University of Oulu

Sioofy-Khojine, AB., Richardson, S.J., Locke, J.M. et al. 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 65, 1701–1709 (2022).

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

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Author: Sioofy-Khojine, Amir-Babak1; Richardson, Sarah J.2; Locke, Jonathan M.2;
Organizations: 1Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
2Exeter Centre of Excellence for Diabetes Research (EXCEED), Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
3Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
4Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
5Present address: Cambridge University Hospitals Genomics Laboratory, Cambridge University Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
6JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
7Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland
8Clinical Microbiology, Turku University Hospital, Turku, Finland
9Present address: 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
10Department for Children and Adolescents, Oulu University Hospital, Oulu, Finland
11Department of Paediatrics, Medical Research Center Oulu, University of Oulu, Oulu, Finland
12Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
13Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
14Center for Child Health Research, Tampere University Hospital, Tampere, Finland
15Department of Immunobiology, Faculty of Life Sciences & Medicine, King’s College London, London, UK
16National Institute for Health Research, Biomedical Research Centre at Guy’s and St Thomas’ National Health Service Foundation Trust, King’s College London, London, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.7 MB)
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Language: English
Published: Springer Nature, 2022
Publish Date: 2022-12-05


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 (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.

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.

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Series: Diabetologia
ISSN: 0012-186X
ISSN-E: 1432-0428
ISSN-L: 0012-186X
Volume: 65
Issue: 10
Pages: 1701 - 1709
DOI: 10.1007/s00125-022-05753-y
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
Funding: The study was supported by a centre grant Diabetes – Genes, Autoimmunity and Prevention (D-GAP) from the JDRF (1-2007-1803) to MP, JAT, P. Bingley (University of Bristol), T. Tree (King’s College London) and D. Dunger (University of Cambridge), a JDRF Career Development Award (5-CDA-2014-221-A-N) to SJR, a JDRF research grant awarded to the network of Pancreatic Organ Donors – Virus (nPOD-V) consortium (JDRF 25-2012-516), a Medical Research Council project grant (MR/P010695/1) awarded to SJR and NGM, a strategic award to JAT from the JDRF (4-SRA-2017-473-A-N) and the Wellcome Trust (07212/A/15/Z) and by the European Commission (Persistent Virus Infection in Diabetes Network [PEVNET] Frame Programme 7, coordinated by HH, contract number 261441). The virus analyses in Tampere University were additionally funded by grants to HH from the Sigrid Juselius Foundation and the Academy of Finland (grant number 288671). This study also reports independent research supported by the National Institute of Health Research Exeter Clinical Research Facility. Funders were not involved in the design and conduct of the study, the collection, analysis and interpretation of the data, or the preparation, review or approval of the manuscript. As such, the content is solely the responsibility of the authors and does not necessarily represent the official views of the funders. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising.
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