Aged mice display a marked decrease in immune reactivity in general but an increase in auto-immune reactivity. During the past five years, this laboratory has been able to generate a substantial amount of information concerning the relationship of changes in B cell responsiveness per se to the overall changes in immune responsiveness in aged mice. Although many aspects of B cell responsiveness appear to be unaltered including the proliferative and antibody forming capacity of competent B cells, specificity repertoire diversity, and the generation of B cells from the bone marrow, we have demonstrated three major alterations which could contribute to the decreased B cell responsiveness of aged individuals. These include: 1) a marked increase in anti- idiotypic down regulation, 2) a decrease in the functional half-life (and consequently the frequency) of mature antigen responsive B cells, and 3) the generation of novel antibody specificities. However no changes in B cell responsiveness have, as yet, been identified that could account for increased auto-reactivity. We propose to extend the above studies to include analyses of the newly identified secondary and Ly-1 B cell lineages and to investigate tolerance, susceptibility and potential auto-reactivity in mature and immature cells of these subpopulations. Investigations of auto-reactivity will be fascilitated by several novel approaches including: 1) isolation and examination of low affinity responses, 2) obtaining T cell help for self antigens by """"""""arming"""""""" T cells with anti-receptor antibodies, and 3) the use of mice expressing the influenza hemagglutinin as a """"""""pseudo-self"""""""" antigen. We also plan an intensive investigation of novel variable utilization in aged mice to determine the molecular and cellular basis for this phenotype we will examine the affect of intrinsic (e.g. strain differences) and extrinsic (e.g. diet and T cells) influences on the aging process. We will also use this approach to correlate anomolies in V gene expression to stages of B cell development by specific reconstitution of SCID mice with purified subpopulations of bone marrow B cell precursors.
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