Physiopathology of natural auto-antibodies: the case for regulation

The cause of autoimmune diseases remains unknown and, as a consequence, disease prediction and prophylaxis are not part of current clinical practice. Many autoimmune syndromes are accompanied by serological evidence of autoimmunity in the form of circulating auto-antibodies (AAb). As normal individuals produce large amounts of AAb, exploring the main differences between such physiologic AAb and those classified as pathogenic may provide the clues needed for new clinical approaches to this group of disorders. Reviewing the differential characteristics of normal and disease-associated autoantibodies, we conclude that the problem will be best tackled if we understand how the organism normally ensures that autoantigen-driven B cell activation does not lead to high titers of autoantibodies and severe autoimmunity. As natural activation of autoreactive B cells occur by both T cell dependent and T cell independent mechanisms, we argue that absence of clonal expansion in normal autoreactive B cells upon activation does not result from lack of appropriate stimulation but, rather, from the presence of negative regulation and suppressive mechanisms.