Viewing Autoimmune Pathogenesis from the Perspective of Antigen Processing and Determinant Hierarchy

Autoimmunity results from the breakdown of immune tolerance to defined target self antigens. Like any foreign antigen, a self antigen is continuously processed by antigen-presenting cells (APCs) and its epitopes are displayed by the major histocompatibility complex on the cell surface (dominant epitopes). However, this self antigen fails to induce a T cell response as the T cells against its dominant epitopes have been purged in the thymus during negative selection. In contrast, the T cells against poorly processed (cryptic) self epitopes escape tolerance induction in the thymus and make it to the periphery. Such T cells are generally harmless as their cognate epitopes in the periphery are not presented efficiently. But, under conditions of inflammation and immune activation, previously cryptic epitopes can be revealed on the APC surface for activation of ambient T cells. This can initiate autoimmunity in individuals who are susceptible owing to their genetic and environmental constellation. Subsequent waves of enhanced processing of other epitopes on the same or different self antigens then cause "diversification" or "spreading" of the initial T cell response, resulting in propagation of autoimmunity. However, depending on the disease process and the self antigen involved, "epitope spreading" may instead contribute to natural regression of autoimmunity. This landmark conceptual framework developed by Eli Sercarz and his team ties together determinant hierarchy, selection of epitope-specific T cells, and the induction/progression of autoimmunity. I am extremely fortunate to have worked with Eli and to have been a part of this fascinating research endeavor.