Structure and Function of an Fc Receptor for IgA and IgM

描述（由申请方提供）：这些研究的总体目标是确定最近鉴定的伊加和IgM Fc受体（Fcalpha/muR）的结构/功能关系。在预测的Fcalpha/muR糖蛋白的氨基末端的Ig样结构域包含在各种物种的多聚IG受体中保守的序列基序，并且预测为IgM和伊加的结合位点。Fcalpha/muR基因在人和小鼠的造血（B和单核细胞/巨噬细胞）和非造血（肾和肠）组织中表达。人类Fcalpha/muR表达的初步研究表明了一个有趣的细胞分布：扁桃体中出现滤泡树突状细胞（FDC），肾脏中出现近端肾小管上皮细胞，小肠隐窝中出现潘氏细胞的生发中心。与小鼠Fcalpha/muR不同，人受体仅由存在于次级淋巴组织中的B细胞而不是存在于循环中的那些表达。一种新的剪接变异体，预计编码可溶性形式的Fcalpha/muR已被确定在肾脏。Fcalpha/muR在FDC上可捕获IgM或伊加免疫复合物，并将完整的抗原呈递给生殖中心的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潘氏细胞中的Fcalpha/muR可能在抗原和微生物进入的入口处起保护作用。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-配体确定Fcalpha/muR的细胞分布和分子性质; 2）将新鉴定的Fcalpha/muR剪接变体定义为可溶形式的受体; 3）确定膜结合的Fcalpha/muR的功能;和4）使用Fca/alphaR缺陷小鼠模型来探索Fca/alphaR的体内功能。

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.