Mononuclear Phagocyte Function in Immunologic Diseases

单核吞噬细胞在免疫疾病中的功能

• 批准号: 7669272
• 负责人: Robert P. Kimberly
• 金额: $ 30.74万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669272
• 关键词: Acute; Affect; Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen Presentation; Antigens; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Binding Proteins; Biological Models; Biology; Calcium Signaling; Celiac Disease; Cells; Cellular biology; Characteristics; Chimera organism; Cytoplasmic Tail; Data; Dendritic Cells; Dimensions; Disease; Event; Extracellular Domain; FCGR3B gene; Family; Fc Receptor; Genetic Variation; Homeostasis; Host Defense; Human; IgA receptor; IgG Receptors; Immune Complex Diseases; Immune System Diseases; Immune response; Immunobiology; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Inflammation; Inflammatory; Interleukin 2 Receptor Gamma; Interleukin-10; Kidney Diseases; Laboratories; Ligand Binding; Ligands; Modeling; Molecular; Mononuclear; Mus; Pathogenesis; Peptides; Phagocytes; Phenotype; Predisposition; Production; Property; Regulation; Regulatory Element; Research Personnel; Rheumatoid Arthritis; Role; Seminal; Series; Signal Transduction; Structure; System; Therapeutic; Therapeutic antibodies; Vasculitis; Work; antibody-dependent cell cytotoxicity; base; cell type; cytokine; design; genetic variant; in vivo; member; molecular assembly/self assembly; mouse model; neonatal sepsis; novel; programs; receptor; receptor function; response; scaffold; vaccine delivery

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).

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不断扩大，在吞噬细胞、B 细胞和树突状细胞生物学中发挥着重要作用。在人类中，三个高度同源的 IgG 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，多个实验室对小鼠模型的开创性研究表明，伽马链相关激活受体（FcRIa、FcRIII/IV）的缺失可减轻急性和持续性炎症性疾病，而抑制性 FcRllb 受体的缺失则会加剧炎症性疾病。然而，对 FcR 非免疫球蛋白配体和 FcR 多种功能的认识，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且可能更加多样化的作用。我们和其他人已经确定了 FcgR 和 Fc-alphaR 胞外结构域的结构和特性差异，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天然存在的遗传变异来影响功能。虽然这些差异已在二分“激活和抑制”框架的背景下考虑，但一些观察结果表明，还有另一个重要特性，我们假设这些特性是由与 FceRI 共同伽马链相关的“激活”受体的独特胞质结构域序列赋予的。事实上，我们的数据表明独特的细胞质结构域在功能中具有新颖且意想不到的作用，不仅对于 IgG 受体，而且对于 γ 链相关的 IgA 受体。 α链的细胞质结构域不仅充当分子组装的支架，而且充当决定受体启动功能的类型和强度的“分子开关”。因此，本提案的具体目标是： 1.使用一系列α链受体嵌合体来控制EC和TM，以表征来自人γ链相关受体的每个α胞质结构域的独特贡献。 2. 定义γ链相关受体独特的α链胞质结构域结合伙伴并确定调控关键点。 3.确定接头结合蛋白的贡献并比较体内受体嵌合体中人CD64(FcRIa)和CD16(FcRIIIa)的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α细胞质结构域等位基因变体，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（例如类风湿性关节炎、乳糜泻、系统性血管炎）的关联。