Studies on the freme-work of mucosal immunity by the functional analysis of novel cadherin family molecule

我们报道了一种新的钙粘蛋白家族分子BILL-钙粘蛋白（cadherin-17），它表达于B细胞上，其表达在B细胞发育和分化过程中受到时空调控。BILL-钙粘蛋白在肠、鼻粘膜和肺等粘膜组织中也有选择性表达，提示B细胞系统与粘膜免疫之间存在未知的联系。我们用BILL-钙粘蛋白基因缺陷的小鼠分析了BILL-钙粘蛋白的功能。BILL-钙粘蛋白缺陷型小鼠具有以下表型。（1）骨髓中的前B细胞群增加约两倍。（2）脾脏生发中心（GC）体积明显缩小。（3）边缘带（MZ）结构受损。（4）腹腔内B1细胞群受损。（5）肠固有层内伊加^+ B细胞定位受损。（6）对T细胞非依赖性抗原的抗体应答消失。（7）T ...更多信息 对鼠伤寒沙门氏菌感染的敏感性显著降低。这些结果表明BILL-钙粘蛋白参与了B淋巴细胞的发育和功能，特别是在B1亚群中。此外，BILL-钙粘蛋白表达于肠上皮细胞表面，与鼠伤寒沙门氏菌的感染机制密切相关，BILL-钙粘蛋白也以含有替代轻链（VpreB/λ5）的分子复合物形式表达于pro-B细胞表面。已知替代轻链在早期B细胞发育中起关键作用。我们分析了替代轻链功能的结构基础，这可能也是BILL-钙粘蛋白与替代轻链相互作用的原因。我们制备了一系列突变替代轻链组分，其中非免疫球蛋白结构域部分的几个氨基酸被取代。对突变型前B细胞受体的功能分析表明，位于λ5组分非免疫球蛋白结构域的进化上保守的β-淀粉样蛋白阵列发挥配体非依赖性的自主受体激活作用，提示β-淀粉样蛋白阵列是使B细胞不依赖微环境即细胞自主分化的自交联基序。少

We have reported a novel cadherin-family molecule, BILL-cadherin (cadherin-17), which is expressed on the B cells and its expression is spatio-temporally regulated in the course of B cell development and differentiation. BILL-cadherin is also selectively expressed in the mucosal tissues, such as intestine, nasal mucosa and lung, indicating the existence of unknown fame-work which connects B-lymhocyte system and mucosal immunity. We analysed the function of BILL-cadherin by using the mice deficient in the corresponding gene. The BILL-cadherin deficient mouse has the following phenotypes.(1)The pro-B cell population is increased about two-fold in bone marrow. (2)The size of germinal centers(GC) in spleen is significantly reduced. (3)The structure of marginal zone(MZ) is impaired. (4)The B1 population in peritoneal cavity is impaired (5)The localization of IgA^+ B cells in the intestinal lamina propria is impaired. (6)The antibody response against T-indepedndent antigen is abrogated. (7)T … More he sensitivity to Salmonella typhimurium infection is significantly desensitized. These results suggest that BILL-cadherin is involved in B-lymphocyte development and function especially in B1-subset. In addition, BILL-cadherin expressed on the intestinal epithelium is most likely involved in the mechanism of Salmonella typhmurium infection.BILL-cadherin is also expressed on the surface of pro-B cells as a molecular complex containing surrogate light chain (VpreB/λ5). The surrogate light chain is known to play the crucial roles in early B-cell development. We analysed the structural basis of the functions of surrogate light chain which might also responsible for the interaction between BILL-cadherin and the surrogate light chain. We made the series of mutant surrogate light chain components in which several amino-acids of nonimmunoglobulin domain part were substituted. The functional analyses of the mutant pre-B cell receptor indicated that the array of evolutionally conserved arginins located in nonimmunoglobulin domain of λ5 component exerts the ligand-independent, autonomous receptor activation, suggesting that the arginin-array in the nonimmunoglobulin domain is the self-crosslinking motif which allow B cells to differentiate independent of microenvironment, namely cell-autonomously. Less