A second mechanism is at play in the periphery, alongside regulatory cells in the control of immune reactivity towards the self: this is the induction of a state of "anergy" in T and B lymphocytes, i.e. their inability (at least transiently) to activate as effector lymphocytes. Recent findings indicate a high frequency of autoreactive T and B lymphocytes in the periphery. In humans, a similar frequency of self-reactive, foreign antigen-specific T cells is observed in the blood, despite the prior central elimination of the most self-reactive cells (see above). It can be shown that they do not divide when stimulated by an autoantigen, that they express the receptor for the antigen to a reduced extent, and that they are therefore anergic. The question arises as to the respective roles of self-reactive cell deletion, control by regulatory cells and anergy. It can be shown in experimental mouse models that the respective roles of these control mechanisms vary according to the site of expression of self antigens (diffuse, lung, intestine, pancreas, etc.), with anergy playing an important role with regard to T cells recognizing tissue autoantigens. It should be noted that the state of anergy is reversible, and in fact offers the "advantage" of enabling the reuse of these cells, which can recognize exogenous antigens (infectious agents) by cross-reactivity without too great a defect in their repertoire, even if this may be at the cost of a risk of autoimmunity.
There is also plasticity between effector T and anergic and regulatory T, insofar as it has been shown experimentally that :
i) under the influence of Treg, effector T cells can become anergic ;
ii) in the absence of Treg, the latter can revert to being effectors;
iii) some anergic T cells can give rise to Treg cells!
Similar processes (anergy) are also at play in B lymphocytes. It is interesting to observe a defect in the induction of anergy during lupus erythematosus, marked by a continuous generation (during relapses) of B lymphocyte clones producing anti-DNA autoantibodies.
In previous lectures, we have focused on the genetic factors involved in autoimmunity. A number of epidemiological and experimental data demonstrate the role of the environment. We know that, through cross-reactivity between an infectious agent protein and a self-protein, an infection can trigger an autoimmune response (as in the case of post-streptococcal rheumatic fever). Conversely, it has been shown that the reduction in infectious stimuli in developed countries is accompanied by an increase in the frequency of autoimmune, inflammatory and allergic diseases. The quality of microbial flora, particularly through the production of short-chain fatty acids that promote the differentiation of naïve T lymphocytes into Treg, undoubtedly plays a crucial role. This is the hygiene theory, reproducible in mice under certain experimental conditions. Finally, the post-translational modification of self-proteins under the effect of toxic agents (tobacco, etc.) is likely to generate neoantigens such as those observed in rheumatoid arthritis (citrullinated proteins).
