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IgG受体家族成员（FcRI, FcRII, FcRIa）通常被定义为“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γ链相关激活受体（FcRIa, FcRIII/IV）的缺失减轻了急性和持续性炎症性疾病，而抑制性FcRllb受体的缺失加剧了炎症性疾病。然而，对FcR的非免疫球蛋白配体和FcR的多种功能的识别，强调了这些受体在机体稳态、传入宿主免疫反应和传出炎症细胞程序中的复杂的、可能更多样化的作用。我们和其他人已经确定了FcgR和Fc-alphaR的细胞外结构域的结构和特性的差异，这些差异通过不同的亲和力、Ig亚类的差异结合和调节这些特性的自然发生的遗传变异来影响功能。虽然这些差异是在“激活和抑制”的二分框架下考虑的，但一些观察表明，我们假设与FceRI共同γ链相关的“激活”受体的独特细胞质结构域序列赋予了另一个重要特性的维度。事实上，我们的数据表明，不仅对IgG受体，而且对γ链相关的IgA受体，独特的细胞质结构域在功能中具有新颖和意想不到的作用。α -链的细胞质结构域不仅作为分子组装的支架，而且作为决定受体启动功能的类型和强度的“分子开关”。因此，这项建议的具体目的是：使用一系列α链受体嵌合体来控制EC和TM，以表征人类γ链相关受体的每个α细胞质结构域的独特贡献。2. 定义γ链相关受体独特的α链细胞质结构域结合伙伴，并确定其调控的关键点。3. 建立接头结合蛋白的作用，并比较人CD64 （FcRIa）和CD16 （FcRllla）在体内受体嵌合体中α细胞质结构域的差异功能。4. 鉴定γ链相关受体的独特人类α细胞质结构域等位基因变异，确定其功能特征，并确定其与宿主防御改变和自身免疫性疾病（如类风湿关节炎、乳糜泻、全身性血管炎）的关联。

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).