This paper considers current concepts of autoimmunity and concludes with a discussion on the need for viable alternatives. It is argued that, if a century of ‘horror autotoxicus’ and over 30 years of active research based on ‘clonal deletion’ models have failed to contribute solutions to the problem, these notions are probably inadequate. Instead, it is proposed that pathological states of autoimmunity should be considered as deviations from normal autoreactivity which is a central property of the immune system. It follows that the study of autoimmune physiology is necessary to the understanding of pathology. Furthermore, the discrimination between destructive immune responses and physiological, self-directed immune activities is thought to be a systemic property based on a particular network organization, rather than the result of isolated clonal properties. These views suggest novel strategies in basic and clinical approaches to autoimmunity, more particularly the possibility of manipulating physiological autoreactivity to compensate diseases which are not of immunological origin.

We monitored in normal adult BALB/c mice the serum concentrations of four natural IgM antibodies, two of which show idiotypic complementarity in in vitro assays. In each individual, serum concentration of all four idiotypes were found to fluctuate in complex dynamical patterns with low correlation. The spectral power of some such patterns was found to be compatible with the existence of a chaotic regime. Groups of normal adult mice were injected intravenously with low (10 ng) or moderate (10 micrograms) doses of either of the two complementary idiotypes in saline. This treatment resulted in a pronounced inhibition of the fluctuation in the serum concentration of both complementary idiotypes for periods up to 3 months. Such compensations were not detected for the two unrelated natural idiotypes and were specifically induced, for they did not occur following the injection of unrelated antibodies. These results indicate the functional operation of an idiotypic network among natural antibodies.

The fundamental concepts of autopoiesis, which emphasize the circular organization underlying both living organisms and cognition, have been criticized on the grounds that since they are conceived as a tight logical chain of definitions and implications, it is often not clear whether they are indeed a scientific theory or rather just a potential scientific vocabulary of doubtful utility to working scientists. This article presents the deployment of the concepts of autopoiesis in the field of immunology, a discipline where working biologists themselves spontaneously have long had recourse to “cognitive” metaphors: “recognition”; a “repertoire” of recognized molecular shapes; “learning” and “memory”; and, most striking of all, a “self versus non-self” distinction. It is shown that in immunology, the concepts of autopoiesis can be employed to generate clear novel hypotheses, models demonstrating these ideas, testable predictions, and novel therapeutic procedures. Epistemologically, it is shown that the self–non-self distinction, while quite real, is misleadingly named. When a real mechanism for generating this distinction is identified, it appears that the actual operational distinction is between (a) a sufficiently numerous set of initial antigens, present from the start of ontogeny, in conditions that allow for their participation in the construction of the system’s organization and operation, and (b) single antigens that are first presented to the system after two successive phases of maturation. To call this a self–non-self distinction obscures the issue by presupposing what it ought to be the job of scientific investigation to explain.

Key words: Autopoiesis, immune system, idiotypic network, self, non-self

According to a classical, antigen-driven view of the immune system, autoimmunity is due to the presence of self-reactive lymphocyte clones which have not been eliminated. However, computer simulations of the immune network show that the greater the degree of connectivity of a clone, the greater its degree of tolerance to chronic antigenic stimulation. This tolerance does not correspond to an absence of response on the part of the system as a whole. On the contrary, stimulation by a ‘tolerogenic antigen’ results in widespread modification and overall activation of the whole network. This suggests that on an autopoietic network view of the immune system, autoimmunity arises not because of the presence of self-reactive clones, which is completely normal, but because such clones are inadequately connected to the network. This amounts to a complete reversal in perspective, whose significance for the clinical treatment of autoimmunity and the future of immunology is discussed.

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.

We have measured the quantities of naturally occurring autoantibodies in the serum of normal, unmanipulated individuals. These changes over time following broad-band complex dynamical patterns that are similar in mouse and man. The patterns more likely reflect the network architecture of the natural antibody repertoire, regulating the activation and decay of individual clones. The temporal changes of both disease-specific and nonspecific autoantibodies are consistently modified in autoimmune individuals.