CELLULAR MECHANISMS OF GERMINAL CENTER REACTION IN AGING

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In aging, deficient de novo germinal center developments results in the complete loss of memory B cells and recall antibody responses. Clinically, this correlates with the decreased secondary antibody responses to tetanus toxoid and flu vaccines. Germinal center development depends on antigen transport by antigen transport (ATC) cells to lymph node follicles where the antigen is trapped and retained on follicular dendritic cells (FDC). The dendrites of the FDCs produce iccosomes (immune-complex-coated bodies) which deliver the antigen to follicular B cells for endocytosis, Ag processing and presentation to T helper cells-a sequence described as the "alternative Ag-transport pathway." Senescence results in atrophic FDCs, which retain little antigen, produce few iccosomes, and induce no germinal centers and beta memory cells. Our recent publication provides new evidence for Antigen transport cells and follicular dendritic cells being derived from bone marrow. Preliminary evidence of the extra follicular origin of FDCs was obtained by showing that ATCs are pre-FDCs. Thus, we examined the blood and bone marrow for the presence of FDC precursors. Data in agreement with the bone marrow derivation of ATCs and FDCs were obtained by identifying a large mononuclear blood cell and a bone marrow cell using the FDC-specific monoclonal Ab. Bone marrow reconstitution studies of Fdc and GCs in old, immunodeficient mice further support the bone marrow derivation of ATCs and FDCs. Therefore, we hypothesize that, in aged individuals, depressed secondary Ab response and GC paucity is due at lest in part to a reduced capacity for Ag transport and defective FDCs, which may in turn be due to a decrease or defects in ATC/FDC bone marrow precursors. Alternatively, the explanation for these age-related deficits may depend on defects in DC functions such as signal 1 (Ag presentation to B cells) and signal 2 (co-stimulatory function of FDCs). To test these hypotheses, we will study the germinal center response and bone marrow deficits in old mice and the accessory functions of isolated old FDCs.