A RHEUMATOID-FACTOR TRANSGENIC MOUSE MODEL OF AUTOANTIBODY REGULATION

To address whether B cells expressing a disease-associated autospecifi city are regulated in normal mice, we have established a rheumatoid fa ctor (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 bi nds only IgG2a of the 'a' allotype (IgG2a(a)) but not IgG2a(b) allowin g us to produce transgenic animals on IgH(a) and IgH(b) backgrounds, w hich either express or lack the self-antigen. Two transgenic lines wer e studied. Using mice which lack the self-antigen, we show by fluoresc ence activated cell sorting and hybridoma analysis that the H and L tr ansgenes are expressed to the exclusion of endogenous genes in most sp lenic B cells. In spite of good allelic exclusion, transgenic mice whi ch are genetically capable of expressing IgG2a(a) have reduced but sig nificant (approximately 50 mug/ml) serum levels. Nonetheless, the freq uency and numbers of transgene-expressing B cells in peripheral lympho id organs of such mice which have the self-antigen are similar to thos e which lack it (IgH(b) mice). Thus, B cells expressing an anti-self I gG2a surface receptor can develop in this system. Whether such B cells are anergic or otherwise regulated in autoantigen-expressing mice is discussed.