Structure and Function of an Fc Receptor for IgA and IgM

描述(申请人提供)：这些研究的总体目标是确定最近发现的免疫球蛋白A和免疫球蛋白M的Fc受体(Fcalpha/MUR)的结构/功能关系。预测的Fcalpha/MUR糖蛋白氨基末端的Ig样结构域包含一个序列基序，该基序在不同物种的聚合Ig受体中保守，被预测为IgM和IgA的结合部位。Fcalpha/mur基因在人类和小鼠的造血系(B细胞和单核/巨噬细胞)和非造血系(肾和肠)组织中都有表达。对Fcalpha/MUR在人类中表达的初步研究表明，在人类中有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，肾脏中的近端肾小管上皮细胞和小肠隐窝中的Paneth细胞。与小鼠Fcalpha/MUR不同，人类受体只由次级淋巴组织中的B细胞表达，而不是循环中的B细胞。在肾脏中发现了一种新的剪接变异体，被预测编码一种可溶性形式的Fcalpha/mur。这些发现导致了一种假设，即Fcalpha/MUR根据表达它的细胞类型而发挥多种功能。FDC上的Fcalpha/MUR可捕获IgM或IgA免疫复合物，并将完整的抗原呈递给生发中心的B细胞。B细胞表达Fcalpha/mur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Paneth细胞中的Fcalpha/MUR可能在抗原和微生物进入的入口起到保护作用。这些假说将通过下列具体目标得到验证：1)通过使用受体特异性抗体和Ig配体来确定Fcalpha/MUR的细胞分布和分子性质；2)将新发现的Fcalpha/MUR剪接变体定义为一种可溶形式的受体；3)确定膜结合的Fcalpha/MUR的功能；以及4)利用Fcalpha/MUR缺陷小鼠模型来探索FCA/AlphaR在体内的功能。

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.