Autoantigens as Partners in Initiation and Propagation of Autoimmune Rheumatic Diseases
Systemic autoimmune diseases are characterized by speciï¬c targeting of a limited group of ubiquitously expressed autoantigens by the immune system. This review examines the mechanisms underlying their selection as immune targets. Initiation of autoimmune responses likely reï¬ects the presentation of antigens with a distinct structure not previously encountered by the immune system, in a proimmune context (injury, malignancy, or infection). Causes of modiï¬ed structure include somatic mutation and posttranslational modiï¬cations (including citrullination and proteolysis). Many autoantigens are components of multimolecular complexes, and some of the other components may provide adjuvant activity. Propagation of autoimmune responses appears to reï¬ect a bidirectional interaction between the immune response and the target tissues in a mutually reinforcing cycle: Immune effector pathways generate additional autoantigen, which feeds further immune response. We propose that this resonance may be a critical principle underlying disease propagation, with speciï¬c autoantigens functioning as the hubs around which ampliï¬cation occurs. INTRODUCTION: A CONCEPTUAL FRAMEWORK Induction of an immune response against self-antigens, which damages self-tissues, is a central feature of autoimmune diseases. Over the last 50 years, there has been signiï¬cant progress in deï¬ning the molecules that are targeted in autoimmune diseases, largely using high-titer autoantibodies as probes (1). The resulting catalog of autoantigens, together with careful clinical descriptions of the distinct disease features associated with such responses, has provided a critical framework to begin to understand the mechanisms responsible for antigen selection in autoimmune diseases (2). It is noteworthy that the antigenic targets of the highly driven immune responses in...