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- Title
HLA‐DR3 mediated CD4 T cell response against GAD65 in type 1 diabetes patients.
- Authors
Chuzho, Neihenuo; Mishra, Neetu; Tandon, Nikhil; Kanga, Uma; Mishra, Gunja; Sharma, Akanksha; Mehra, Narinder K.; Kumar, Neeraj
- Abstract
Aim: We planned this study to identify diabetogenic glutamic acid decarboxylase (GAD65) peptides possibly responsible for human leucocyte antigen (HLA)‐DR3/DQ2‐mediated activation of GAD65‐specific CD4 T cells in type 1 diabetes (T1D). Methods: Top 30 GAD65 peptides, found to strongly bind in silico with HLA‐DR3/DQ2 molecules, were selected and grouped into four pools. The peptides were used to stimulate CD4 T cells of study subjects in 16‐h peripheral blood mononuclear cell culture. CD4 T cells' stimulation in terms of interferon‐gamma (IFN‐γ), interleukin (IL)‐17, tumor necrosis factor‐alpha (TNF‐α), and IL‐10 expression was analyzed using flow cytometry. Results: Although all four GAD65 peptide pools (PP1‐4) resulted in significantly higher expression of IFN‐γ by CD4 T cells (p =.003, p <.0001, p =.026, and p =.002, respectively), only pool 2 showed significant increase in IL‐17 expression (p <.0001) in T1D patients vs healthy controls. Interpeptide group comparison for immunogenicity revealed significantly higher IFN‐γ and IL‐17 expressions and significantly lower IL‐10 expression for PP2 compared to other groups (p <.0001, p =.02, and p =.04, respectively) in patients but not in controls. Further, group 2 peptides resulted in significant increase in CD4 T cells' expression of IFN‐γ and IL‐17 (p =.002 for both) and significant decrease in IL‐10 (p =.04) in HLA‐DRB1*03‐DQA1*05‐DQB1*02+ patients vs HLA‐DRB1*03‐DQA1*05‐DQB1*02+ controls. The CD4 T cells' expression of IL‐17 was significantly higher (p =.03) in recently diagnosed vs long‐standing HLA‐DRB1*03‐DQA1*05‐DQB1*02+ T1D patients. Conclusion: GAD65 peptides, particularly those belonging to PP2, induced CD4 T cells to express IFN‐γ and IL‐17 cytokines in T1D patients, suggesting that group 2 peptides possibly presented by HLA‐DR3 molecule to CD4 T cells shift immune balance toward inflammatory phenotype in patients.
- Subjects
MONONUCLEAR leukocytes; T cells; TYPE 1 diabetes; TUMOR necrosis factors; CD4 antigen; HISTOCOMPATIBILITY antigens
- Publication
Journal of Diabetes, 2023, Vol 15, Issue 7, p607
- ISSN
1753-0393
- Publication type
Article
- DOI
10.1111/1753-0407.13406