A hallmark of autoimmune disease is an increase in the incidence of self-reactive B lymphocytes with the subsequent production of autoantibodies. Although it seems clear that regulatory defects are intimately associated with the onset, if not the continuance, of autoimmunity, there is little information on whether there are fundamental differences in the B cell precursor pool. One of the primary goals of this proposal is to determine if, in fact, there is a skewing of the available B cell specificity repertoire toward autoantigens or some discernable alteration in the composition of the B cell repertoire prior to the onset of autoimmunity. This will be accomplished by analyzing the immune repertoire of autoimmune vs normal strains of mice at various ages for the frequency of B cells 1) reactive with foreign and autoantigens, 2) expressing predominant idiotypes, and 3) using and expressing certain VH and VL gene families. This will be accomplished by using B cell cloning assays idiotype inhibition assays, and in situ hybridization with radiolabeled VH and VL gene probes. In addition, innate differences in the B cell precursor pool will be explored using long term bone marrow cultures. Several autoimmune mouse models and their normal counterparts will be used including NZB, MRL/lpr/lpr, and BXSB. These studies should provide significant new insights into the mechanisms of the autoimmune disease process and the involvement of the B lymphocyte lineage.
Showing the most recent 10 out of 13 publications
