B7 INTEGRIN DEFICIENCY IMPAIRS B CELL GUT HOMING, DECREASES LUMINAL IGA LEADING TO DYSBIOSIS AND WORSENING OF CROHN’S LIKE MURINE ILEITIS

Abstract BACKGROUND Integrin α4β7 mediates lymphocyte trafficking to the intestinal lamina propria (LP), a process central to gut immune homeostasis. Therapeutic blockade of this pathway by vedolizumab, a monoclonal antibody against α4β7, has proven effective in the treatment of inflammatory bowel disease (IBD). We have shown that IgA-producing B cells rely on β7-dependent homing to migrate to LP, where they mature to professional IgA-producing resident plasma cells to maintain barrier integrity and regulate the microbiota. In previous work, we demonstrated the critical role of the α4β7-MAdCAM-1 pathway for homeostasis between the host and its microbiota during chronic colitis in the IL-10-/- model. Given that homing determinants to the ileum and colon may be only partially overlapping (e.g., CCR9), we investigated how α4β7 contributes to B-cell gut homing, ileitis severity and ileal microbial communities in a model of chronic ileitis (ie, TNFΔARE model). METHODS We generated β7 deficient TNFΔARE mice (TNFΔARE+/- Itgb7-/-) and compared ileitis severity and disease progression with that of β7-sufficient TNFΔARE controls (TNFΔARE+/- Itgb7+/+) using a semi-quantitative histological scoring system. Ileal memory B cells and IgA+ plasma cells were isolated from the LP and quantified by flow cytometry. Fecal IgA levels were determined by ELISA. Stool microbial composition was profiled by 16S rRNA sequencing, and downstream bioinformatic analyses performed in R of TNFΔARE mice, TNFΔARE+/- Itgb7-/- mice compared with that of TNFΔARE+/- IgA-/- mice. RESULTS TNFΔARE+/- Itgb7-/- mice developed worse ileitis across the disease time course compared with TNFΔARE+/- Itgb7+/+ controls (n = 20, p < 0.05). This was accompanied by a marked reduction in ileal lamina propria B cells (n = 10, p < 0.001), particularly IgA+ plasma cells (n = 11, p < 0.05). Consistently, fecal IgA levels were significantly decreased (n = 14, p < 0.0001). Metagenomic analysis revealed distinct alterations in community composition, including separation of groups in principal coordinate analysis (PCoA; n = 12) in which the β7- and IgA-deficient clustered most closely. CONCLUSIONS Itgb7-deficit results in worse ileitis, decreased LP IgA+ antibody secreting cells, (ASC) lower luminal IgA and shifts in microbial communities in stool of TNFΔARE+/- Itgb7-/- mice that recapitulate those of IgA deficiency. Thus, α4β7-MAdCAM-1 interactions are required for ASC homing to ilea, maintenance of luminal IgA and homeostasis between the microbiota and its host.