Inhibitory Fcgamma receptors: Role in Autoimmunity

描述(申请人提供)：自身免疫性疾病是发病率较高的疾病，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的产生过程，最终导致免疫复合体的形成。Ig G免疫复合物与含有激活基序的Fcγ受体(FcgR)相互作用可启动炎症反应。这一通路可被抑制性FcgRs结合所抑制。抑制性FcgRIIb受体通过影响B细胞或单核巨噬细胞对免疫复合体介导的炎症的反应性，通过停止细胞激活的能力潜在地改变自身免疫性疾病的发生或进展。FcgRIIB基因的靶向缺失会导致严重的免疫复合体介导的超敏反应和致死性自身免疫。自身免疫性疾病与抑制性FcgRllb受体缺陷之间的关系在人类中尚未见报道。在这个建议中，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控的过程。我们已经确定了减少FcgRIIb在单核细胞和B细胞中表达的细胞因子。此外，我们在人类中发现了抑制性FcgRlIB启动子区域的新的单核苷酸多态(SNPs)。这些SNP改变了B细胞和髓系细胞中FcgRIIB的转录调控。在初步研究中，我们证实了FcgRIIB启动子SNPs与系统性红斑狼疮(SLE)的相关性。其具体目的是：1)研究FcgRIIB基因表达的获得性调控因素；2)研究FcgRIIB基因结构和功能的遗传变化；3)评价FcgRIIB基因作为SLE候选基因的可能性。阐明获得性和遗传性因素在调节FcgRIIb功能在人类细胞中表达的相对贡献，将有助于我们对自身免疫性疾病的分子发病机制的理解，并将促进基于机制的治疗的发展。

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.