Molekulare Mechanismen und physiologische Funktion der durch kommensale Bakterien induzierten intestinalen IgA-Immunantwort

哺乳动物的肠腔内分布着密度极大的共生微生物菌群。单层和相对脆弱的肠道上皮形成了对下面的肠道组织的屏障。目前尚不清楚是什么阻止了对肠道细菌的炎症反应和系统免疫反应，以及为什么这些机制在克罗恩·S病和溃疡性结肠炎等疾病中崩溃。如小鼠的实验所示，肠道免疫系统持续对肠道细菌的定植做出反应，产生大量的IgA特异性抗体，并跨上皮分泌IgA，这些上皮细胞仍然局限于肠粘膜。这种免疫反应不同于经典的体液免疫反应。3个关键问题将在拟议的项目中解决：(A)在生理条件下，共生细菌在多大程度上和通过哪些细胞类型渗透上皮细胞？(B)随后的免疫球蛋白A反应在多大程度上和如何限制穿透，是否改变肠道菌群的组成或分布？(C)导致完全同型特异性IgA诱导的分子机制是什么？

The mammalian lower intestinal lumen is colonized with a commensal microbial flora of enormous density. The single-layered and relatively fragile intestinal epithelium forms the barrier to the underlying intestinal tissue. It is poorly understood what prevents inflammatory reactions and systemic immune responses to intestinal bacteria and why such mechanisms breakdown in diseases like Crohn¿s disease and ulcerative colitis. As shown in mice, the intestinal immune system continuously responds to intestinal bacterial colonization with a massive IgA-specific antibody production and IgA secretion across the epithelium that remains restricted to the intestinal mucosa. This immune response is distinct from classical humoral immune responses. 3 key questions will be addressed in the proposed project: (A) to which extent and through which cell types do commensal bacteria penetrate the epithelium under physiologic condidtions? (B) To which extent and how does the ensuing IgA response limit penetration and does it change composition or distribution of the intestinal flora? (C) What are the largely unknown molecular mechanisms leading to the entirely isotype-specific IgA induction?