Advanced aging is widely associated with complex changes in immune functions. The patterns of antibody responses in aged humans and animals vary, depending on the host and accompanied by profound changes in antibody structure, which may compromise the objective of this program is to investigate the mechanisms underlying the molecular and functional shifts in the antibody repertoire of aged mice and humans. This long-range goal will be achieved by combination of cellular and molecular approaches. Project 1 will investigate the age-related changes in the developmental program of bone marrow B cells and the role of aged bone marrow stromal cells in this process. The possible alteration of V-D-J gene rearrangement is altered in aged B cells will be determined, in project 2 by examining the junctional diversity of antibody molecules from young and aged individuals. The usage of specific VH gene families by aged human B cells will be determined (Project 2), and, the genetic shift in responses to specific haptens will be studied in Projects 3 and 4, by examining the difference in genetic segments encoding the H and L chains of antibody from young and aged mice. The next major aim is to asses the changes in affinity maturation of the aged antibody repertoire. Project 5 is to examine the frequency of somatic hypermutations in V genes of young and aged B cells in response to antigen, and to compare it with extent of affinity selection of specific clones in the splenic antibody foci and germinal centers, using an in situ genomic analysis. The biological significance of the genetic and somatic changes in the repertoire will be assessed in studies on fine specificity, affinity and protective activity of antibodies from the aged mice. The role of T cells in shaping the antibody repertoire of aged animals will be studies in several ways. CD4+ lymphocytes from young and aged mice will be separated by functional markers (Pgp-1,CD45R, FcRmu or Il-1R) and tested for their responsiveness to various ligands, including specific antigens and for changes in the lymhokine production. (Project 7). Selected T cell populations will be also tested for their ability to modulate the clonal repertoire of developing B cells, to provide help for specific antibody responses and to drive the somatic diversification of antibody repertoire in vivo (projects 2 and 3).
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