Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A.
Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A.
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DOI：
10.1053/j.gastro.2017.11.277
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发表时间：
2018-03
期刊：
影响因子：
29.4
通讯作者：
Shin EC
中科院分区：
文献类型：
--
作者：
Choi YS;Jung MK;Lee J;Choi SJ;Choi SH;Lee HW;Lee JJ;Kim HJ;Ahn SH;Lee DH;Kim W;Park SH;Huh JR;Kim HP;Park JY;Shin EC
CD4+CD25+Foxp3+ T-regulatory （Treg）细胞控制免疫应答并维持免疫稳态。然而，在炎症条件下，Treg细胞产生促进炎症的细胞因子。我们研究了急性甲型肝炎（AHA）患者的Treg细胞产生肿瘤坏死因子（TNF），并检查了这些细胞的特征及其与临床因素的关系。我们分析了韩国63名住院时（和一些后来的时间点）的AHA患者和19名健康献血者的血液样本。在肝移植过程中采集暴发性AHA患者的肝组织。从全血中分离外周血单个核细胞（PBMCs），从肝组织中分离淋巴细胞，用流式细胞术分析。在抗cd3和抗cd28刺激后，用免疫荧光法测定Treg细胞（CD4+CD25+Foxp3+）的细胞因子产量。根据DNA甲基化模式确定Treg细胞的表观遗传稳定性。流式细胞术分析Treg细胞的表型，并使用rorr γt抑制剂ML-209抑制TNF的产生。将Treg缺失的pbmc与分离的Treg细胞共培养，进行Treg细胞抑制实验。与对照组相比，AHA患者CD4+CD25+Foxp3+ Treg细胞在抗cd3和抗cd28刺激下产生TNF的比例更高（11.2% vs 2.8%）。DNA甲基化分析证实了Treg细胞的身份。产生TNF的Treg细胞具有t -辅助性17细胞的特征，包括RORγt的上调，这是产生TNF所必需的。与对照组的Treg细胞相比，Treg细胞的抑制功能降低。AHA患者血液中产生tnf的Treg细胞的频率与其血清丙氨酸转氨酶水平相关。与健康人的Treg细胞相比，AHA患者的Treg细胞功能发生了改变。AHA患者的Treg细胞产生更高水平的TNF，获得t -辅助性17细胞的特征，并且抑制活性降低。这些细胞的存在与AHA患者的严重肝损伤有关。
CD4+CD25+Foxp3+ T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors. We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea. Liver tissues were collected from patients with fulminant AHA during liver transplantation. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and lymphocytes were isolated from liver tissues and analyzed by flow cytometry. Cytokine production from Treg cells (CD4+CD25+Foxp3+) was measured by immunofluorescence levels following stimulation with anti-CD3 and anti-CD28. Epigenetic stability of Treg cells was determined based on DNA methylation patters. Phenotypes of Treg cells were analyzed by flow cytometry, and an RORγt inhibitor, ML-209 was used to inhibit TNF production. Treg cell suppression assay was performed by co-culture of Treg-depleted PBMCs and isolated Treg cells. A higher proportion of CD4+CD25+Foxp3+ Treg cells from patients with AHA, compared with controls, produced TNF upon stimulation with anti-CD3 and anti-CD28 (11.2% vs 2.8%). DNA methylation analysis confirmed the identity of the Treg cells. TNF-producing Treg cells had features of T-helper 17 cells, including upregulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared to Treg cells from controls. The frequency of TNF-producing Treg cells in AHA patients’ blood correlated with their serum level of alanine aminotransferase. Treg cells from patients with AHA have altered functions, compared with Treg cells from healthy individuals. Treg cells from patients with AHA produce higher levels of TNF, gain features of T-helper 17 cells, and have reduced suppressive activity. The presence of these cells is associated with severe liver injury in patients with AHA.
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DOI：
10.1084/jem.20060772
发表时间：
2006-07-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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影响因子：
2.4
作者：
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通讯作者：
Zaratti, Laura
影响因子：
13.5
作者：
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通讯作者：
Lemon, SM
调节性T细胞在类风湿关节炎和抗TNFALPHA治疗中的逆转功能受损。
影响因子：
15.3
作者：
Ehrenstein, MR;Evans, JG;Singh, A;Moore, S;Warnes, G;Isenberg, DA;Mauri, C
通讯作者：
Mauri, C
DOI：
10.4049/jimmunol.0803474
发表时间：
2010-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Moncrieffe H;Nistala K;Kamhieh Y;Evans J;Eddaoudi A;Eaton S;Wedderburn LR
通讯作者：
Wedderburn LR