Structure and Function of an Fc Receptor for IgA and IgM

描述（由申请人提供）：这些研究的总体目标是确定最近发现的IgA和IgM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igg样结构域包含一个序列基序，该序列基序在多种物种的聚合Ig受体中是保守的，并且预计是IgM和IgA的结合位点。Fcalpha/muR基因在人和小鼠的造血（B细胞和单核细胞/巨噬细胞）和非造血（肾和肠）组织中均有表达。对人类Fcalpha/muR表达的初步研究表明了一个有趣的细胞分布：生发中心在扁桃体中出现滤泡树突状细胞（FDC），在肾脏中出现近端小管上皮细胞，在小肠隐窝中出现Paneth细胞。与小鼠的Fcalpha/muR不同，人的受体仅由驻留在次级淋巴组织中的B细胞表达，而不是存在于循环中的B细胞。在肾脏中发现了一种新的剪接变体，该变体预计会编码一种可溶性形式的Fcalpha/muR。这些发现导致了Fcalpha/muR根据表达它的细胞类型发挥多种功能作用的假设。FDC上的Fcalpha/muR可能捕获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Paneth细胞中的Fcalpha/muR可能在抗原和微生物的入口处起保护作用。这些假设将通过以下具体目标进行验证：1)利用受体特异性抗体和igg配体确定Fcalpha/muR的细胞分布和分子性质；2)将新发现的Fcalpha/muR剪接变异体定义为可溶性受体；3)确定膜结合的Fcalpha/muR的功能；4)建立Fca/ mrr缺失小鼠模型，探讨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.