A RHEUMATOID-FACTOR TRANSGENIC MOUSE MODEL OF AUTOANTIBODY REGULATION

To address whether B cells expressing a disease-associated autospecificity are regulated in normal mice, we have established a rheumatoid factor (RF) transgenic model of autoimmunity, using V genes derived from an IgA anti-IgG2a RF isolated from an autoimmune MRL/lpr mouse. As we wished to study induction of tolerance during B cell development, we cloned the V(H) gene into an IgM expression vector. The RF we chose binds only IgG2a of the 'a' allotype (IgG2a(a)) but not IgG2a(b) allowing us to produce transgenic animals on IgH(a) and IgH(b) backgrounds, which either express or lack the self-antigen. Two transgenic lines were studied. Using mice which lack the self-antigen, we show by fluorescence activated cell sorting and hybridoma analysis that the H and L transgenes are expressed to the exclusion of endogenous genes in most splenic B cells. In spite of good allelic exclusion, transgenic mice which are genetically capable of expressing IgG2a(a) have reduced but significant (approximately 50 mug/ml) serum levels. Nonetheless, the frequency and numbers of transgene-expressing B cells in peripheral lymphoid organs of such mice which have the self-antigen are similar to those which lack it (IgH(b) mice). Thus, B cells expressing an anti-self IgG2a surface receptor can develop in this system. Whether such B cells are anergic or otherwise regulated in autoantigen-expressing mice is discussed.