title: Sensitization to gliadin induces moderate enteropathy and insulitis in nonobese diabetic-DQ8 mice.
abstract: Celiac disease (CD) is frequently diagnosed in patients with type 1 diabetes (T1D), and T1D patients can exhibit Abs against tissue transglutaminase, the auto-antigen in CD. Thus, gliadin, the trigger in CD, has been suggested to have a role in T1D pathogenesis. The objective of this study was to investigate whether gliadin contributes to enteropathy and insulitis in NOD-DQ8 mice, an animal model that does not spontaneously develop T1D. Gliadin-sensitized NOD-DQ8 mice developed moderate enteropathy, intraepithelial lymphocytosis, and barrier dysfunction, but not insulitis. Administration of anti-CD25 mAbs before gliadin-sensitization induced partial depletion of CD25(+)Foxp3(+) T cells and led to severe insulitis, but did not exacerbate mucosal dysfunction. CD4(+) T cells isolated from pancreatic lymph nodes of mice that developed insulitis showed increased proliferation and proinflammatory cytokines after incubation with gliadin but not with BSA. CD4(+) T cells isolated from nonsensitized controls did not response to gliadin or BSA. In conclusion, gliadin sensitization induced moderate enteropathy in NOD-DQ8 mice. However, insulitis development required gliadin-sensitization and partial systemic depletion of CD25(+)Foxp3(+) T cells. This humanized murine model provides a mechanistic link to explain how the mucosal intolerance to a dietary protein can lead to insulitis in the presence of partial regulatory T cell deficiency.
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University Medical Centre, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Galipeau
authors.forename: Nestor E
authors.initials: NE
authors.lastname: Rulli
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jury
authors.forename: Xianxi
authors.initials: X
authors.lastname: Huang
authors.forename: Romina
authors.initials: R
authors.lastname: Araya
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Murray
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Chirdo
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005903:Gliadin / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007410:Intestinal Diseases / Q000150:complications / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010195:Pancreatitis / Q000150:complications / Q000276:immunology*
chemical_list: D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D005903:Gliadin