Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes
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Islet autoimmunity usually starts with the appearance of autoantibodies against either insulin (IAA) or GAD65 (GADA). This categorises children with preclinical type 1 diabetes into two immune phenotypes, which differ in their genetic background and may have different aetiology. The aim was to study whether Coxsackievirus group B (CVB) infections, which have been linked to the initiation of islet autoimmunity, are associated with either of these two phenotypes in children with HLA-conferred susceptibility to type 1 diabetes.
All samples were from children in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Individuals are recruited to the DIPP study from the general population of new-born infants who carry defined HLA genotypes associated with susceptibility to type 1 diabetes. Our study cohort included 91 children who developed IAA and 78 children who developed GADA as their first appearing single autoantibody and remained persistently seropositive for islet autoantibodies, along with 181 and 151 individually matched autoantibody negative control children, respectively. Seroconversion to positivity for neutralising antibodies was detected as the surrogate marker of CVB infections in serial follow-up serum samples collected before and at the appearance of islet autoantibodies in each individual.
CVB1 infections were associated with the appearance of IAA as the first autoantibody (OR 2.4 [95% CI 1.4, 4.2], corrected p = 0.018). CVB5 infection also tended to be associated with the appearance of IAA, however, this did not reach statistical significance (OR 2.3, [0.7, 7.5], p = 0.163); no other CVB types were associated with increased risk of IAA. Children who had signs of a CVB1 infection either alone or prior to infections by other CVBs were at the highest risk for developing IAA (OR 5.3 [95% CI 2.4, 11.7], p < 0.001). None of the CVBs were associated with the appearance of GADA.
CVB1 infections may contribute to the initiation of islet autoimmunity being particularly important in the insulin-driven autoimmune process.
KeywordsCoxsackievirus group B Glutamic acid decarboxylase autoantibody (GADA) Insulin autoantibody (IAA) Islet autoimmunity Logistic regression Plaque reduction assay Type 1 Diabetes Prediction and Prevention (DIPP) Virus neutralising antibodies
Coxsackie and adenovirus receptor
Coxsackievirus group B
Islet cell antibody
Type 1 Diabetes Prediction and Prevention
The authors wish to thank J. Almond and V. Lecoutier (Sanofi-Pasteur, Marcy L’Etoile, France) as well as O. Simell (University of Turku, Turku, Finland) for excellent collaboration and A. Karjalainen, M. Kekäläinen, E. Jalonen, M. Ovaskainen and M. Lumme for their excellent technical assistance. The study was approved by the ethics committees of the participating university hospitals and the parents of the participating children gave their informed written consent to the participation in the study.
The corresponding author performed the laboratory analysis, researched the data and wrote the manuscript. HHy, JI, MK, JT, RV, MV-M provided the DIPP data and samples. NN, SO, OHL, OP, TR and MMH partially researched the data and all reviewed/edited manuscript. HHu and JL performed statistical analysis and reviewed the manuscript, MV-M, OHL, MMH, JL, JI, RV, MK, JT, OP and TR reviewed/edited the manuscript. HHy designed the study and contributed to the discussion and reviewed/edited the manuscript. HHy is the guarantor of this work and as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All co-authors have approved the final version.
This study was funded by the Competitive Research Funding of the Hospitals in Tampere, Oulu and Turku, the JDRF, the Academy of Finland, Diabetes Research Foundation in Finland, Sigrid Juselius Foundation, Reino Lahtikari Foundation, Sohlberg’s Foundation and the European Commission (Persistent Virus Infection in Diabetes Network [PEVNET] Frame Programme 7, Contract No. 261441). In addition, it was partly funded by Sanofi Pasteur and Vactech Ltd.
Compliance with ethical standards
Duality of interest
HHy and MK are minor (5%) shareholders and members of the board of Vactech Ltd., which develops vaccines against picornaviruses. Companies owned by their families are also shareholders of Vactech Ltd. No other potential conflicts of interest relevant to this article are reported. The sponsors funded the study but did not participate in the study design or the interpretation of the data.
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