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: 6850789
• 负责人: Hiromi Kubagawa
• 金额: $ 29万
• 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/6850789
• 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定义IGA和IGM最近确定的FC受体的结构/功能关系（FCALPHA/MUR）。预测的fcalpha/mUR糖蛋白的氨基末端的Ig样结构域包含一个序列基序，该基序在各种物种的聚合物Ig受体中保守，并被预测为IgM和IgA的结合位点。 FCALPHA/MUR基因在人类和小鼠的造血（B和单核细胞/巨噬细胞）和非脊髓质（肾脏和肠道）组织中均表达。人类FCALPHA/MUR表达的初步研究表明了一个有趣的细胞分布：扁桃体中卵泡树突状细胞（FDC）出现的生发中心，肾脏近端肾小管上皮细胞中的肾脏和小肠隐窝中的Paneth细胞。与小鼠FCALPHA/MUR不同，人体受体仅由驻留在次级淋巴组织中而不是循环中存在的B细胞表达。在肾脏中发现了一种新型的剪接变体，该变体被预测，该变体可以编码一种可溶性的FCalpha/MUR形式。这些发现导致了以下假设：FCALPHA/MUR起着多种功能作用，具体取决于表达的细胞类型。 FDC上的FCALPHA/MUR可能会捕获IgM或IgA免疫复合物，并将完整的抗原呈现给生发中心的B细胞。 B细胞的FCALPHA/MUR表达可能与细胞活化密切相关。另一方面，肾小管上皮细胞和肠道细胞中的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特定目的进行检验：1）通过使用受体特异性抗体和Ig-凸质确定FCALPHA/MUR的细胞分布和分子性质； 2）将新鉴定的FCalpha/MUR剪接变体定义为一种可溶性形式的受体形式； 3）确定膜结合的FCALPHA/MUR的功能； 4）采用FCALPHA/MIR缺陷小鼠模型来探索FCA/alphar的体内功能。