Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes.
Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes.
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DOI：
10.1007/s00125-016-4067-4
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发表时间：
2016-11
期刊：
影响因子：
8.2
通讯作者：
Morgan, Noel G.
中科院分区：
文献类型：
--
作者：
Richardson, Sarah J.;Rodriguez-Calvo, Teresa;Gerling, Ivan C.;Mathews, Clayton E.;Kaddis, John S.;Russell, Mark A.;Zeissler, Marie;Leete, Pia;Krogvold, Lars;Dahl-Jorgensen, Knut;von Herrath, Matthias;Pugliese, Alberto;Atkinson, Mark A.;Morgan, Noel G.
人类胰腺β细胞可能是1型糖尿病自身死亡的同谋，但这是如何发生的仍不清楚。一个潜在的影响因素是HLA I类抗原的过度表达。这是第一次描述大约30年前，但从来没有充分的特点，最近被质疑为人工制品。因此，我们研究了来自三个队列的1型糖尿病患者胰腺中蛋白质和RNA水平的HLA I类表达。来自患有糖尿病的胰腺器官供体网络（nPOD）的具有残余含胰岛素胰岛的1型糖尿病患者的胰腺样品（n = 26），糖尿病病毒检测研究（DiViD）和英国新近发作的1型糖尿病收集物针对HLA I类同种型进行免疫染色，信号转导子和转录激活子1（STAT 1）、NLR家族CARD结构域包含5（NLRC 5）和胰岛激素。从nPOD和DiViD样品中通过激光捕获显微切割分离的胰岛中提取RNA，并使用基因表达阵列进行分析。在所有三种组织收集的1型糖尿病患者的含胰岛素胰岛中观察到HLA I类的高表达，并在RNA和蛋白质水平上得到证实。β 2-微球蛋白（产生功能性HLA I类复合物所需的第二种组分）的表达也升高。"经典的" HLA I类同种型（即HLA-ABC）以及"非经典的" HLA分子HLA-F在含胰岛素的胰岛中高表达。这种过度表达与转录调节因子NLRC 5的可检测上调无关。然而，它与所有三个队列中STAT1表达的增加密切相关。胰岛HLA I类分子的高表达发生在新近发病的1型糖尿病患者的含胰岛素胰岛中，并且在许多病程长达11年的患者中也可检测到，此后下降。胰岛细胞HLA I类高表达不是一种假象，而是1型糖尿病免疫发病机制的标志。这种反应与STAT1的表达升高密切相关，并且这些反应在1型糖尿病患者中独特地发生，从而导致他们对自身免疫介导的破坏的选择性易感性。本文的在线版本（doi：10.1007/s00125 - 016 - 4067 - 4）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it. Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays. Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of β2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both ‘classical’ HLA class I isoforms (i.e. HLA-ABC) as well as a ‘non-classical’ HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5. However, it was strongly associated with increased STAT1 expression in all three cohorts. Islet hyperexpression of HLA class I molecules occurred in the insulin-containing islets of patients with recent-onset type 1 diabetes and was also detectable in many patients with disease duration of up to 11 years, declining thereafter. Islet cell HLA class I hyperexpression is not an artefact, but is a hallmark in the immunopathogenesis of type 1 diabetes. The response is closely associated with elevated expression of STAT1 and, together, these occur uniquely in patients with type 1 diabetes, thereby contributing to their selective susceptibility to autoimmune-mediated destruction. The online version of this article (doi:10.1007/s00125-016-4067-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
7.7
作者：
Leete, Pia;Willcox, Abby;Morgan, Noel G.
通讯作者：
Morgan, Noel G.
影响因子：
4.8
作者：
Moore, Fabrice;Naamane, Najib;Eizirik, Decio L.
通讯作者：
Eizirik, Decio L.
影响因子：
3.9
作者：
Eizirik, Decio L.;Moore, Fabrice;Ortis, Fernanda
通讯作者：
Ortis, Fernanda
DOI：
10.1073/pnas.1008684107
发表时间：
2010-08-03
影响因子：
11.1
作者：
Meissner, Torsten B.;Li, Amy;Kobayashi, Koichi S.
通讯作者：
Kobayashi, Koichi S.
影响因子：
8.2
作者：
FOULIS, AK;LIDDLE, CN;WEIR, RS
通讯作者：
WEIR, RS