We have been attempting to identify the genes that specify certain immunologic and virologic abnormalities of NZB mice and define their etiologic roles in production of autoimmune disease and lymphoid malignancy. Two autosomal dominant loci (Nzv-1 and Nzv-2) determine the exceptionally high grade expression of xenotropic retroviruses in NZB mice. Secondly, the expression of high levels of serum gp70, a retroviral protein, is related to a complex set of genes in NZB mice. In crosses between NZB and the nonautoimmune virus negative SWR strain, the expression of xenotropic virus, high serum gp70, autoantibodies and autoimmune disease segregate independently. Furthermore, there is an intrinsic abnormality of B cells in NZB mice, which can be detected from fetal life and is independent of T cells. This is characterized by extremely large amounts of IgM produced spontaneously by NZB-B cells in short-term cultures. We have identified 2 genetic systems relevant to this phenomenon and localized the abnormality to a specific subset of B cells. In summary, we seem to be observing a basic disorder of gene regulation in NZB mice where several groups of unlinked genetic systems are spontaneously activated, with ensuing high-grade expression of the corresponding gene products.