HLA‐DR3 mediated CD4 T cell response against GAD65 in type 1 diabetes patients

目的:我们进行这项研究以确定与1型糖尿病(T1D)中人类白细胞抗原(HLA)‐DR3/DQ2介导的谷氨酸脱羧酶(GAD65)特异性CD4 T细胞激活可能相关的致糖尿病性GAD65肽。 方法:选取与HLA‐DR3/DQ2分子在体外结合强烈的前30个GAD65肽, 分为4个池组。使用这些肽来刺激研究对象的CD4 T细胞, 在16小时PBMC培养中分析CD4 T细胞对干扰素(IFN‐γ), 白介素(IL)‐17, 肿瘤坏死因子‐α(TNF‐α)和IL‐10的激活表达, 使用流式细胞术进行分析。 结果:所有四个GAD65肽池(PP1‐4)都导致CD4 T细胞的IFN‐γ表达明显增加(p=0.003,...

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Published inJournal of diabetes Vol. 15; no. 7; pp. 607 - 621
Main Authors Chuzho, Neihenuo, Mishra, Neetu, Tandon, Nikhil, Kanga, Uma, Mishra, Gunja, Sharma, Akanksha, Mehra, Narinder K., Kumar, Neeraj
Format Journal Article
LanguageEnglish
Published Australia John Wiley & Sons, Inc 01.07.2023
Wiley Publishing Asia Pty Ltd
Subjects
Antibodies
Biomarkers
CD4-Positive T-Lymphocytes - metabolism
Cytokines
Diabetes
Diabetes Mellitus, Type 1 - genetics
Glutamate Decarboxylase
HLA-DR3 Antigen
HLA-DRB1 Chains - genetics
Humans
Interleukin-10
Interleukin-17
Leukocytes, Mononuclear
Lymphocytes
Original
Peptides
Tumor necrosis factor-TNF
type 1 diabetes
细胞因子
CD4 T细胞
CD4 T cells
cytokines
1型糖尿病
HLA
GAD65
Online AccessGet full text
ISSN1753-0393
1753-0407
1753-0407
DOI10.1111/1753-0407.13406

