This application presents our overall plan to investigate the cellular and molecular basis of the increased autoantibody response of old mice.
The first aim i s to understand the cellular basis of autoantibody production in old mice. The increased spontaneous production of autoantibodies by conventional, non-autoimmune, non-immunized old mice is associated with significant changes in the distribution of lymphocytes. We found increased numbers of peritoneal cells, Ly1-bearing B cells, and low density, activated lymphocytes in old mice. The contribution of these lymphoid populations to the increased production of autoantibodies by old mice will be studied.
The second aim i s to determine if long-lived peripheral T cells in old mice are responsible for the selection of the autoantibody B cell repertoire. It has been found that the level of autoanti- idiotypic antibody, one of the autoantibodies produced in greater quantity in old as compared to young mice, is regulated by peripheral T cells in old mice. These cells appear to select B cells of this specificity in the absence of antigen, perhaps through idiotype-anti-idiotypic interactions. The role of peripheral T cells from old mice on the selection of the B cells specific for autoantibodies to erythrocytes, thyroglobulin, DNA and immunoglobulin will be investigated.
The third aim i s to examine the utilization of the immunoglobulin heavy chain variable region (VH) gene families by autoantibody forming cells in old mice. The increased number of activated and Ly1-bearing B cells in old mice is similar to that found in neonatal mice, as is the increased representation of autoantibodies, autoanti-idiotypic antibodies multi-reactive antibodies and antibodies with high """"""""connectivity"""""""" within the B cell repertoire. Recently, fetal and neonatal mice have been found to utilize preferentially the most D-proximal VH gene families. The utilization of heavy chain variable region genes by B cells, in general, from old mice and autoantibody producing B cells from old mice in particular will be determined.
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