The age-related decline in cells and functions of the immune system is well known. There is also a known age related decline in DNA double strand break [DSB] repair in human lymphocytes, more pronounced in females than in males. The role of DSB repair in the completion of DNA recombination processes such as VDJ joining and isotype switching and the consequences of impaired repair for lymphocytes will be assessed with respect to changes with age in mice, as well as in lines of mice transgenic for either a T-cell receptor gene or an immunoglobulin gene, where the transgenic arrays can be used as reporters for unresolved DSBs. Experiments will define the pool sizes of developing lymphoid populations in various age and gender groups and correlate these data with the number of DSBs remaining unresolved in vivo at the specific sites cut by the VDJ joining process. Several strains of mice will be investigated including ones with tendencies to autoimmune disease. One of the consequences of having fewer successful VDJ joins might be prolonged or increased evidence of RAG activity, which may manifest as increased Ig lambda light chain usage due to Ig kappa light chain deletion which can be measured by RS recombination. RS recombination will therefore also be monitored in developing bone marrow B-cell populations. Known molecules associated with DSB repair will be assayed where prominent increases in double stranded breaks are observed. Together, the data will help trace the connections between the efficiency of genomic housekeeping and the integrity of cells of the immune system, with particular reference to the immune decline seen in aging.
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