Diabetes-specific HLA-DR-restricted proinflammatory T-cell response to wheat polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes.
Diabetes-specific HLA-DR-restricted proinflammatory T-cell response to wheat polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes.
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作者：
Mojibian M;Chakir H;Lefebvre DE;Crookshank JA;Sonier B;Keely E;Scott FW
有证据表明，一些 1 型糖尿病患者存在肠道屏障和免疫系统功能障碍，这可能与饮食中摄入小麦多肽 (WP) 有关。然而，关于小麦异常免疫反应的频率及其性质存在疑问，并且尚不清楚这种反应是否是糖尿病特异性的。在 1 型糖尿病患者和健康对照受试者中，使用羧基荧光素二乙酸琥珀酰亚胺酯 (CFSE) 增殖测定法测量外周 CD3+ T 细胞对 WP、卵清蛋白、麦醇溶蛋白、α-麦醇溶蛋白 33 聚肽、破伤风类毒素和植物血凝素的免疫反应。在 WP 刺激的外周血单核细胞 (PBMNC) 上清液中分析 1 型辅助 T 细胞 (Th1)、Th2 和 Th17 细胞因子，并通过 PCR 分析 HLA。在 42 名患者中，20 名患者的 WP 的 CD3+ T 细胞增殖增加，被归类为应答者；对其他饮食抗原的增殖反应不太明显。来自患者的 WP 刺激的 PBMNC 显示出混合的促炎细胞因子反应，其中含有大量的 IFN-γ、IL-17A 和增加的 TNF。主要乳糜泻风险基因 HLA-DQ2 没有显着差异。几乎所有应答者都携带糖尿病风险基因 HLA-DR4。抗 DR 抗体阻断 WP 反应并抑制 Th1 和 Th17 细胞因子的分泌。大量 WP 刺激的 IL-6 未被阻断。 T 细胞对 WP 的反应经常出现在 1 型糖尿病患者中，并且与 HLA-DR4 相关，但与 HLA-DQ2 无关。部分患者对 WP 存在 HLA-DR 限制性 Th1 和 Th17 反应，表明肠道免疫组织中存在与糖尿病相关的炎症状态，与口服耐受缺陷和可能的肠道屏障功能障碍相关。
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. 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. 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. 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.