The origin of autoantibodies

Autoimmune diseases are characterized by the appearance of autoantibodies (autoAb) which may participate in their pathogenesis, but autoAb have also been found in normals with a variety of other conditions. The production of hybridomas from lymphocytes of unimmunized normal mice and healthy humans and analysis of the monoclonal autoAb (m-autoAb) obtained, showed that many had polyspecific autoAb reactivity, binding to many seemingly unrelated self-antigens, or to several organs. Most m-autoAb were of the IgM class and shared a common cross-reactive idiotype (CRI). Low levels of Ab with similar binding pattern and idiotype are continuously represented in the serum of mice and humans who have no evidence of autoimmune or other disease. Very similar Ab appear in autoimmune diseases. Studies of m-autoAb derived from lupus-prone mice and from patients with systemic lupus erythematosus (SLE) and other autoimmune diseases also revealed polyspecific binding, IgM isotype and CRI. Moreover, these CRI, which were almost identical with the idiotypes of natural autoAb in normals, may identify a group of pathogenic Ab in the lupus mice and SLE patients. Since the data clearly suggest that lymphocytes that make autoAb are common and are part of the normal B cell repertoire coded by widely dispersed germline genes, there remain the basic problems of the function of these autoAb in health, as well as the question of their regulation and activation in vivo. Several postulated functions and immunoregulatory mechanisms are discussed and the possible role of certain factors, especially viruses, in enhancing autoAb production and autoimmunity, is assessed.