Regulation of Persistent Ab Responses by Fc Receptors

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Receptors for the Fc portion of IgG (FcgammaRs) are widely distributed on hematopoetic cells and play an important role in immune regulation by linking antibody-mediated responses with effector and regulatory cell activity. The murine FcgammaR FcgammaRIIB is a low affinity receptor and thus binds IgGs only in the form of immune complexes (ICs). This receptor contains an immunoreceptor tyrosine based inhibitory motif (ITIM) that is a potent inhibitor of signal transduction via receptors with immunoreceptor tyrosine activation motifs, such as the B cell antigen receptor (BCR), when co-crosslinked with the BCR via IC binding. In the previous funding period we discovered that levels of FcgammaRIIB expression are dramatically altered during the germinal center (GC) reaction, being down regulated on GC B cells and upregulated on follicular dendritic cells (FDCs). Moreover, FcgammaRIIB deficient mice display perturbations in the GC response. We also found that homologous cross-linking of FcgammaRIIB on B cell lines results in induction of an apoptotic response, and this does not require the presence of the ITIM motif. Finally, mice with an FcgammaRIIB deficiency on a C57BL/6 background were observed to develop high liters on anti-nuclear antigen antibody, and systemic autoimmune disease. The latter finding is consistent with previous suggestions that dysregulated expression of FcgammaRIIB can contribute to loss of B cell tolerance. These findings have motivated the development of hypotheses asserting that FcgammaRIIB plays a central role in regulating the outcome of the GC reaction. However, the different hypotheses that have been forwarded ascribe widely divergent levels of importance to FcgammaRIIB expression and function on GC B cells versus FDCs, as well as to the 1C trapping, BCR inhibitory, and apoptosis inducing capacities of this receptor. Therefore, in the next funding period we propose to: 1) analyze the GC response, memory B cell development and predisposition to systemic autoimmunity in mice with selective deficiencies of FcgammaRIIB in B cells versus stromal elements including FDCs;2) perform analogous studies on mice with either complete or selective B cell and FDC deficiencies in the ITIM signaling pathway of FcgammaRIIB;and, 3) utilize a novel VH "knockin" line of mice expressing chromatin/arsonate "dual reactive" BCRs to determine if global or selective FcgammaRIIB deficiencies alter negative selection of autoreactive B cells during the GC response. The results of these studies will provide important new insights into how regulation of the functions and expression of FcgammaRIIB in various cell types are orchestrated towards the normal development of immune memory and maintenance of tolerance, and how perturbations in these regulatory pathways can contribute to the development of autoimmune disease.
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