FcgRIIB links CRP signals with ITGAM functions: a G x G x G model of SLE.

描述(申请人提供)：研究表明，CRP、FCGR2B和ITGAM基因的微小变异与系统性红斑狼疮(SLE)有关。机制研究表明，这些基因的蛋白质产物(分别是血液蛋白C反应蛋白、免疫受体Fc3RIIB和黏附分子/补体受体整合素1M)可以三方相互作用来调节树突状细胞(DC)的活性，树突状细胞的功能障碍可以促进自身免疫。这为探索复杂疾病的基因x基因模型提供了一个独特的机会，即Fc3RIIB是否在SLE中将CRP信号与ITGAM功能联系起来？事实上，从小鼠模型中获得的令人信服的体内数据已经证实：(I)人CRP转基因小鼠免受狼疮的发展，(Ii)Fc3RIIB缺陷的小鼠容易发生狼疮，(Iii)ITGAM缺乏会加速狼疮的发生和恶化小鼠的病程，并且体外支持的数据已经证实(Iv)CRP与Fc3RIIB结合，(V)Fc3RIIB的连接导致树突状细胞上ITGAM的表达上调。CRP、FCGR2B和ITGAM基因变异与SLE之间的特殊统计关联，在小鼠模型中观察到的这些基因/基因产物的刺激性生物学，以及体外机制相互作用的证据，都表明CRP、Fc3RIIB和ITGAM关联改变自身免疫的发生和/或发展的可能性。我们假设CRPxFCGR2BxITGAM途径在体内起作用，抑制DC的激活状态并促进免疫耐受，因此，干扰这一途径的一个或多个基因的变异遗传增加了SLE的风险。在这个项目中，我们将使用高通量体外试验和转基因小鼠方法，将FCGR2B表达的遗传变异与：(I)血液中CRP的遗传/环境变异，(Ii)ITGAM功能，以及(Iii)SLE风险和因果关系联系起来。我们可以接触到一大批健康的和受系统性红斑狼疮影响的人，以及确保验证这一三基因模型是可行的并有可能成功所需的适当的临床和基础研究核心设施。我们已经组建了一个独特的研究团队，他们将把他们在CRP、Fc3RIIB和ITGAM生物学、炎症和自身免疫以及功能基因组学和转基因方面的综合专业知识同时用于解决这个问题。在人类系统中的研究将在体外调查选定的FCGR2B变体对DC的CRP反应性的功能后果及其影响ITGAM介导的细胞事件的能力，而在小鼠系统中的研究将验证人类FCGR2B表达在DC介导的免疫耐受中的重要性。成功完成我们的目标将大大增加我们对SLE易感性及其临床谱的了解。 与公共卫生相关：每年都有越来越多新的和潜在重要的基因变异被发现，它们与许多常见的复杂疾病有关，但除非我们更好地了解这些与疾病相关的基因变异的功能，并了解它们如何导致和/或导致疾病，否则我们将无法将日益增长的基因数据与公共健康联系起来。在我们的项目中，我们希望建立三个基因(CRP、FCGR2B和ITGAM基因)与系统性红斑狼疮相关的生物学原因。如果我们能够破译这三个基因与狼疮相关的遗传证据的生物学原因，那么我们就可以更好地预测谁可能会患上这种疾病，并更好地治疗那些已经患有这种疾病的人。

DESCRIPTION (provided by applicant): Studies show that small variations in the CRP, FCGR2B, and ITGAM genes are associated with systemic lupus erythematosus (SLE). Mechanistic studies suggest the protein products of these genes (the blood protein C-reactive protein, the immunoreceptor Fc3RIIB, and the adhesion molecule/complement receptor integrin 1M, respectively) can interact in a tripartite fashion to modulate the activity of dendritic cells (DC), a cell type whose dysfunction can promote autoimmunity. This presents a unique opportunity to explore a gene x gene x gene model of a complex disease, i.e. does Fc3RIIB link CRP signals with ITGAM functions in SLE? Indeed, compelling in vivo data obtained from mouse models have established that (i) human CRP transgenic mice are protected from development of lupus, (ii) Fc3RIIB deficient mice are prone to developing lupus, and (iii) ITGAM deficiency hastens the onset and worsens the course of lupus in mice, and supporting in vitro data have established that (iv) CRP binds to Fc3RIIB and (v) ligation of Fc3RIIB leads to upregulation of ITGAM expression on DCs. The exceptional statistical association between CRP, FCGR2B, and ITGAM genetic variation and SLE, the provocative biology of these genes/gene products observed in mouse models, and the in vitro evidence for mechanistic interaction all point to the likelihood that CRP, Fc3RIIB, and ITGAM associate to alter the onset and/or development of autoimmunity. We hypothesize that a CRPxFCGR2BxITGAM pathway operates in vivo that dampens the activation state of DCs and fosters immune tolerance, such that inheritance of variants of one or more of these genes that perturbs this pathway increases SLE risk. In this project we will use high-throughput in vitro tests and transgenic mouse approaches to relate genetic variation in FCGR2B expression to: (i) genetic/environmental variation in blood CRP, (ii) ITGAM function, and (iii) SLE risk and causality. We have access to a large group of healthy and SLE affected people and the appropriate clinical and basic research core facilities needed to ensure that validation of this three-gene model is feasible and likely to succeed. We have assembled a unique team of investigators who will bring their combined expertise in CRP, Fc3RIIB, and ITGAM biology, inflammation and autoimmunity, and functional genomics and transgenics simultaneously to bear on the problem. Studies in the human system will investigate in vitro functional consequences of select FCGR2B variants on CRP responsiveness of DCs and their ability to effect ITGAM-mediated cellular events, and studies in the mouse system will be performed to verify the importance of human FCGR2B expression on DC mediated immune tolerance. Successful completion of our goals will add significantly to our understanding of SLE susceptibility and its clinical spectrum. PUBLIC HEALTH RELEVANCE: Each year more and more new and potentially important gene variants are discovered that are implicated in many common complex diseases, but until we understand better the function of these disease associated gene variants, and learn how they contribute to and/or cause disease, we will be unable to relate the growing genetic data to public health. In our project we hope to establish the biological cause of association of three genes (the CRP, FCGR2B, and ITGAM genes) to systemic lupus erythematosus. If we can decipher the biological reasons for the genetic evidence of association of these 3 genes to lupus, then we can better predict who might develop the disease, and better treat those that already have the disease.