The potential for autoreactivity that has been well documented in normal individuals implies that natural autoimmune responses must serve some physiologic function. To investigate the genetic mechanisms involved in the emergence of such responses, we have determined the sequences of heavy (VH) and light (VL) chain variable region genes for several human monoclonal autoantibodies and compared these with corresponding sequences reported for other antibodies and autoantibodies. Our data reveal that natural autoantibodies can be encoded by nonmutated germline VHand VLgenes which are essentially identical to V genes expressed in early B cell ontogeny as well as in some B-Iineage tumors. Taken together with other structural data on human autoantibodies, these findings suggest that natural autoimmune responses originate early in ontogeny and that such antibodies may play a regulatory role in development of the normal immune repertoire and possibly in suppressing pathogenic autoimmune or malignant responses.