A unifying principle for autoantigenicity: Transforming self-molecules into autoantigens by association with dermatan sulfate polysaccharide (159.25)

Abstract

Abstract Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are chronic and disabling diseases that affect hundreds of millions of people worldwide. Despite great advances in biomedical research, etiology and pathogenesis of systemic autoimmune diseases have remained mysterious. In particular, the question of why and how a small, seemingly disparate subset of self-molecules become autoantigenic holds a key to understanding the basic principles of autoimmunity. Based on our recent data, we propose a unifying principle for autoantigenicity. We discovered that dermatan sulfate (DS) is an important functional link between cell turnover, autoantigens (autoAgs), autoAbs, autoreactive B-1a cells, and autoimmunity. By selectively interacting with autoAgs released from apoptotic/dead cells, DS can tether many autoAg molecules along its polymeric chain and convert singular self-molecules into multivalent polymer-like antigens, thus changing the “self”-nature of this molecule. Polymeric DS-autoAg complexes are potent stimulators of autoreactive B-1a cells that secrete autoAbs and present autoAgs to autoreactive T cells. This principle provides a mechanistic explanation for how only certain self-molecules derived from dead cells become autoantigenic. This principle also explains how microbial pathogens may convert self-molecules to autoantigens and provides clues to how environmental factors may contribute to autoimmunity and trigger autoimmune diseases.