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

描述(由申请人提供)： Ig G Fc受体家族由激活受体和抑制受体组成，提供对感染和肿瘤的平衡免疫反应。FcGammaRllb(CD32B)是唯一一个含有酪氨酸抑制基序(ITIM)的Fc受体，在维持小鼠模型的免疫稳态中起着关键作用。然而，在人类中，高度同源的FcGammaR11a的存在和缺乏特异性的单抗极大地阻碍了在正常和疾病条件下FcGammaR11b生物学的研究。我们最近开发了一种FcGammaRllb特异性mAb4F5，并发现在活动期SLE中，FcGammaRllb在淋巴系和髓系细胞中的表达存在差异调节，在B淋巴细胞中FcGammaR11b的表达存在失调。基于这些观察和从小鼠模型中获得的知识，我们假设FcGammaRllb的表达是以组织特异性的方式调节的，FcGammaRllb的异常调节可能与人类狼疮的发病有关。本研究的具体目的是：1)检测FcGammaR11b在淋巴和髓系白细胞以及循环内皮细胞(CECs)中的表达和调控情况，这些细胞与FcGammaR11b的天然基因变异体和体外刺激有关。2)通过对FCGR2B基因的调控元件和组织特异性转录因子的研究，阐明FcGammaR11b调控组织特异性的分子机制。3)通过分析FcGammaR11b在SLE循环髓系和血管内皮细胞中的调节，并与SLE B淋巴细胞中FcGammaR11b的调节异常进行比较，探讨FcGammaR11b在SLE中潜在的组织特异性调节异常。我们将对观察到的SLE B淋巴细胞FcGammaR11b调节失调的分子机制进行剖析。研究FcGammaRllb在SLE中的组织特异性调节和FcGammaRllb的异常调节，不仅有助于阐明维持免疫稳态的机制，而且可能为自身免疫性疾病的靶向治疗提供新的知识。

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.