Abstract
Autoimmune diseases are defined as pathologies of adaptive immunity by the presence of autoantibodies or MHC-restricted autoantigen-reactive T cells. Because autoreactivity is a normal process based on mechanisms producing repertoires of antibodies and T cell receptors, crucial questions about disease mechanisms and key steps for interference have been outstanding. We defined 25 years ago the 'remnant epitopes generate autoimmunity' (REGA)-model in which extracellular proteases from innate immune cells generate autoantigens. Here, we refine the REGA-model, tested in diseases ranging from organ-specific autoimmune diseases to systemic lupus erythematosus. It now constitutes a paradigm in which remnant epitopes generate, maintain, and regulate autoimmunity; are dependent on genetic and epigenetic influences; are produced in a disease phase-specific manner; and have therapeutic implications when targeted.