Increased intestinal permeability results in B/T cell mediated responses that protect from development of colitis

Abstract

Junctional Adhesion Molecule A (JAM‐A) is a tight junction protein known to regulate intestinal epithelial permeability and leukocyte migration. We have previously shown that JAM‐A−/− mice have increased colonic permeability and B cell lymphoid hyperplasia but do not develop spontaneous colitis. We also observed that JAM‐A−/− mice have increased levels of serum and fecal IgA. To study the role of lymphocytic responses to increased colonic permeability, we generated B/T cell deficient (JAM‐A−/− × RAG1−/−) double knockout mice. JAM‐A−/− × RAG1−/− were more susceptible to dextran sulfate sodium (DSS) induced colitis, manifested by premature mortality and greater body weight loss than JAM‐A+/+ mice. In addition, JAM‐A−/− and JAM‐A−/− × RAG1−/− mice showed increased bacterial translocation to secondary lymphoid organs and colonic submucosa. Broad‐spectrum antibiotic treatment of JAM‐A−/− × RAG1−/− mice significantly reduced disease progression. These data suggest that colonic B cell hyperplasia and increased IgA production serve as protective responses to enhanced translocation of microbial products under conditions of increased mucosal permeability. Furthermore, these findings show that dysfunctional adaptive immunity predisposes to pathologic gut inflammation particularly under conditions of increased colonic permeability. This work is supported by NIH grants DK061379, DK59888 and AA017870.