.

Idiotypic networks: toward a renaissance?

Idiotypic networks, after being a dominating paradigm for more than a decade, have fallen out of fashion in parallel with the rapid success of molecular immunobiology. Today signs of a possible renaissance in idiotypic network studies are visible. For system biologists and also for physicists, the network idea remains attractive. Herein, a short account of the historical development of the paradigm is given. The necessary technical and conceptual ingredients for a theoretical description of idiotypic networks are briefly reviewed, and previous approaches are discussed. We also describe a minimalistic model developed in our group that allows for understanding the random evolution toward a highly non-trivial complex architecture. In the network, a connected large cluster of idiotype clones and many disconnected ones coexist, thus resembling the notion of central and peripheral parts proposed in the 'second-generation' version of the paradigm. The connected cluster consists of groups of idiotypic clones with clearly distinct statistical properties. The simplicity of the model allows for calculating the size of the groups and the number of inter- and intragroup links, which define the architecture. Aspects of idiotypic interactions in experimental medicine are discussed, along with the challenges to theory and experimentation.

Interference from Heterophilic Antibodies in the Olympus Ferritin Method

The effect of a substance present in a sample that alters the correct value of the result is referred to as analytical interference (1). Heterophilic antibodies consist of both natural antibodies and autoimmune antibodies that exhibit weak binding and polyspecificity, reacting with multiple heterogeneous antigens. Some heterophilic antibodies can react with human and animal immunoglobulins by binding to epitopes located on either the F(ab) or Fc region, although in healthy persons there is a predominance of idiotypic interactions (2). We detected what appeared to be this type of interference in a study comparing the Olympus® immunoturbidimetric assay (ITA) for ferritin on the AU-5400 automated analyzer with the Roche® electrochemiluminescence immunoassay for ferritin on the Modular E-170 analyzer. Ferritin concentrations …

Recombinant idiotypic TCRβ chain immunization in mice generates antigen specific T cell response

Vaccination remains the most cost-effective means of preventing infectious diseases. Success of vaccination depends on generation of effective memory response. Understanding the mechanism of generation and maintenance of immunological memory would help in the design of rational vaccines. T lymphocytes play a central role in the generation of protective immune response against many microbial infections. A hypothesis known as relay hypothesis was earlier proposed, which explains the maintenance of immunological memory through interaction of idiotypic and anti-idiotypic lymphocytes. In the present study, we have shown that immunization with a model antigen, chicken ovalbumin specific T cell receptor beta chain (idiotypic TCR) generates TCR specific antibody and anti-idiotypic T cell responses as well as ovalbumin specific T cell response. We further show that boosting of ovalbumin primed mice with ovalbumin specific idiotypic TCRβ DNA or TCRβ protein gives memory response for ovalbumin. This study provides experimental evidence for perpetuation of immunological memory through idiotypic network interactions.

Influence of isotypes of disease-associated autoantibodies on the expression of natural autoantibody repertoires in humans

Current understanding of immune network interactions mediated by immunoglobulins focuses on the role of idiotypes expressed on antibody variable regions. Idiotype interactions account significantly for the functional integrity of natural self-reactive antibody repertoires, whereas immunoglobulin isotypes are not considered to direct natural autoimmunity. Autoimmune thrombocytopenic purpura (AITP), a bleeding disorder caused by clonally restricted platelet-specific autoantibodies of the IgM or IgG isotype, is an excellent model to investigate the impact of isotype differences of immunoglobulins on the selection of natural self-reactive antibody repertoires in humans. Using specific analytical techniques to characterize the natural self-reactive antibody repertoire (i.e. quantitative immunoblotting, affinity biosensor technology), we here demonstrate that isotype differences of disease-associated autoantibodies are associated with altered natural self-reactive antibody repertoires in humans. Our data suggest that regulation of natural autoreactivity by antibody isotype might occur under certain conditions. The control of natural self-reactive antibody repertoires by immunoglobulin isotypes at a supraclonal level may provide a structural basis for non-organ-specific broad alterations of natural self-reactive antibody repertoires in organ-specific autoimmune diseases.

Idiotypic and Anti‐Idiotypic Antibodies Produced in Immune Response to Bacteria Lactobacillus acidophyllus

Lactobacilli are nonpathogenic gram‐positive inhabitants of the normal human intestine known for their health‐promoting effects. In our earlier work, it is shown that human monoclonal antibody isolated from sera of a patient with Waldenstrom macroglobulinaemia possess innate antibody characteristics and binds to lactic acid bacteria. According to the immune network model, immunization with this bacteria could induce the perturbations in immune system that might result in production of anti‐Lactobacillus antibodies, human monoclonal antibody like (Ab1) and anti‐idiotypic antibody (Ab2). In this study, BALB/c mice were immunized with two doses of bacteria Lactobacillus acidophilus in complete and incomplete Freund's adjuvant and phosphate‐buffered saline (PBS), respectively. Seven days after the last immunization, sera from immunized mice were collected and the presence of Lactobacillus‐specific Ab1 and Ab2 were determined by ELISAs. In the sera of immunized mice, antibodies specific to bacteria Lactobacillus acidophilus were shown. The concentration of Lactobacillus‐specific antibodies was higher in the sera of hyperimmunized mice (mice immunized with 1 mg of IgM DJ) than in sera of mice immunized with 100 times lower doses of immunogen (0.01 mg per doses). Moreover, Ab1 and Ab2 antibodies were detected in the sera of Lactobacillus‐hyperimmunized mice. In this study, we have shown the idiotypic network interactions in mice immunized with bacteria Lactobacillus acidophilus.

Will the idiotypic network help to solve natural tolerance?

A recent paper on immunity and tolerance to antigenic determinants on antibody variable-regions (idiotypes) brings back to light the potential of idiotypic interactions among antibodies, B cells and T cells in the regulation of specific immune activities. The functional significance of idiotypic regulation has been established in a variety of systems, both concerning the establishment of ‘pre-immune’ diversity repertoires as well as the clonal regulation of immune responses to foreign and self-antigens. Also, recently the requirement for ‘dominant’ regulatory mechanisms in natural tolerance has received increasing support. It might thus be fruitful to evaluate the possibility that an idiotypic network has a fundamental role in the operation of the regulatory T cells that establish and maintain self-tolerance.

Generalization of single immunological experiences by idiotypically mediated clonal connections

Clonal interactions of B cells by idiotope-specific mutual recognition of their antigen receptors with the participation of T cells were assumed to form a web of unknown density, referred to as the idiotypic network. Although these clonal connections were proposed to fulfill important internal regulatory functions, their biological significance, especially in relation to antigen-induced immune responses, remained a mystery. In view of this, we postulate that the basic function of the idiotypic internal connection between B and T cell antigen receptors is to transform antigen-induced cellular activations, by idiotypic crossreactivity, into the regulation of cell clones with different antigen specificities. This process leads not only to the suppression of major clones but also to the activation of minor ones. The latter activating property may allow the generalization of single antigenic experiences, so that the immune system in its entirety benefits in its battle against environmental microbes. Such idiotypic clonal interactions are particularly effective in early ontogeny. During a short neonatal imprinting period, maternal immunological knowledge in the form of somatically mutated, high-affinity IgG antibodies, acquired through a continuous encounter with external antigens, guides the initial ontogenetic development of the immune system and so exerts long-lasting transgenerational advantageous effects in the offspring.