CD39 mediated regulation of Th17-cell effector function is impaired in juvenile autoimmune liver disease.
CD39 mediated regulation of Th17-cell effector function is impaired in juvenile autoimmune liver disease.
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DOI：
10.1016/j.jaut.2016.05.005
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发表时间：
2016-08
影响因子：
12.8
通讯作者：
Longhi MS
中科院分区：
文献类型：
--
作者：
Liberal R;Grant CR;Ma Y;Csizmadia E;Jiang ZG;Heneghan MA;Yee EU;Mieli-Vergani G;Vergani D;Robson SC;Longhi MS
T辅助型17(Th17)细胞参与自身免疫组织损伤。CD39是一种胞外核苷酸酶，催化细胞外ATP/ADP的水解，最终产生免疫抑制的腺苷。功能性CD39的表达对免疫细胞具有免疫抑制作用。随着幼年自身免疫性肝病(AILD)患者CD39淋巴细胞比例的降低，我们探讨了Th17细胞上是否存在CD39表达的降低，以及这种现象是否与效应器功能增强和炎症有关。对38例幼年AILD患者(22例自身免疫性肝炎和16例自身免疫性硬化性胆管炎)、8例疾病对照(DC)和16例健康人(HS)进行了研究。用流式细胞仪检测外周血细胞表型；抑制细胞增殖/效应细胞因子的产生能力；用薄层层析法测定胞外酶活性；用实时定量聚合酶链式反应或Western Blot检测腺苷受体、腺苷脱氨酶(ADA)和磷酸二酯酶(PDE)的表达。来自HS的CD39+Th17(Th17CD39+)细胞似乎被激活，并含有高频率的淋巴细胞产生调节性细胞因子。然而，在AILD中，Th17CD39+细胞显著减少，不能产生AMP/腺苷，从而限制了对靶细胞增殖和IL-17产生的控制。与HS相比，AILD患者的Th17细胞A2A腺苷受体表达降低，而PDE4A、PDE4B和ADA的表达水平相似。肝脏免疫组织化学检测仅见罕见的Th17CD39+细胞。幼年AILD患者Th17CD39+细胞数量减少，质的缺陷。CD39和A2a的低水平表达可能有助于Th17细胞效应特性的持续存在和该病的无拘束炎症。
T-helper-type 17 (Th17) cells are involved in autoimmune tissue damage. CD39 is an ectonucleotidase that catalyzes extracellular ATP/ADP hydrolysis, culminating in the generation of immunosuppressive adenosine. Functional CD39 expression confers immunosuppressive properties upon immune cells. As the proportion of CD39 lymphocytes is decreased in juvenile autoimmune liver disease (AILD), we have explored whether decreased CD39 expression is present on Th17 cells and whether this phenomenon is associated with heightened effector function and inflammation. Thirty-eight patients with juvenile AILD (22 autoimmune hepatitis and 16 autoimmune sclerosing cholangitis), 8 disease controls (DC) and 16 healthy subjects (HS) were studied. Peripheral blood cell phenotype was determined by flow cytometry; ability to suppress by inhibition of cell proliferation/effector cytokine production; ectoenzymatic activity by thin layer chromatography; expression of adenosine receptor, adenosine deaminase (ADA) and phosphodiesterases (PDE) by quantitative real-time PCR or by Western Blot. CD39+ Th17 (Th17CD39+) cells from HS appear activated and contain high frequencies of lymphocytes producing regulatory cytokines. In AILD, however, Th17CD39+ cells are markedly diminished and fail to generate AMP/adenosine, thereby limiting control of both target cell proliferation and IL-17 production. When compared to HS, Th17 cells from AILD patients also show lower A2A adenosine receptor expression while displaying similar levels of PDE4A, PDE4B and ADA. Only rare Th17CD39+ cells are observed by liver immunohistochemistry. Th17CD39+ cells in juvenile AILD are both quantitatively decreased and qualitatively deficient. Low levels CD39 and A2A expression may contribute to the perpetuation of Th17 cell effector properties and unfettered inflammation in this disease.
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