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,Diabetologia

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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
Diabetologia ( IF 8.4 ) Pub Date : 2022-07-22 , DOI: 10.1007/s00125-022-05753-y
Amir-Babak Sioofy-Khojine ₁ , Sarah J Richardson ₂ , Jonathan M Locke ₂ , Sami Oikarinen _{1,

3} , Noora Nurminen ₁ , Antti-Pekka Laine ₄ , Kate Downes _{5,

6} , Johanna Lempainen _{4,

7,

8} , John A Todd _{5,

9} , Riitta Veijola _{10,

11} , Jorma Ilonen ₄ , Mikael Knip _{12,

13,

14} , Noel G Morgan ₂ , Heikki Hyöty _{1,

3,

14} , Mark Peakman _{15,

16} , Martin Eichmann _{2,

15}

Affiliation

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.
Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Cambridge University Hospitals Genomics Laboratory, Cambridge University Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.
Clinical Microbiology, Turku University Hospital, Turku, Finland.
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, National Institute for Health and Care Research/Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
Department for Children and Adolescents, Oulu University Hospital, Oulu, Finland.
Department of Paediatrics, Medical Research Center Oulu, University of Oulu, Oulu, Finland.
Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Center for Child Health Research, Tampere University Hospital, Tampere, Finland.
Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, UK.
National Institute for Health Research, Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust, King's College London, London, UK.

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^Thr) 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.

Graphical abstract

中文翻译：

外周血单核细胞中肠道病毒 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

目标/假设

肠道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 （解旋酶 C 结构域 1 诱导的干扰素）的变异导致遗传易感性，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)，支持肠道病毒感染与 1 型糖尿病之间的潜在联系糖尿病。

方法

我们使用分子技术检测了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，该队列由 79 名儿童或 72 名成人组成，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方法检测了 1 型糖尿病死后捐献者 ( n = 43) 胰岛中的肠道病毒蛋白 VP1。

结果

我们观察到，与外周血的非细胞区室相比，对细胞区室进行采样时检测灵敏度增强（OR 21.69；95% CI 3.64，229.20； p <0 id=81>p =0.0065）。此外，我们发现携带IFIH1常见变异（rs1990760、Thr946Ala）易感等位基因（946 ^Thr ）的个体更有可能在外周血中检测出肠道病毒呈阳性（OR 3.07；95% CI 1.02，8.58； p = 0.045））。相反，使用免疫组织化学发现， IFIH1的常见变异与 1 型糖尿病供者胰岛中肠道病毒 VP1 蛋白的检测之间没有相关性。