Systemic autoimmune disease states are known to be associated with abnormal cell growth or differentiation. In the murine models of systemic lupus erythematosus (SLE), specific genotypes result in dysregulated growth of certain lymphocyte subpopulations. Although genes underlying autoimmune syndromes have been characterized by mendelian genetics, it has not yet been possible to characterize them at the molecular level. Recently, it has become clear that cellular proto-oncogenes can regulate cell growth and differentiation. Therefore, we have studied the expression of five different proto-oncogenes; myc, myb, abl, bas, and raf, in organs and cells of various autoimmune strains. These genes were selected because each has previously been associated with abnormal hemopoietic cell growth, and because each has been at least partially characterized at the molecular and functional level. We have found selective abnormal proto-oncogene expression associated with the characteristic abnormal cell growth or differentiation of lymphocytes of autoimmune mice. The lymph nodes of MRL-lpr/lpr mice are packed with unusual T cells. These had a marked increase in myb expression. There was a 20-40-fold increase in myb RNA in lymph nodes of lpr/lpr mice on several different genetic backgrounds. The gld/gld mouse has a very similar unusual T cell in the lymph nodes: it also had a comparable increase in myb RNA in the nodes. In contrast, myb expression was not elevated in the other autoimmune mouse strains lacking these abnormal T cells. Whereas such lpr/lpr mice had increased myb expression in the lymph nodes and splenic T cells, they had markedly subnormal myb expression in the thymus, an organ with high myb in normal and in the other autoimmune strains. These results suggest that one phase of intrathymic differentiation in other mice occurs in the periphery of lpr/lpr mice. The spleens of NZB and male BXSB mice had increased myc expression which was found to be associated with B cells upon cell separation. Similarly, increased bas and abl expression was associated with autoimmune B cells. The xid gene, which retards or prevents the expression of murine lupus by retarding B cell maturation, was associated in BXSB.xid, NZB.xid, and MRL-lpr/lpr.xid congenic mice with marked reduction in expression of myc, bas, and abl in the spleens containing B cells, but not of myb in the lpr/lpr.xid nodes containing primarily the unusual T cells. Raf expression was found to be associated in lpr/lpr and gld/gld mice with both the unusual T cells and splenic B cells.(ABSTRACT TRUNCATED AT 400 WORDS)