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Diabetes-Specific HLA-DR–Restricted Proinflammatory T-Cell Response to Wheat Polypeptides in Tissue Transglutaminase Antibody–Negative Patients With Type 1 Diabetes Majid Mojibian 1 , 2 , Habiba Chakir 1 , 2 , David E. Lefebvre 1 , 2 , Jennifer A. Crookshank 1 , Brigitte Sonier 1 , 2 , Erin Keely 3 and Fraser W. Scott 1 , 2 , 3 1 Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada; 2 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada; 3 Department of Medicine, University of Ottawa, Ottawa, Canada. Corresponding author: Fraser W. Scott, fscott{at}ohri.ca . Abstract 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, questions arise regarding the frequency of abnormal immune responses to wheat and their nature, and it remains unclear whether such responses are diabetes specific. RESEARCH DESIGN AND METHODS In type 1 diabetic patients and healthy control subjects, the immune response of peripheral CD3 + T-cells to WPs, ovalbumin, gliadin, α-gliadin 33-mer peptide, tetanus toxoid, and phytohemagglutinin was measured using a carboxyfluorescein diacetate succinimidyl ester (CFSE) proliferation assay. T–helper cell type 1 (Th1), Th2, and Th17 cytokines were analyzed in WP-stimulated peripheral blood mononuclear cell (PBMNC) supernatants, and HLA was analyzed by PCR. RESULTS Of 42 patients, 20 displayed increased CD3 + T-cell proliferation to WPs and were classified as responders; proliferative responses to other dietary antigens were less pronounced. WP-stimulated PBMNCs from patients showed a mixed proinflammatory 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 WPs was frequently present in type 1 diabetic patients and associated with HLA-DR4 but not HLA-DQ2. The presence of an HLA-DR–restricted Th1 and Th17 response to WPs 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 1723 . Received November 12, 2008. Accepted April 20, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

We are exposed to millions of microbial and dietary antigens via the gastrointestinal tract, which likely play a key role in type 1 diabetes (T1D). We differentiated the effects of these two major environmental factors on gut immunity and T1D. Diabetes-prone BioBreeding (BBdp) rats were housed in specific pathogen-free (SPF) or germ-free (GF) conditions and weaned onto diabetes-promoting cereal diets or a protective low-antigen hydrolyzed casein (HC) diet, and T1D incidence was monitored. Fecal microbiota 16S rRNA genes, immune cell distribution, and gene expression in the jejunum were analyzed. T1D was highest in cereal-SPF (65%) and cereal-GF rats (53%) but inhibited and delayed in HC-fed counterparts. Nearly all HC-GF rats remained diabetes-free, whereas HC-fed SPF rats were less protected (7 vs. 29%). Bacterial communities differed in SPF rats fed cereal compared with HC. Cereal-SPF rats displayed increased gut CD3+ and CD8α+ lymphocytes, ratio of Ifng to Il4 mRNA, and Lck expression, indicating T-cell activation. The ratio of CD3+ T cells expressing the Treg marker Foxp3+ was highest in HC-GF and lowest in cereal-SPF rats. Resident CD163+ M2 macrophages were increased in HC-protected rats. The cathelicidin antimicrobial peptide (Camp) gene was upregulated in the jejunum of HC diet–protected rats, and CAMP+ cells colocalized with CD163. A cereal diet was a stronger promoter of T1D than gut microbes in association with impaired gut immune homeostasis.

In type 1 diabetes, the environmental factors that induce the patient's immune system to attack and destroy the insulin-secreting Beta-cells are not known. There is evidence that some cases of type 1 diabetes could be wheat related. Exposure to wheat protein was a risk factor for development of type 1 diabetes autoantibodies in high-risk infants, and as many as 2%-8% of type 1 diabetic patients have celiac disease, also known as gluten-sensitive enteropathy. Here, Mojibian et al report the case of a highly wheat-sensitive patient with type 1 diabetes/celiac disease who displayed strong antibody and T-cell responses to this protein.

The inflammatory cascade and the coagulation system are intimately connected; several coagulation proteins have been demonstrated to regulate inflammatory events. Studies have shown that fibrinogen is able to promote cellular adhesion and transendothelial migration through interactions with ICAM-1 and Mac-1, prompting speculation that related proteins may have similar roles. Fgl2 prothrombinase shares significant homology to the fibrinogen-γ chain; in particular the P1 domain of fibrinogen, which is responsible for interactions with Mac-1, is highly conserved in Fgl2. We hypothesized that soluble Fgl2 has an immunomodulatory effect through interactions with a cell-surface receptor. We further speculated that Fgl2 interacts with this putative receptor through its fibrinogen-related domain, and may bind to Mac-1 through the conserved P1 region. We found that Fgl2 binds to RAW 264.7 cells in a specific and dose-dependent manner (K d = 185 nM), and that this binding is not dependent on Mac-1.