Mononuclear Phagocyte Function in Immunologic Diseases

描述(由申请人提供)：我们对Fc受体在免疫生物学中的作用的认识继续扩大，在吞噬细胞、B细胞和树突状细胞生物学中发挥重要作用。在人类中，三个高度同源的免疫球蛋白受体家族(FcRI、FcRII、FcRIa)的成员通常被概念化为“激活”或“抑制”受体。事实上，在几个实验室的小鼠模型的开创性工作中，已经表明缺乏伽马链相关激活受体(FcRIa，FcRIII/IV)可以缓解急性和持续性炎症疾病，而缺乏抑制性FcR11b受体会加剧炎症疾病。然而，对FCR的非免疫球蛋白配体和FCR的多种功能的认识，强调了这些受体在机体内稳态、传入宿主免疫反应和传出炎症细胞程序中复杂的、可能更多样化的作用。我们和其他人已经确定了FcgR和Fc-alphaR胞外结构域的结构和性质的差异，这些差异通过不同的亲和力、Ig亚类的不同结合以及调节这些性质的自然发生的遗传变异来影响功能。虽然这些差异已被考虑在二分的“激活和抑制”框架的背景下，一些观察表明，还有另一个重要性质的维度，我们假设是由与FceRI共同伽马链相关的“激活”受体的独特细胞质结构域序列赋予的。事实上，我们的数据表明了独特的细胞质结构域在功能上的一个新的和意想不到的作用，不仅是对免疫球蛋白受体，而且对与伽马链相关的IgA受体也是如此。α链的细胞质结构域不仅是分子组装的支架，而且是决定受体启动功能的类型和强度的“分子开关”。因此，这一建议的具体目的是：1.使用一系列阿尔法链受体嵌合体来控制EC和TM，以表征每个α细胞质结构域在人类伽马链相关受体中的独特贡献。2.明确γ链相关受体的独特的α链胞质结构域结合伙伴，确定调控的关键点。3.确定接头结合蛋白的作用，比较人CD64(FcRIa)和CD16(FcR111a)的α细胞质结构域在体内受体嵌合体中的差异功能。4.鉴定人类唯一的γ链相关受体α胞浆区等位基因变异，确定其功能特征，并建立其与宿主防御和自身免疫性疾病(如类风湿性关节炎、乳糜泻、全身性血管炎)的关系。

DESCRIPTION (provided by applicant): Our appreciation of the role of Fc receptors in immunobiology continues to expand with important roles in phagocytes, B cells and dendritic cell biology. In humans, members of the three families of highly homologous IgG receptors (FcRI, FcRII, FcRIa) have typically been conceptualized as "activating" or "inhibitory" receptors. Indeed, in seminal work in mouse models from several laboratories, it has been shown that the absence of gamma-chain-associated activating receptors (FcRIa, FcRIII/IV) mitigates both acute and sustained inflammatory disease while the absence of the inhibitory FcRllb receptor exacerbates inflammatory disease. However, the recognition of non-immunoglobulin ligands for FcR and of the multiple functions for FcR, underscore intricate, and perhaps more diverse, roles for these receptors in organismal homeostasis, in the afferent host immune response, and in efferent inflammatory cell programs. We, and others, have identified differences in the structure and properties of the extracellular domains of both FcgR and Fc-alphaR which influence function through different affinities, differential binding of Ig subclasses and naturally occurring genetic variants which modulate these properties. While these differences have been considered in the context of the dichotomous "activating and inhibitory" framework, several observations indicate that there is another dimension of important properties which we hypothesize is conferred by the unique cytoplasmic domain sequences of the "activating" receptors associated with the FceRI common gamma-chain. Indeed, our data indicate a novel and unanticipated role in function for the unique cytoplasmic domains, not only for IgG receptors but also for the gamma-chain-associated IgA receptor. The cytoplasmic domains of the alpha-chains serve not only as a scaffold for molecular assemblies but also act as a "molecular switch" determining both the type and intensity of receptor-initiated function. Accordingly, the specific aims of this proposal are: 1. using a series of alpha-chain receptor chimeras to control for EC and TM, to characterize the unique contributions of each alpha cytoplasmic domain from the human gamma-chain-associated receptors. 2. to define the unique alpha-chain cytoplasmic domain binding partners of gamma-chain-associated receptors and identify the key points of regulation. 3. to establish the contributions of adaptor binding proteins and compare-the differential function of the alpha cytoplasmic domains for human CD64 (FcRIa) and CD16 (FcRllla) in receptor chimeras in vivo. 4. to identify unique human alpha cytoplasmic domain allelic variants for the gamma-chain associated receptors, to determine their functional characteristics and to establish their association with altered host defense and autoimmune disease (eg, rheumatoid arthritis, celiac disease, systemic vasculitis).