title: Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis.
abstract: Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r(-/-)Rag1(-/-) mice to acute colitis. Although negligible contributions of adaptive immunity in F11r(+/+)Rag1(-/-) mice were observed, F11r(-/-)Rag1(-/-) mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4(+) T cells in F11r(-/-) mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4(+) T cells and TGF-β. Absence of IgA in F11r(+/+)Igha(-/-) mice did not affect disease, whereas F11r(-/-)Igha(-/-) mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Manirath
authors.initials: M
authors.lastname: Khounlotham
authors.forename: Wooki
authors.initials: W
authors.lastname: Kim
authors.forename: Eric
authors.initials: E
authors.lastname: Peatman
authors.forename: Porfirio
authors.initials: P
authors.lastname: Nava
authors.forename: Oscar
authors.initials: O
authors.lastname: Medina-Contreras
authors.forename: Caroline
authors.initials: C
authors.lastname: Addis
authors.forename: Stefan
authors.initials: S
authors.lastname: Koch
authors.forename: Benedicte
authors.initials: B
authors.lastname: Fournier
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Denning
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018988:Bacterial Translocation / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D016264:Dextran Sulfate; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; C498686:F11r protein, mouse; D018398:Homeodomain Proteins; D007070:Immunoglobulin A; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C064658:RAG-1 protein; D016264:Dextran Sulfate