外周血单个核细胞中肠道病毒 RNA 的检测与 1 型糖尿病风险基因 IFIH1 的易感等位基因的存在以及疾病阶段相关。
Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage.
机构信息
Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Exeter Centre of Excellence for Diabetes Research (EXCEED), Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
出版信息
Diabetologia. 2022 Oct;65(10):1701-1709. doi: 10.1007/s00125-022-05753-y. Epub 2022 Jul 22.
AIMS/HYPOTHESIS: Enteroviral infection has been implicated consistently as a key environmental factor correlating with the appearance of autoimmunity and/or the presence of overt type 1 diabetes, in which pancreatic insulin-producing beta cells are destroyed by an autoimmune response. Genetic predisposition through variation in the type 1 diabetes risk gene IFIH1 (interferon induced with helicase C domain 1), which encodes the viral pattern-recognition receptor melanoma differentiation-associated protein 5 (MDA5), supports a potential link between enterovirus infection and type 1 diabetes.
METHODS
We used molecular techniques to detect enterovirus RNA in peripheral blood samples (in separated cellular compartments or plasma) from two cohorts comprising 79 children or 72 adults that include individuals with and without type 1 diabetes who had multiple autoantibodies. We also used immunohistochemistry to detect the enteroviral protein VP1 in the pancreatic islets of post-mortem donors (n=43) with type 1 diabetes.
RESULTS
We observed enhanced detection sensitivity when sampling the cellular compartment compared with the non-cellular compartment of peripheral blood (OR 21.69; 95% CI 3.64, 229.20; p<0.0001). In addition, we show that children with autoimmunity are more likely to test positive for enterovirus RNA than those without autoimmunity (OR 11.60; 95% CI 1.89, 126.90; p=0.0065). Furthermore, we found that individuals carrying the predisposing allele (946) of the common variant in IFIH1 (rs1990760, Thr946Ala) are more likely to test positive for enterovirus in peripheral blood (OR 3.07; 95% CI 1.02, 8.58; p=0.045). In contrast, using immunohistochemistry, there was no correlation between the common variant in IFIH1 and detection of enteroviral VP1 protein in the pancreatic islets of donors with type 1 diabetes.
CONCLUSIONS/INTERPRETATION: Our data indicate that, in peripheral blood, antigen-presenting cells are the predominant source of enterovirus infection, and that infection is correlated with disease stage and genetic predisposition, thereby supporting a role for enterovirus infection prior to disease onset.
目的/假设：肠道病毒感染一直被认为是与自身免疫出现和/或显性 1 型糖尿病存在相关的关键环境因素，在这种情况下，胰腺产生胰岛素的β细胞被自身免疫反应破坏。1 型糖尿病风险基因 IFIH1（具有解旋酶 C 结构域的 1 型干扰素诱导）的遗传易感性发生变异，该基因编码病毒模式识别受体黑色素瘤分化相关蛋白 5（MDA5），这支持了肠道病毒感染与 1 型糖尿病之间存在潜在联系。
方法
我们使用分子技术检测了来自两个队列的 79 名儿童或 72 名成人的外周血样本（分离的细胞区室或血浆）中的肠道病毒 RNA，这些队列包括有和没有 1 型糖尿病的个体，这些个体有多种自身抗体。我们还使用免疫组织化学方法检测了 43 名 1 型糖尿病死后供体胰岛中的肠道病毒蛋白 VP1。
结果
与外周血非细胞区室相比，我们观察到在采样细胞区室时检测敏感性增强（比值比 21.69；95%置信区间 3.64，229.20；p<0.0001）。此外，我们表明，有自身免疫的儿童比没有自身免疫的儿童更有可能检测到肠道病毒 RNA 呈阳性（比值比 11.60；95%置信区间 1.89，126.90；p=0.0065）。此外，我们发现，携带常见变异 IFIH1（rs1990760，Thr946Ala）易感性等位基因（946）的个体更有可能在外周血中检测到肠道病毒（比值比 3.07；95%置信区间 1.02，8.58；p=0.045）。相比之下，使用免疫组织化学方法，在 1 型糖尿病供体的胰岛中，IFIH1 的常见变异与肠道病毒 VP1 蛋白的检测之间没有相关性。
结论/解释：我们的数据表明，在外周血中，抗原呈递细胞是肠道病毒感染的主要来源，并且感染与疾病阶段和遗传易感性相关，从而支持肠道病毒感染在疾病发作之前发生的作用。
Zotero 插件