A diabetes-specific HLA-DR restricted pro-inflammatory T cell response to wheat polypeptides in tissue transglutaminase antibody negative patients with type 1 diabetes

  1. Majid Mojibian1,2,
  2. Habiba Chakir1,2,
  3. David E. Lefebvre1,2,
  4. Jennifer A. Crookshank1,
  5. Brigitte Sonier1,2,
  6. Erin Keely3 and
  7. Fraser W. Scott (fscott{at},2,3
  1. 1Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
  2. 2Department of Biochemistry, Microbiology and Immunology
  3. 3Department of Medicine, University of Ottawa, Ottawa, Canada


    Objective: There is evidence of gut barrier and immune system dysfunction in some patients with type 1 diabetes, possibly linked with exposure to dietary wheat polypeptides (WP). However, the frequency of abnormal immune responses to wheat, their nature and whether such responses are diabetes-specific remains unclear.

    Research design and methods: In type 1 diabetes patients and healthy control subjects, the immune response of peripheral CD3+ T cells to WP, ovalbumin, gliadin, α-gliadin 33-mer peptide, tetanus toxoid and PHA was measured using a CFSE proliferation assay. Th1, Th2 and Th17 cytokines were analyzed in WP-stimulated PBMC supernatants and HLA was analyzed by PCR.

    Results: Twenty out of 42 patients displayed increased CD3+ T cell proliferation to WP and were classified as responders; proliferative responses to other dietary antigens were less pronounced. WP-stimulated PBMC of patients showed a mixed pro-inflammatory cytokine response with large amounts of IFN-γ, IL-17A and increased TNF. HLA-DQ2, the major celiac disease risk gene was not significantly different. Nearly all responders carried the diabetes risk gene, HLA-DR4. Anti-DR antibodies blocked the WP response and inhibited secretion of Th1 and Th17 cytokines. High amounts of WP-stimulated IL-6 were not blocked.

    Conclusions: T cell reactivity to WP was frequently present in type 1 diabetes patients and associated with HLA-DR4 but not HLA-DQ2. The presence of an HLA-DR restricted, Th1 and Th17 response to wheat polypeptides in a subset of patients indicates a diabetes-related inflammatory state in the gut immune tissues associated with defective oral tolerance and possibly gut barrier dysfunction.


      • Received April 20, 2009.
      • Accepted April 20, 2009.