Natural anti-immunoglobulin autoantibodies: irrelevant by-products or immunoregulatory molecules?

Anti-immunoglobulin autoantibodies (anti-Ig auto-Abs), particularly IgM-anti-IgG (classical rheumatoid factor), have been studied mainly in the context of rheumatoid arthritis. In this article we focus on other members of the anti-Ig family, including the natural IgG-anti-F(ab')2 auto-Ab, and look for clinical and experimental findings supporting a role of these antibodies in the regulation of the immune response. We discuss the evidence for suppression of auto- and alloreactive B cells by IgG-anti-F(ab')2 auto-Ab and the role of this Ab in the pathogenesis of certain diseases, such as autoimmune hemolytic anemia. The structure of the antibody's antigen-binding site was clarified by isolating the VL and VH gene segments from the cDNA of B cells. Sequence analyses revealed germline gene identity of VL chains and 88% homology with the closest germline gene of VH chains. Finally, we discuss hypothetical models concerning the immunoregulatory role of natural anti-Ig auto-Abs.