the Tissue-Specific Expression and Regulation of the Inhibitory lgG Fc Receptor

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DESCRIPTION (provided by applicant): The IgG Fc receptor family is comprised of both activating and inhibitory receptors to provide a balanced immune response to infections and tumors. FcgammaRllb (CD32B) is the only Fc receptor harboring a tyrosine-based inhibitory motif (ITIM) and plays a critical role in the maintenance of immune homeostasis in murine models. However, in humans, the existence of highly homologous FcgammaRlla and the lack of specific monoclonal antibodies have greatly hampered study of FcgammaRllb biology under both normal and disease conditions. We have recently developed an FcgammaRllb-specific mAb 4F5 and found a differential regulation of FcgammaRllb expression in lymphoid and myeloid-lineage cells and a dysregulation of FcgammaRllb in B lymphocytes in active SLE. Based on these observations and knowledge obtained from murine models, we hypothesize that FcgammaRllb expression is regulated in a tissue-specific manner and dysregulation of FcgammaRllb may contribute to the pathogenesis of human lupus. The specific aims of this proposal are to 1) Examine the expression and regulation profile of FcgammaRllb in lymphoid and myeloid-lineage leukocytes and circulating endothelial cells (CECs) related to its natural genetic variants and by ex vivo stimulants. 2) Elucidate the molecular mechanisms underlying the tissuespecific regulation of FcgammaRllb by characterizing the regulatory elements in FCGR2B gene and the tissue-specific transcription factors. 3) Explore the potential tissue-specific dysregulation of FcgammaRllb in SLE by analyzing the regulation of FcgammaRllb in SLE circulating myeloid and endothelial cells and comparing with the dysregulation of FcgammaRllb in SLE B lymphocytes. The molecular mechanism for the observed dysregulation of FcgammaRllb in SLE B lymphocytes will be dissected. Studies of the tissue-specific regulation of FcgammaRllb and the dysregulation of FcgammaRllb in SLE may not only shed light on the mechanism for the maintenance of immune homeostasis, but also may provide new knowledge for targeting FcgammaRllb in the therapeutics of autoimmune diseases.