Autoimmunity

The immune system is able to discriminate between self and nonself, but there are often ambiguities with this formulation. First, it certainly is intended to stress the fact that the immune system is designed for the important role of fighting against external pathogens, whereas it should be harmless for the components of the organism. There are two ways to be harmless. One is simply not to “show off,” the second is to be present, but silent. Immunologists long lived with the idea originally put forward by Ehrlich in 1901 of the horror autotoxicus, thus considering that autoantibodies, and more generally autoimmunity, could not exist. This was even strengthened by Burnet, when he proposed the clonal selection theory, based on the elimination of autoreactive lymphocytes (the so-called “forbidden clones”), leading to immune tolerance. On these bases, autoimmunity may only be considered to be a pathological deviation, with the emergence of autoimmune diseases. Discovery of the interactions between idiotype and anti-idiotype and of the existence of natural antibodies endowed with auto reactivity made it necessary to reconsider the problem.

A long debate has taken place for years between immunologists, first on the existence, and then on the nature, of natural antibodies and their possible autoimmune properties. Identification of “natural” monoclonal antibodies that were polyspecific clarified the situation, because it was demonstrated that these antibodies contained variable (V) regions of both the heavy and the light chains that were mostly not mutated, and like the germline gene from which they were derived. As a result, these antibodies could be considered the first circle of antibody defense, with some polyspecificity that is the best witness of a certain degeneracy of recognition by the immune system. Deliberate immunization will stimulate clones that have the best affinity for the antigen, and this affinity will be amplified by the mechanism of somatic hypermutation, as the specificity becomes more precise. To be polyspecific immediately implies that both auto- and xenospecificities may be found, as was shown using a large panel of random antigens for screening. Autoimmunity has also been described in the T-cell population and is subject to the same comments, with the exception that T cells do not mutate upon antigenic stimulation.

The entire repertoire expressed at a given time by the immune system is probably best visualized as a large network of interacting molecules that regulate each other. Deliberate immunization would result in transient perturbation of this equilibrium. Deviation to the production of aggressive B- and T-cell clones would thus be a central alteration of this equilibrium, ensuring some leakiness for the negative selection of potentially aggressive clones.