Germinal centers (GC) are microscopically distinguishable structures in secondary lymphoid tissue where Ag-specific B cells are stimulated to proliferate, isotype switch, somatically hypermutate (SHM), and generate Ab-forming cells and memory cells. FDC-networks are fixed in GCs while T cells and B cells are free to circulate. Nevertheless, FDCs release chemokines that attract lymphocytes to help organize the follicle and participate in the GC reaction. Although FDCs represent only ~1-5% of GC cells, the extensive network enables FDCs to be in intimate contact with numerous B and T cells. In primary follicles FDCs are resting but activation occurs during GC reactions and FDC membrane molecules are upregulated, and production of chemokines and cytokines appears to increase. We hypothesize that activated FDCs play a vital role in creating the environment where B cell proliferation, Ig class switching, SHM, selection of high affinity B cells, and production of high affinity Ab leading to affinity maturation take place. By use of GC cells (B cells, CD4 T cells and FDCs), we propose to study the GC reaction in vitro where the influence of resting as well as activated FDCs and their products can be manipulated and tested. Features and functions of FDCs in GCs include: 1) The GC light zone where FDC-networks engage B cells and T cells and this is distinct from the GC dark zone where B cells proliferate;2) Molecules on activated FDCs that we believe are important in FDC-B cell-T cell interactions including: Ag-Ab complexes, CD21L, CD23, CD32/FcyRIIB, CD40, CD44, CD54/ICAM-1, CD106/VCAM-1, and CD320/8D6;3) Products secreted by FDCs that influence GC reactions include CXCL-12, CXCL-13, and IL-6. We propose to determine if these FDC molecules promote B cell proliferation, Ig class switching, SHM, selection of high affinity B cells, and production of high affinity Ab. In addition, we recently developed techniques that allow us to generate FDC-reticula and GC """"""""light zone like"""""""" areas in vitro. We propose to determine the influence of FDC-reticula in discrete """"""""light zone like"""""""" areas on: trapping of Ag-Ab complexes, expression of CD23, CD32, CD40, CD44, D54, CD106, CD320, as well as production of CXCL-12, CXCL-13, and IL-6. We believe an understanding of important molecules in the GC microenvironment is fundamental to being able to manipulate humoral immunity to the benefit of mankind.
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| El Shikh, Mohey Eldin M; El Sayed, Rania M; Szakal, Andras K et al. (2009) T-independent antibody responses to T-dependent antigens: a novel follicular dendritic cell-dependent activity. J Immunol 182:3482-91 |
