Structure and Function of an Fc Receptor for IgA and IgM

IgA 和 IgM Fc 受体的结构和功能

• 批准号: 7018461
• 负责人: Hiromi Kubagawa
• 金额: $ 28.32万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7018461
• 关键词: B lymphocyte; antibody receptor; antibody specificity; antigen presentation; binding sites; cell population study; clinical research; dendritic cells; gene expression; gene targeting; genetic models; genetically modified animals; human subject; immune response; immunoglobulin A; immunoglobulin M; laboratory mouse; laboratory rabbit; messenger RNA; protein quantitation /detection; protein structure function; receptor mediated endocytosis; solubility; species difference; transfection

DESCRIPTION (provided by applicant): The overall goal of these studies is to define the structure/function relationship of a recently identified Fc receptor for IgA and IgM (Fcalpha/muR). The Ig-like domain at the amino terminus of the predicted Fcalpha/muR glycoprotein contains a sequence motif that is conserved in the polymeric Ig receptor of various species and is predicted to be the binding site for IgM and IgA. The Fcalpha/muR gene is expressed in both hematopoietic (B and monocyte/macrophages) and non-hematopoietic (kidney and intestine) tissues in both humans and mice. Preliminary studies of Fcalpha/muR expression in humans indicate an interesting cellular distribution: germinal centers with the appearance of follicular dendritic cells (FDC) in tonsil, proximal tubular epithelial cells in kidney and Paneth cells in small intestinal crypts. Unlike the mouse Fcalpha/muR, the human receptor is expressed only by the B cells that reside in secondary lymphoid tissues rather than those present in the circulation. A novel splice variant that is predicted to encode a soluble form of Fcalpha/muR has been identified in the kidney. These findings have led to the hypothesis that Fcalpha/muR plays multiple functional roles depending upon the cell types expressing it. Fcalpha/muR on FDC may trap IgM or IgA immune complexes and present the intact antigens to B cells in germinal centers. Fcalpha/muR expression by B cells may be closely linked with cellular activation. On the other hand, Fcalpha/muR in renal tubular epithelial cells and intestinal Paneth cells may play a protective role at portals of entry for antigens and microorganisms. These hypotheses will be tested through the following Specific Aims: 1) Determine the cellular distribution and molecular nature of Fcalpha/muR by using receptor-specific antibodies and Ig-ligands; 2) Define the newly identified Fcalpha/muR splice variant as a soluble form of receptor; 3) Determine the function of the membrane-bound Fcalpha/muR; and 4) Employ an Fcalpha/muR-deficient mouse model to explore the in vivo function of the Fca/alphaR.

描述（由申请人提供）：这些研究的总体目标是确定最近鉴定的 IgA 和 IgM Fc 受体 (Fcalpha/muR) 的结构/功能关系。预测的 Fcα/muR 糖蛋白氨基末端的 Ig 样结构域包含在不同物种的聚合 Ig 受体中保守的序列基序，并预测为 IgM 和 IgA 的结合位点。 Fcalpha/muR 基因在人和小鼠的造血组织（B 细胞和单核细胞/巨噬细胞）和非造血组织（肾和肠）中表达。对人类 Fcalpha/muR 表达的初步研究表明了一种有趣的细胞分布：扁桃体中出现滤泡树突状细胞 (FDC) 的生发中心、肾脏中的近端管状上皮细胞和小肠隐窝中的潘氏细胞。与小鼠 Fcalpha/muR 不同，人类受体仅由次级淋巴组织中的 B 细胞表达，而不是循环中的 B 细胞表达。已在肾脏中鉴定出一种新的剪接变体，预计该变体可编码可溶形式的 Fcalpha/muR。这些发现导致了这样的假设：Fcalpha/muR 根据表达它的细胞类型发挥多种功能作用。 FDC 上的 Fcalpha/muR 可能捕获 IgM 或 IgA 免疫复合物，并将完整抗原呈递给生发中心的 B 细胞。 B 细胞的 Fcalpha/muR 表达可能与细胞激活密切相关。另一方面，肾小管上皮细胞和肠潘氏细胞中的Fcalpha/muR可能在抗原和微生物的入口处发挥保护作用。这些假设将通过以下具体目标进行检验： 1) 使用受体特异性抗体和 Ig 配体确定 Fcalpha/muR 的细胞分布和分子性质； 2) 将新鉴定的Fcalpha/muR剪接变体定义为受体的可溶形式； 3)确定膜结合的Fcalpha/muR的功能； 4) 采用Fcalpha/muR缺陷小鼠模型来探索Fca/alphaR的体内功能。