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.

This article investigates the following basic question: in the relatively stable molecular environment of a vertebrate body, can a dynamic idiotypic immune network develop a natural tolerance to endogenous components? Our approach is based on stability analysis and computer simulation using a model that takes into account the dynamics of two agents of the immune system, namely, B-lymphocytes and antibodies. We investigate the behavior of simple immune networks in interaction with an Ag whose concentration is being held constant as a function of the connectivity matrix of the network. The latter is characterized by the total number of clones, N, and the number of clones, C, with which each clone interacts. The idiotypic network models typically become unstable in the presence of this type of Ag. We show that idiotypic networks that can be found in particular connected regions of NC-space show tolerance towards auto-Ag without the need for ad hoc mechanisms that prevent an immune response. These tolerant network structures provide dynamical regimes in which the clone which interacts with the auto-Ag is suppressed instead of being excited such that an unbounded immune response does not occur. Possible implications for the future treatment of auto-immune disease such as IvIg-treatment are discussed in the light of these results. Moreover, we propose an experimental approach to verify the results of the present theoretical study.

In the present study we have analyzed the changes in the expressed antibody repertoire and in temporal fluctuations of antibody levels in serum that followed infusion of normal IgG (IVIg) in a patient with autoimmune thyroiditis. Administration of IVIg resulted in the stimulation of IgM production, in alterations of expressed antibody activity in serum that could not merely be accounted for by the passive transfer of antibody specificities contained in IVIg, in transient down-regulation of B cells clones expressing a specific disease-related idiotype and in the increase in serum in recipient’s autoantibodies specifically reactive with F(ab′)2 fragments of IVIg. In addition, infusion of IVIg shifted the pattern of spontaneous fluctuations of autoantibody activities in the patient’s serum from a pattern indicative of disconnected events in the immune network to a pattern similar to that which is consistently observed in healthy controls. These results suggest that normal IgG may modulate autoreactivity by selecting expressed antibody repertoire through V region-dependent interactions with antibodies.

Key words: autoimmunity, IgG, intravenous immunoglobulin (IVIg), immune networks

After some ten years of faltering development, the network approach in immunology is finally heading toward steady ground. At a recent international workshop, experimentalists and theoreticians discussed some of the latest developments, including an impressive array of novel results and applications to fundamental properties of biological immune networks: connectivity, patterns of dynamic activity, ontogenesis, and tolerance.

Immunology is about to emerge from the shadow of its original sin, that of being born from the medicine of infectious diseases, and to cast aside its long-dominant paradigm of vaccination – a heteronomous view par excellence. This happens just when the cognitive sciences are waking up from the dominance of the digital computer as their main metaphor. If we are willing to accept the central importance of autonomous process in both the neural and immune networks, they can teach us how we think with our entire body.

Network approaches have had little impact on immunology because they have addressed the wrong questions. They have concentrated on the regulation of clonal immune responses rather than on the supraclonal properties of the immune system that emerge from its network organization, such as natural tolerance and memory. Theoretical advances, observations in unimmunized mice and humans, and the success of novel therapeutics in autoimmune diseases have recently promoted a new burst of research on the structure, temporal dynamics and metadynamical plasticity of immune networks.

Excerpt: In recent years, immunology has undergone an important change by admitting that immune components might operate as a network. Initially the concept was applied restrictedly to a web of variable regions (V-regions) in immunoglobulin molecules (Ig), and had little significance other than some form of regulation of immune responses. More recently, this view of the network has been fleshed out to include not only antibodies that link to other antibodies (i.e., anti-idiotypic antibodies), but also V-regions expressed on the surface of B and T lymphocytes at various development stages, as well as components of the somatic self (i.e., markers on cell surfaces and soluble macromolecules circulating in the body fluids). The initial ideas on immune networks (IN) were incomplete because they concentrated on the regulation of clonal immune responses, which are a manifestation of the system’s capacity to defend the body from infections, rather than on properties of the immune system (IS) that emerge from its network organization, such as natural tolerance and memory. We have called second generation immune networks this wave of research that includes theoretical advances, observations in unimmunized mice and humans, and novel therapeutics in autoimmune diseases, these generating a new burst of interest on IN. The main point of the present chapter is to consider the next step; one that follows naturally from assuming the second generation stance, i.e., that INs are a biological reality. In this perspective, the focus of interests change quite drasti­cally from the previous paradigm. Classically, immune responses represent the bulk of immunological lore. In the new perspective, immune responses are relegated to a peripheral role since infections are not always present and, when they are, the corresponding specific responses are mounted by an array of normally inactive, dis­connected B and T cells. These stand in high contrast to the naturally or internally activated, highly connected lymphocytes, the core of the IN. We speak, therefore, of a peripheral immune system, which is concerned with “conventional” immune responses to microbial antigens, accountable by the clonal selection theory. This contrast with the central immune system concerned with internally activated cells, tightly arranged in an interacting network.

This paper provides a conceptual framework to accommodate important recent developments in immunology (genetic determination, cellular interactions, suppression). The basic idea is to look at the immune system as a closed network of interactions which self-determines its ongoing pattern of stability and its capacities of interaction with its environment. Thus, all immune events are understood as a form of self-recognition, and whatever falls outside this domain, shaped by genetics and ontogeny, is simply non-sensical. This paradigm, stemming from the ideas of Jerne, represents almost a logical inversion of the Burnetian idea of self-discrimination. A detailed discussion of the immunological evidence that substantiates this view is presented, together with some new concepts (eigenbehavior, cognitive domains). Although the paper is addressed to biologists and immunologists, we make extensive use of system-theoretic notions in a non-mathematical form (recursion, nets and trees, self-organization).

Key words: immune networks, models, biological, immunosuppression, anti-idiotipic antibodies, immunoregulation, recursion