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Abstract 目的:我们进行这项研究以确定与1型糖尿病(T1D)中人类白细胞抗原(HLA)‐DR3/DQ2介导的谷氨酸脱羧酶(GAD65)特异性CD4 T细胞激活可能相关的致糖尿病性GAD65肽。 方法:选取与HLA‐DR3/DQ2分子在体外结合强烈的前30个GAD65肽, 分为4个池组。使用这些肽来刺激研究对象的CD4 T细胞, 在16小时PBMC培养中分析CD4 T细胞对干扰素(IFN‐γ), 白介素(IL)‐17, 肿瘤坏死因子‐α(TNF‐α)和IL‐10的激活表达, 使用流式细胞术进行分析。 结果:所有四个GAD65肽池(PP1‐4)都导致CD4 T细胞的IFN‐γ表达明显增加(p=0.003, p<0.0001, p=0.026 和 p=0.002, 分别), 只有池2在T1D患者与健康对照组之间显示出显著的IL‐17表达增加(p<0.0001)。肽间组间比较显示, 在患者中, PP2组与其他组相比, IFN‐γ和IL‐17的表达显著增加, IL‐10的表达显著降低(p<0.0001, p=0.02 和 p=0.04), 但在对照组中没有显示出明显差异。此外, 2号组肽对于HLA‐DRB1 * 03‐DQA1 * 05‐DQB1 * 02 + 患者而言, 导致CD4 T细胞的IFN‐γ和IL‐17表达显著增加(p=0.002), 而IL‐10表达显著降低(p=0.04)。在HLA‐DRB1 * 03‐DQA1 * 05‐DQB1 * 02 +的最近诊断的T1D患者中, CD4 T细胞的IL‐17表达显著增加(p=0.03)。 结论:GAD65肽, 尤其是属于PP2的肽段, 在T1D患者中能够诱导CD4 T细胞表达IFN‐γ和IL‐17细胞因子, 这表明在患者中2号组肽可能通过HLA‐DR3分子递呈给CD4 T细胞, 使免疫平衡朝向炎症表型转变。
AbstractList AimWe 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).MethodsTop 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.ResultsAlthough 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.ConclusionGAD65 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.
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). 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. 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. 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.
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).AIMWe 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).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.METHODSTop 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.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.RESULTSAlthough 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.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.CONCLUSIONGAD65 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.
目的:我们进行这项研究以确定与1型糖尿病(T1D)中人类白细胞抗原(HLA)‐DR3/DQ2介导的谷氨酸脱羧酶(GAD65)特异性CD4 T细胞激活可能相关的致糖尿病性GAD65肽。 方法:选取与HLA‐DR3/DQ2分子在体外结合强烈的前30个GAD65肽, 分为4个池组。使用这些肽来刺激研究对象的CD4 T细胞, 在16小时PBMC培养中分析CD4 T细胞对干扰素(IFN‐γ), 白介素(IL)‐17, 肿瘤坏死因子‐α(TNF‐α)和IL‐10的激活表达, 使用流式细胞术进行分析。 结果:所有四个GAD65肽池(PP1‐4)都导致CD4 T细胞的IFN‐γ表达明显增加(p=0.003, p<0.0001, p=0.026 和 p=0.002, 分别), 只有池2在T1D患者与健康对照组之间显示出显著的IL‐17表达增加(p<0.0001)。肽间组间比较显示, 在患者中, PP2组与其他组相比, IFN‐γ和IL‐17的表达显著增加, IL‐10的表达显著降低(p<0.0001, p=0.02 和 p=0.04), 但在对照组中没有显示出明显差异。此外, 2号组肽对于HLA‐DRB1 * 03‐DQA1 * 05‐DQB1 * 02 + 患者而言, 导致CD4 T细胞的IFN‐γ和IL‐17表达显著增加(p=0.002), 而IL‐10表达显著降低(p=0.04)。在HLA‐DRB1 * 03‐DQA1 * 05‐DQB1 * 02 +的最近诊断的T1D患者中, CD4 T细胞的IL‐17表达显著增加(p=0.03)。 结论:GAD65肽, 尤其是属于PP2的肽段, 在T1D患者中能够诱导CD4 T细胞表达IFN‐γ和IL‐17细胞因子, 这表明在患者中2号组肽可能通过HLA‐DR3分子递呈给CD4 T细胞, 使免疫平衡朝向炎症表型转变。
Highlights The CD4 T cells of type 1 diabetes (T1D) patients particularly having HLA‐DRB1*03‐DQA1*05‐DQB1*02 haplotype are reactive against a particular region of the glutamic acid decarboxylase (GAD65) protein.GAD65 peptides encompassing 288–308 amino acid positions (peptide pool 2) may be favored by the HLA‐DR3 molecule for presentation to CD4 T cells in T1D.Interleukin (IL)‐17 producing CD4 T cells (Th17) possibly have an important role in driving inflammatory CD4 T cell response in T1D.Two cytokines, IFN‐γ and IL‐17, might have a key role in HLA‐DR3 mediated CD4 T cell immune response to GAD65 protein in T1D.
Author Mishra, Neetu
Sharma, Akanksha
Kumar, Neeraj
Mishra, Gunja
Tandon, Nikhil
Kanga, Uma
Chuzho, Neihenuo
Mehra, Narinder K.
AuthorAffiliation 2 Symbiosis School of Biological Sciences Symbiosis International (Deemed University) Pune India
3 Department of Endocrinology and Metabolism All India Institute of Medical Sciences New Delhi India
1 Indian Council of Medical Research (ICMR)‐National Institute of Pathology Safdarjung Hospital Campus New Delhi India
5 Emeritus Scientist (ICMR), and Former Dean (Research) All India Institute of Medical Sciences New Delhi India
4 Department of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi India
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CitedBy_id crossref_primary_10_3389_fimmu_2023_1270488
crossref_primary_10_3389_fimmu_2024_1462384
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Copyright 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
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2023 The Authors. published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
Copyright_xml – notice: 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
– notice: 2023. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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Issue 7
Keywords type 1 diabetes
细胞因子
CD4 T细胞
CD4 T cells
cytokines
1型糖尿病
HLA
GAD65
Language English
License 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Snippet 目的:我们进行这项研究以确定与1型糖尿病(T1D)中人类白细胞抗原(HLA)‐DR3/DQ2介导的谷氨酸脱羧酶(GAD65)特异性CD4 T细胞激活可能相关的致糖尿病性GAD65肽。 方法:选取...
We planned this study to identify diabetogenic glutamic acid decarboxylase (GAD65) peptides possibly responsible for human leucocyte antigen...
AimWe planned this study to identify diabetogenic glutamic acid decarboxylase (GAD65) peptides possibly responsible for human leucocyte antigen...
Highlights The CD4 T cells of type 1 diabetes (T1D) patients particularly having HLA‐DRB1*03‐DQA1*05‐DQB1*02 haplotype are reactive against a particular region...
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SubjectTerms Antibodies
Biomarkers
CD4-Positive T-Lymphocytes - metabolism
Cytokines
Diabetes
Diabetes Mellitus, Type 1 - genetics
Glutamate Decarboxylase
HLA-DR3 Antigen
HLA-DRB1 Chains - genetics
Humans
Interleukin-10
Interleukin-17
Leukocytes, Mononuclear
Lymphocytes
Original
Peptides
Tumor necrosis factor-TNF
Title HLA‐DR3 mediated CD4 T cell response against GAD65 in type 1 diabetes patients
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