Inhibitory Fcgamma receptors: Role in Autoimmunity

描述（申请人提供）：自身免疫性疾病是一种发病率较高的疾病，其病因和发病机制尚不清楚。自身反应性淋巴细胞启动自身抗体产生的过程，并最终导致免疫复合物的形成。IgG免疫复合物与含有活化基序的Fc γ受体（FcgR）的相互作用引发炎症反应。该途径可以通过抑制性FcgR的结合来抑制。凭借停止细胞活化的能力，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应答性来潜在地改变自身免疫性疾病的发展或进展。FcgRIIB基因的靶向缺失导致小鼠中严重的免疫复合物介导的超敏反应和致命的自身免疫。在人类中尚未报道自身免疫性疾病与抑制性FcgRIIb受体缺乏的关联。在这个提议中，我们提出的证据表明，抑制性FcgRIIb受体的表达和功能是一个高度调节的过程。我们已经鉴定了降低单核细胞和B细胞中FcgRIIb表达的细胞因子。此外，我们已经鉴定了人中抑制性FcgRlIB的启动子区中的新的单核苷酸多态性（SNP）。这些SNP改变B细胞和骨髓细胞中FcgRIIB的转录调节。在初步研究中，我们已经证明了FcgRIIB启动子SNP与系统性红斑狼疮（SLE）的关联。具体目标是：1）表征参与FcgRIIB基因表达调节的获得性因子; 2）表征FcgRIIB结构和功能的遗传改变;和3）评估FcgRIIB作为SLE的候选基因。阐明调控人细胞中FcgRIIb功能表达的获得性和遗传性因子的相对贡献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疗法的发展。

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.