Regulation of mucosal IgA and allergic inflammation by intestinal epithelial cells

 描述(由申请人提供)：粘膜表面的上皮细胞是宿主抵抗外源产品和病原体的第一道屏障。肠上皮细胞(IEC)因其在消化和选择性吸收摄入的食物分子中的作用而被广泛研究。IEC产生细胞因子，影响经典抗原提呈细胞和其他天然细胞的分化，从而形成获得性免疫反应。这些细胞还表达聚合免疫球蛋白受体，允许聚合免疫球蛋白在上皮细胞之间运输，并在管腔内以分泌型IgA抗体的形式分泌。然而，IEC在过敏反应中的作用仍然知之甚少，IEC中的特定信号通路如何影响胃肠道的过敏反应，以及如何影响远处粘膜部位的过敏反应，如呼吸道，仍不清楚。我们将阐述这样一个假设，即在肠道上皮细胞中选择先天信号通路可以形成过敏原特异性抗体同型反应，并促进IgA抗体，这可以防止变态反应性炎症的发展，或减少远处变态反应性炎症的程度。利用转基因小鼠和所选先天信号通路的药物抑制剂，我们建议1)解决肠上皮细胞中非规范的NFB信号如何激活 细胞在变态反应性致敏过程中调节适应性免疫反应；2)建立免疫球蛋白A和免疫球蛋白B细胞对抗变态反应性炎症的保护机制。

 DESCRIPTION (provided by applicant): Epithelial cells lining mucosal surfaces represent the first barrier of the host against exogenous products and pathogens. Intestinal epithelial cells (IEC) have been extensively studied for their role in the digestion and selective absorption of ingested food molecules. IEC produce cytokines that influence the differentiation of classical antigen presenting and other innate cells and subsequently, shape adaptive immune responses. These cells also express the receptor for polymeric immunoglobulins, which allows the transport of polymeric IgA across the epithelium and their secretion as secretory IgA antibodies in the lumen. However, the role of IEC in allergic responses remains poorly understood and it remains unclear how specific signaling pathways in IEC affect allergic sensitization in the GI tract and impact allergic responses at distant mucosal sites such as the airways. We will address the overall hypothesis that selected innate signaling pathway in intestinal epithelial cells shape allergen-specific antibody isotype responses and promote IgA antibodies, which can prevent the development, or reduce the magnitude of allergic inflammation at distant sites. Using genetically modified mice and pharmaceutical inhibitors of the selected innate signaling pathway we propose to 1) address how activation of the non-canonical NFB signaling in intestinal epithelial cells regulate adaptive immune response during allergic sensitization; 2) Establish mechanisms of protection against allergic inflammation by IgA and IgA+ B cells.