The immune system is usually seen as a collection of independent (specific) lymphocyte clones. Randomly generated and activated at random, these lymphocytes follow only their individual, clonal history. Thus, in traditional descriptions, immunological activity is neither systemic nor historical and is never “physiological”. However, recent descriptions show an abundant “auto”- reactivity in healthy organisms, an evidence of internal connectivity. The two major sources of immunogenic contacts, namely, dietary proteins and products of the autochthonous microbiota fail to induce progressive “secondary-type” clonal expansions (or “memory”). Natural IgM may arise in “antigen-free” organisms as they do in conventionally raised animals; actually, clonal receptors of both T and B lymphocytes are formed in antigen-free intracellular environments and are not driven by antigen exposure. Early in ontogenesis natural immunoglobulins are organized in characteristic patterns of reactivity which are robustly stable throughout healthy living;these patterns depend on genes known to be important in immunological activity. Predictable (not-random) variations on these patterns occur during infectious and autoimmune diseases, both in humans and experimental animals, which are correlated with different clinical states of these diseases. All this is incompatible with a random process driven by independent lymphocytes. In different pathological conditions, ranging from immunodeficiencies to parasite, allergic and autoimmune diseases, the organism develops oligoclonal expansions of T lympho- cytes. In addition, oligoclonality is associated with high IgE titers and eosinophilia. We propose, therefore, that the physiology of the immune system is conservative and remains stable throughout healthy living. In several types of experimental and clinical diseases, this stability is broken by oligoclonal expansions of T cells. Specific immune responses, understood as the progressive expansion of oligoclonal lympho- cytes, are expressions of immunopathology rather than immune physiology. A new explanation of the protective effects of anti-infectious vaccination is offered.

Historically, immunology emerged as a biomedical science, concerned with host defense and production of anti-infectious vaccines. In the late 50s, selective theories were proposed and from then on, immunology has been based in a close association with the neo-Darwinian principles, such as random generation of variants (lymphocyte clones), selection by extrinsic factors (antigens)-and, more generally, on genetic determinism and functionalism. This association has had major consequences:

Oral tolerance inhibits T-cell dependent reactions to antigens previously contacted by oral route. Parenteral re-exposure to orally-tolerated antigens inhibits immune responses to unrelated antigens, a phenomenon we have called ''indirect effects" of oral tolerance. We examined the requirements of previous irradiation of C57BL/6 and BALB/c recipients to successful transfer of oral tolerance and its indirect effects using 1 Â 10 8 splenocytes. When DTH reactions were evaluated, irradiation was not required to transfer both oral tolerance and its indirect effects. C57BL/6, but not BALB/c recipients, required irradiation to adopt suppressed antibody responses to tolerizing antigen. In BALB/c recipients, the indirect effect was transferred only if serum from the tolerant donors was added to the transferred splenocytes. CFSE labeled donor cells were not eliminated from non-irradiated C57BL/6, although unable to suppress antibody responses. Our results provide further evidences on the existence of a functional barrier in immunocompetent recipients that hinders the adoptive transfer of different immunological activities. Interactions between cells and serum components may be necessary to bypass this barrier.

Background: Polyclonal B-cell activation is well known to occur in Plasmodium infections, but its role in pathogenesis or protection remains unclear. However, protective properties of natural antibodies have previously been demonstrated in other contexts.