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

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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?