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Original Article

Diabetes-Specific HLA-DR–Restricted Proinflammatory 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. Scott1,2,3
  1. 1Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada;
  2. 2Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada;
  3. 3Department of Medicine, University of Ottawa, Ottawa, Canada.
  1. Corresponding author: Fraser W. Scott, fscott{at}ohri.ca.
Diabetes 2009 Aug; 58(8): 1789-1796. https://doi.org/10.2337/db08-1579
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  • FIG. 1.
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    FIG. 1.

    Antigen-specific CD3+ T-cell proliferation. 1.2 × 106 CFSE-labeled PBMNCs from patients with type 1 diabetes (T1D) or healthy control subjects were cultured for 8 days in the absence or presence of different concentrations of WPs. On day 8, cells were stained with Cy-chrome conjugated anti-CD3 monoclonal antibody. CDI was calculated based on a fixed number of 5,000 CD3+ CFSEbright cells using the following formula: CDI = number of CD3+, CFSEdim cells with antigen/number of CD3+, CFSEdim cells without antigen (medium). The horizontal line indicates the mean.

  • FIG. 2.
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    FIG. 2.

    T-cell proliferation in response to WPs and other antigens or mitogen. 1.2 × 106 CFSE-labeled PBMNCs from patients with type 1 diabetes (T1D) or healthy control subjects were cultured for 8 days in the absence or presence of WP, ovalbumin (OVA), gliadin, 33-mer, insulin, tetanus toxoid (TT), or phytohemagglutinin (PHA) (see research design and methods for details). On day 8, cells were stained with Cy-chrome–conjugated anti-CD3 monoclonal antibody. CDI was calculated. A CDI value greater than the control mean + 3 SD (CDI >14.6) was used to define a positive response to WP. P values indicate statistical difference compared with control subjects. The horizontal lines indicate the means.

  • FIG. 3.
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    FIG. 3.

    WP-stimulated cytokine secretion by PBMNC at day 8 of culture. Box and Whisker plots with individual values for control and diabetic subjects. IFN-γ, TNF, IL-6, IL-4, and IL-10 were measured by flow CBA. IL-17A was measured by ELISA. Each plot includes the mean (dashed line), median (solid line), distribution, and range. (For IL-4, the difference between control and type 1 diabetic [T1D] subjects is significant when the circled outlier value in the control group is removed [P = 0.03].)

  • FIG. 4.
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    FIG. 4.

    Graphic representation of the relationship between wheat-induced T-cell response and high-resolution HLA diabetes risk alleles. Box and Whisker plots with individual values for diabetic subjects. Each plot includes the mean (bold line), median (solid thin line), distribution, and range. A: Distribution of T-cell proliferation (CDI) to WP in type 1 diabetic patients with HLA-DRB1*03 and HLA-DRB1*04 or in those heterozygous for HLA-DRB1*03/*04. A CDI value greater than mean + 3 SD of the control group (CDI >14.6, dashed line) was used to define a positive proliferation response. One of the type 1 diabetic patients with HLA-DRB1*03+/*04− showed positive responses to WP (○). Type 1 diabetic patients who carried one risk allele HLA-DRB1*04 (10 of 20) or patients who carried both risk genes HLA-DRB1*03/*04 (9 of 12) showed positive reactivity to WP. High-resolution results of HLA-DR are labeled beside each individual. B: Distribution of T-cell proliferation (CDI) to WP in type 1 diabetic patients with HLA-DQB1*02 and HLA-DQB1*03 or in those heterozygous for HLA-DQB1*02/*03. High-resolution analyses for HLA-DQB1*02 and *03 are labeled beside each symbol. ↓ (beside 0201) means all individuals in the column carry HLA-DQB1*0201. (Three of the 42 type 1 diabetic individuals are neither DR3 nor DR4, and therefore they are not included in this figure. One of the seven individuals with DR3/non-DR4 in the left panel is heterozygous for DQ*02/*03 and was therefore placed in the middle column in the right panel [DQ*02*03]. Differences in high-resolution haplotypes between responders and nonresponders were not evaluated statistically because of the small sample size.)

  • FIG. 5.
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    FIG. 5.

    Role of HLA-DR in the type 1 diabetes T-cell and cytokine response to WPs. A: The T-cell response to wheat protein (6.2 μg/ml) was calculated as CDI in 14 patients and compared with cells cultured in the presence of anti–HLA-DR monoclonal antibody (5 μg/ml) or with isotype control antibody. B: Cytokine profiles of supernatants from WP-stimulated PBMNC of patients were evaluated in the absence and presence of monoclonal HLA-DR antibodies using Th1/Th2 CBAs for IFN-γ, IL-4, TNF, IL-10, and IL-6 or an ELISA kit for IL-17A.

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  • TABLE 1

    Description of control subjects and patients with type 1 diabetes

    GroupnSex ratio (female/male)AgeDuration of diabetes (years)
    Type 1 diabetic patients4228/1426.7 (8–41)11.2 ± 7
    Healthy control subjects2211/1124.5 (18–32)NA
    • Data are means (range) or means ± SD unless otherwise indicated. NA, not applicable.

  • TABLE 2

    HLA-DR and -DQ in type 1 diabetic responders and nonresponders

    nDR3DR4DR3/DR4DQ2DQ3
    Nonresponders224159144164
    Responders205095 (P = 0.01)45 (P = 0.04)50 (P = 0.75)95 (P = 0.02)
    • Data are % unless otherwise indicated. T-cell proliferation (CDI) to WP was evaluated in type 1 diabetic patients. Patients with a CDI value greater than mean + 3 SD of the control group (CDI >14.6) were classified as responders. Those below were classified as nonresponders. The percentage of individuals with the indicated HLA haplotypes in these groups was calculated.

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August 2009, 58(8)
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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, Habiba Chakir, David E. Lefebvre, Jennifer A. Crookshank, Brigitte Sonier, Erin Keely, Fraser W. Scott
Diabetes Aug 2009, 58 (8) 1789-1796; DOI: 10.2337/db08-1579

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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, Habiba Chakir, David E. Lefebvre, Jennifer A. Crookshank, Brigitte Sonier, Erin Keely, Fraser W. Scott
Diabetes Aug 2009, 58 (8) 1789-1796; DOI: 10.2337/db08-1579
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