Mononuclear Phagocyte Function in Immunologic Diseases

单核吞噬细胞在免疫疾病中的功能

• 批准号: 6662704
• 负责人: Robert P. Kimberly
• 金额: $ 43.27万
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6662704
• 关键词: alleles; antibody receptor; biological signal transduction; chemical association; clinical research; cytokine; cytoplasm; disease /disorder model; disease /disorder proneness /risk; genetic polymorphism; human subject; immune complex diseases; immunogenetics; immunoglobulin structure; immunopathology; inflammation; laboratory mouse; laboratory rabbit; pathologic process; phagocytes; polymerase chain reaction; protein isoforms; protein structure function; receptor expression; systemic lupus erythematosus

DESCRIPTION (provided by applicant): Recently, our appreciation of the role of Fcgamma receptors in immunobiology has expanded substantially. The recognition that there are also non-Ig ligands for FcgammaR and that there are multiple functions for the Fcgamma underscores a role for these receptors in immune system homeostasis and in modulation of the antigen-driven immune repertoire, as well as in efferent inflammatory cell programs. Three observations highlights this perspective: First, FcgammaRIa and FcgammaRIIa are recognized as the human receptors for CRP, a critical opsonin for the innate immune system. Second, the presentation of antigen in the context of antibody amplifies the host immune response by >100=fold, a response abrogated in FcgammaRI and FcgammaRIII knock-out mice. Third, FcgammaRIa preferentially stimulates IL-10 production and down regulates inflammation compared the other "activating" receptor in mouse, FcgammaRIIIa although both receptors use the same gamma-chain for their tyrosine (ITAM)-based signaling. Additional observations provide further indications that important biological properties are not captured by the dichotomous "activating and inhibitory" receptor framework: First, the role(s) of the alpha-chain cytoplasmic (CY) domain has now been established for cytokine production. Second, the observations that the alpha CY domain modulates both tyrosine phosphorylation (pY) and antigen presentation suggests a basis for the special role of the FcgammaRI in response and response amplification to antigen. Our data now indicate a novel and unanticipated role in function for the unique CY domains of the ligand-binding alpha-chains which lack pY signaling motifs. Accordingly, the specific aims of this proposal are: to define the unique alpha-chain CY domain binding partners for the gamma-chain-associated FcgammaRia and to define their contributions to early signaling events, to gene transcription and to antigen presentation. to define the unique alpha-chain CY domain binding partners of other gamma-chain-associated receptors (FcgammaRIIIa, FcalphaRia, ILT/LIR) and, through analysis of a series of alpha-chain CY chimeras, to characterize the unique contributions of each alpha-chain CY domain; to identify unique human alpha-chain CY domain allelic variants for the gamma-chain associated receptors, to determine their functional characteristics and to establish their association with altered host defense and immune disease (e.g., RA, SLE, IgA nephropathy). Understanding the unique properties of the CY will enable such unique properties to be harnessed to therapeutic advantage.

描述（由申请人提供）：最近，我们对 免疫生物学中的FCGAMMA受体大大扩展。认可 fcgammar也有非gig配体，并且有多个配体 Fcgamma的功能强调了这些受体在免疫中的作用 系统稳态和调节抗原驱动的免疫曲目， 以及传出的炎症细胞程序。三个观察结果 强调了这一观点： 首先，Fcgammaria和Fcgammariia被认为是人类受体 CRP，对先天免疫系统的关键调整。 其次，在抗体的背景下呈现抗原会放大 宿主免疫反应由> 100 =折叠，在fcgammari中废除的反应， Fcgammariii敲除小鼠。 第三，FCGammaria优先刺激IL-10的产生和下降调节 炎症比较了小鼠fcgammariiia中的其他“激活”受体 尽管两个受体都使用相同的伽马链作为酪氨酸 （ITAM）基于信号。 其他观察结果提供了进一步的迹象表明重要的生物学 二分法“激活和抑制”不会捕获特性 受体框架： 首先，α-链细胞质（CY）结构域的作用已已 建立用于细胞因子的生产。 其次，观察到αCy域调节两个酪氨酸的观察 磷酸化（PY）和抗原呈递提出了特殊的基础 Fcgammari在对抗原的响应和反应扩增中的作用。 我们的数据现在表明了独特的功能中新颖而意外的作用 缺乏PY信号基序的配体结合α链的CY域。 因此，该提案的具体目的是： 定义独特的alpha链CY域绑定伙伴 与伽马链相关的FCGammaria，并定义它们对早期的贡献 信号事件，基因转录和抗原表现。定义 其他独特的alpha链CY域约束伙伴 γ链相关受体（Fcgammariiia，fcalpharia，iLT/LIR），以及 通过分析一系列α-链Cy Chimeras，以表征 每个α-链CY域的独特贡献；识别独特的人 伽马链相关的α链CY域等位基因变体 受体，确定其功能特征并确定其功能特征 与改变的宿主防御和免疫疾病的关联（例如RA，SLE，IGA 肾病）。 了解CY的独特特性将使如此独特 要利用具有治疗优势的特性。