Inhibitory Fcgamma receptors: Role in Autoimmunity

描述（由申请人提供）：自身免疫性疾病是一种发病率高，病因和发病机制尚不清楚的疾病。自身反应性淋巴细胞启动自身抗体的产生过程，并最终导致免疫复合物的形成。IgG免疫复合物与含有激活基序的Fc γ受体（FcgR）相互作用引发炎症反应。这一途径可被抑制性fcgr的结合所抑制。由于抑制细胞活化的能力，抑制性FcgRIIb受体可以通过影响B细胞或单核吞噬细胞对免疫复合物介导的炎症的反应性，潜在地改变自身免疫性疾病的发生或进展。靶向删除FcgRIIB基因可导致小鼠严重的免疫复合物介导的超敏反应和致命的自身免疫。自身免疫性疾病与抑制FcgRllb受体缺乏的关联尚未在人类中报道。在本提案中，我们提出证据表明，抑制性FcgRIIb受体的表达和功能是一个高度调控的过程。我们已经确定了在单核细胞和B细胞中降低FcgRIIb表达的细胞因子。此外，我们已经在人类的抑制FcgRlIB的启动子区域发现了新的单核苷酸多态性（snp）。这些snp改变了FcgRIIB在B细胞和髓细胞中的转录调控。在一项初步研究中，我们证实了FcgRIIB启动子snp与系统性红斑狼疮（SLE）的关联。具体目的是：1)表征参与调控FcgRIIB基因表达的获得性因子；2)表征FcgRIIB结构和功能的遗传改变；3)评估FcgRIIB作为SLE的候选基因。阐明在人类细胞中调控FcgRIIb功能表达的获得性因素和遗传因素的相对作用，将促进我们对自身免疫性疾病分子发病机制的理解，并将促进基于机制的治疗方法的发展。

DESCRIPTION (provided by applicant): Autoimmune diseases are diseases with high morbidity, whose etiology and pathogenesis are poorly understood. Self-reactive lymphocytes initiate the process of autoantibody production and ultimately lead to formation of immune complexes. Interaction of IgG immune complexes with Fc gamma receptors (FcgR) containing an activation motif initiates an inflammatory response. This pathway can be inhibited by colligation of inhibitory FcgRs. By virtue of the ability to cease cell activation, inhibitory FcgRIIb receptors can potentially modify the development or progression of autoimmune diseases by influencing either B cell or mononuclear phagocytes' responsiveness to immune complex-mediated inflammation. Targeted deletion of the FcgRIIB gene leads to severe immune complex-mediated hypersensitivity reactions and fatal autoimmunity in mice. Association of autoimmune diseases and deficiency of inhibitory FcgRllb receptors has not been reported in humans. In this proposal we present evidence that the expression and function of inhibitory FcgRIIb receptors is a highly regulated process. We have identified cytokines that reduce the expression of FcgRIIb in monocytes and B cells. In addition, we have identified novel single nucleotide polymorphisms (SNPs) in the promoter region of the inhibitory FcgRlIB in humans. These SNPs alter the transcriptional regulation of FcgRIIB in B cells and myeloid cells. In a preliminary study we have demonstrated association of FcgRIIB promoter SNPs with systemic lupus erythematosus (SLE). The specific aims are: l) to characterize acquired factors involved in the regulation of FcgRIIB gene expression; 2) to characterize the genetic alterations of FcgRIIB structure and function; and 3) to evaluate FcgRIIB as a candidate gene for SLE. Elucidating the relative contribution of acquired and genetic factors that regulate the expression of FcgRIIb function in human cells will advance our understanding of the molecular pathogenesis of autoimmune diseases and will facilitate the development of mechanism-based therapies.