HLA‐DR3介导的CD4 T细胞对1型糖尿病患者GAD65的应答
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-07-01
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| Series: | Journal of Diabetes |
| Subjects: | |
| Online Access: | https://doi.org/10.1111/1753-0407.13406 |
| _version_ | 1797780517992529920 |
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| author | Neihenuo Chuzho Neetu Mishra Nikhil Tandon Uma Kanga Gunja Mishra Akanksha Sharma Narinder K. Mehra Neeraj Kumar |
| author_facet | Neihenuo Chuzho Neetu Mishra Nikhil Tandon Uma Kanga Gunja Mishra Akanksha Sharma Narinder K. Mehra Neeraj Kumar |
| author_sort | Neihenuo Chuzho |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T23:45:13Z |
| format | Article |
| id | doaj.art-29ef37f916e442c4abfe137d2e417e0c |
| institution | Directory Open Access Journal |
| issn | 1753-0393 1753-0407 |
| language | English |
| last_indexed | 2024-03-12T23:45:13Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes |
| spelling | doaj.art-29ef37f916e442c4abfe137d2e417e0c2023-07-14T08:11:48ZengWileyJournal of Diabetes1753-03931753-04072023-07-0115760762110.1111/1753-0407.13406HLA‐DR3介导的CD4 T细胞对1型糖尿病患者GAD65的应答Neihenuo Chuzho0Neetu Mishra1Nikhil Tandon2Uma Kanga3Gunja Mishra4Akanksha Sharma5Narinder K. Mehra6Neeraj Kumar7Indian Council of Medical Research (ICMR)‐National Institute of Pathology Safdarjung Hospital Campus New Delhi IndiaSymbiosis School of Biological Sciences Symbiosis International (Deemed University) Pune IndiaDepartment of Endocrinology and Metabolism All India Institute of Medical Sciences New Delhi IndiaDepartment of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi IndiaIndian Council of Medical Research (ICMR)‐National Institute of Pathology Safdarjung Hospital Campus New Delhi IndiaDepartment of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi IndiaEmeritus Scientist (ICMR), and Former Dean (Research) All India Institute of Medical Sciences New Delhi IndiaIndian Council of Medical Research (ICMR)‐National Institute of Pathology Safdarjung Hospital Campus New Delhi IndiaAbstract 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.https://doi.org/10.1111/1753-0407.13406CD4 T细胞细胞因子GAD65HLA1型糖尿病 |
| spellingShingle | Neihenuo Chuzho Neetu Mishra Nikhil Tandon Uma Kanga Gunja Mishra Akanksha Sharma Narinder K. Mehra Neeraj Kumar HLA‐DR3介导的CD4 T细胞对1型糖尿病患者GAD65的应答 Journal of Diabetes CD4 T细胞 细胞因子 GAD65 HLA 1型糖尿病 |
| title | HLA‐DR3介导的CD4 T细胞对1型糖尿病患者GAD65的应答 |
| title_full | HLA‐DR3介导的CD4 T细胞对1型糖尿病患者GAD65的应答 |
| title_fullStr | HLA‐DR3介导的CD4 T细胞对1型糖尿病患者GAD65的应答 |
| title_full_unstemmed | HLA‐DR3介导的CD4 T细胞对1型糖尿病患者GAD65的应答 |
| title_short | HLA‐DR3介导的CD4 T细胞对1型糖尿病患者GAD65的应答 |
| title_sort | hla dr3介导的cd4 t细胞对1型糖尿病患者gad65的应答 |
| topic | CD4 T细胞 细胞因子 GAD65 HLA 1型糖尿病 |
| url | https://doi.org/10.1111/1753-0407.13406 |
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