In humans, celiac disease (CeD) is a T-cell-driven gluten-sensitive enteropathy (GSE) localized to the small bowel (duodenum). The presence of antibodies specific for gluten- and self-antigens are commonly used diagnostic biomarkers of CeD and are considered to play a role in GSE pathogenesis. Previously, we have described an apparent T-cell-mediated GSE in CD19-/- mice, which develop weak and abnormal B cell responses. Here, we expand on this observation and use a mouse model of complete B cell deficiency (JH-/- mice), to show that absence of a humoral immune response also promotes development of a GSE. Furthermore, 16S analysis of microbial communities in the small intestine demonstrates that a gluten-free diet suppresses the expansion of anaerobic bacteria in the small intestine and colonization of the small intestine by a specific pathobiont. Finally, we also observe that SI enteropathy in mice fed a gluten-rich diet is positively correlated with the abundance of several microbial peptidase genes, which supports that bacterial metabolism of gluten may be an important driver of GSE in our model. Collectively, results from our experiments indicate that JH-/- mice will be a useful resource to investigators seeking to empirically delineate the contribution of humoral immunity on GSE pathogenesis, and support the hypothesis that humoral immunity promotes tolerance to gluten.
B-cell-intrinsic major histocompatibility complex class II (MHCII) antigen presentation is central to the development of T-cell-dependent antibody responses. However, the physiological significance of B-cell-intrinsic MHCII signaling during homeostatic conditions and infection are unknown. Here, using a B-cell-intrinsic MHCII knockout mouse model, we demonstrate that B-cell-intrinsic MHCII signaling is important for the development of systemic IgG1 and mucosal, high-affinity IgA responses. We also show that the conditional ablation of MHCII signaling on B cells results in a change in the microbiota composition, exhibiting a significant increase in the mucin-degrading bacteria Akkermansia muciniphila. This change in the microbiome is also associated with elevated bacterial dissemination from the gut into the systemic compartment under homeostatic conditions. Additionally, using a Citrobacter rodentium model of acute gastrointestinal infection, we also demonstrate the relevance of B-cell-intrinsic MHCII signaling in limiting invasion of the systemic compartment by an opportunistic enteric pathogen. Results from these experiments demonstrate that B-cell-intrinsic MHCII signaling is an important factor minimizing the physiological cost of microbial colonization of the gut. Supported by NIH R21AI142409, R01AI155887
The expression of major histocompatibility complex class II (MHCII) molecules is essential for the formation of germinal centers (GC) in lymphoid follicles, which are the primary sites for the generation of T-cell-dependent (TD) high-affinity antibody responses. Gut peyer's patches (PPs) are the dominant peripheral lymphoid tissues that give rise to TD antibody (primarily immunoglobulin A (IgA)) responses generated against the gut microbiota. While it is anticipated, a requirement of B-cell-intrinsic MHCII expression for GC formation has never been formally described. Additionally, while anti-commensal TD IgA responses have been shown to regulate microbiota composition and function, to what degree B-cell-intrinsic MHCII influences this process is also undefined. Here, we use a RAG1−/− adoptive transfer model, where RAG1−/− mice are either reconstituted with naive CD4+ T cells and MHCII+ B cells or naive CD4+ T cells and MHCII−B cells to address these gaps in our knowledge. Results from these experiments demonstrate that B-cell-intrinsic MHCII signaling is a strict requirement for GC-TFH cell development. Consequently, B-cell-intrinsic MHCII signaling promotes the generation of high-affinity anti-commensal IgA responses in the gut, which lead to increased species richness within the fecal but not small intestinal microbial community. Collectively, our data suggest that B-cell-intrinsic MHCII signaling is crucial for the generation of high-affinity anti-commensal IgA responses generated against the gut microbiota, and that this response favors a more diverse bacterial community.
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