Autoimmune diseases are the result of specific immune responses directed against structures of the self. The organism possesses powerful mechanisms to avoid immune auto-aggression. The acquired ability of the immune system to avoid responsiveness to self-antigens is defined as ‘tolerance', and is obtained by the cooperative efforts of central and peripheral mechanisms, which allow a rapid and efficient removal of pathogens (e.g. viruses or bacteria) in the absence of self-recognition. The failure of self-tolerance can result in autoimmunity, which comes in many forms but still targets a limited selection of the total available autologous determinants. This selectivity must reflect the underlying mechanisms of the autoimmune reaction, as well as the particular features of the autoantigens that are targeted.

Table 1. Characteristics of autoreactive antibodies

Tolerance Breakdown

Today, it is well accepted that autoimmune reactions are part of the physiological functioning of the immune system. Natural self-reactive antibodies are found at low concentration in the serum of normal individuals (Table 1). They usually are of IgM isotype, with low avidity for the antigen. Natural antibodies are probably used by the organism to facilitate the clearance of senescent cells and autoantigens, and therefore prevent the activation of cognate autoimmune responses. Autoantibodies involved in the pathogenesis of autoimmune diseases are found at relatively high concentration in patients' sera (Table 1). They are usually of IgG isotype, with high avidity for the antigen, and with V regions documenting somatic hyper mutations. In other words, these autoantibodies are the product of a T-helper cell-dependent activation of B cells, which mature in conditions of prolonged contact with the antigen and undergo clonal selection. What is the mechanism that drives the immune system to switch from a harmless natural autoimmune response to the production of very dangerous IgG autoantibodies? The answer is probably within the sophisticated mechanisms that regulate the maintenance of tolerance. Several hypotheses have been formulated to explain the breakdown of tolerance (Table 2). Some of them are well supported by experimental models.

Table 2. Mechanisms hypothesized to be involved in the breakdown of tolerance

Autoantigen Selection

The issues involved in autoantigen selection have been recently reviewed and are summarized briefly in Table 3. As autoimmune diseases are diverse, and their genetic and functional mechanisms may be dissimilar, so autoantigens may be targeted for different reasons in different conditions. The necessary features of an autoantigen in SLE may not be the same as those in thyroiditis. Nevertheless, the selection of each autoantigen clearly depends on certain of its features as well as those of the immune system. Understanding the basis of this selection would help us to understand the pathogenesis of the diseases with which they are associated.

Table 3. Common features described for autoantigens