肠病毒感染一直被认为是与自身免疫的出现和/或明显的1型糖尿病的存在相关的关键环境因素。其中产生胰岛素的胰腺β细胞被自身免疫反应破坏。遗传易感性通过1型糖尿病风险基因IFIH1(干扰素诱导的解旋酶C结构域1)的变异,它编码病毒模式识别受体黑色素瘤分化相关蛋白5(MDA5),支持肠道病毒感染和1型糖尿病之间的潜在联系。
我们使用分子技术来检测来自两个队列的外周血样本(在分离的细胞区室或血浆中)中的肠道病毒RNA,这两个队列包括79名儿童或72名成人,其中包括患有和不患有1型糖尿病且具有多种自身抗体的个体。我们还使用免疫组织化学检测了1型糖尿病死后供体(n=43)的胰岛中的肠道病毒蛋白VP1。
我们观察到,与外周血的非细胞区室相比,对细胞区室采样时的检测灵敏度提高(OR21.69;95%CI3.64,229.20;p<0.0001)。此外,我们显示,与没有自身免疫的儿童相比,有自身免疫的儿童更有可能肠道病毒RNA检测呈阳性(OR11.60;95%CI1.89,126.90;p=0.0065).此外,我们发现,携带IFIH1常见变异体(rs1990760,Thr946Ala)易感等位基因(946Thr)的个体更有可能在外周血中检测出肠道病毒阳性(OR3.07;95%CI1.02,8.58;p=0.045).相比之下,使用免疫组织化学,IFIH1的常见变异与1型糖尿病患者胰岛中肠道病毒VP1蛋白的检测无相关性.
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,感染与疾病阶段和遗传易感性相关,从而支持在疾病发作之前肠道病毒感染的作用。
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.
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.
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 (946Thr) 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.
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.