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

哺乳动物的下肠腔是一个巨大密度的共生微生物菌群定植。单层且相对脆弱的肠上皮形成了肠下层组织的屏障。人们还不太清楚是什么阻止了炎症反应和对肠道细菌的全身免疫反应，以及为什么这些机制在克罗恩病和溃疡性结肠炎等疾病中失效。正如在小鼠中所示，肠道免疫系统持续响应肠道细菌定植，产生大量IgA特异性抗体，IgA分泌穿过上皮，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。在拟议的项目中将解决3个关键问题：(A)在生理条件下，共生细菌在多大程度上通过哪些细胞类型渗透上皮？(B)随后的IgA反应在多大程度上以及如何限制渗透，它是否改变了肠道菌群的组成或分布？(C)导致完全同型特异性IgA诱导的大部分未知的分子机制是什么？

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?