In this two-part series, Argyrios N. Theofilopoulos summarizes the current state of affairs in the field of autoimmunity. Part I integrates the collective mechanistic theories of autoimmune diseases. The most straightforward explanation to emerge with regard to organ-specific diseases is the concept that these are caused by inappropriate, yet conventional, immunological responses against self-antigens for which tolerance has never been established. A similar mechanism may be operative in systemic autoimmunity, but other abnormalities such as defects in the apoptosis machinery may also be invoked. Part II will address the genetic contributions predisposing to autoimmune syndromes.

It has long been hypothesized that the development of the immune system is triadic in nature: useless cells are discarded, useful cells are retained and dangerous cells are destroyed or inactivated. In recent years, studies with transgenic and endogenous superantigen (SAg)-expressing mice have strongly suggested that this hypothesis is essentially correct, with the ultimate outcome likely to be dependent on the degree with which antigen receptors react with self-constituents. Specifically, it appears that, as T cells mature in the thymus, those that rearrange and display self major histocompatibility complex (MHC) and peptide-reactive T-cell receptors (TCRs) of a certain affinity/avidity are maintained and propagated within the thymus (positive selection); but, prior to their export to the periphery, those with receptors of dangerously high affinity/avidity are eliminated or inactivated (negative selection) 1-3. Elimination or inactivation of emerging B cells reactive with membrane-bound self-antigens or soluble selfantigens, respectively, has also been documented 4, 5. Thus, through these editing processes, a state of selftolerance is achieved. However, despite the recent acquisition of extensive information relating to the mechanisms of self-tolerance, our understanding of the mechanisms leading to pathogenic autoimmunity is still fragmentary and incomplete. Nevertheless, recent advances in this area have begun to assemble the missing pieces of the puzzle. The purpose of this review is to synthesize the widely dispersed concepts