Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes
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Abstract
Aims/hypothesis
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.
Methods
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.
Results
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.
Conclusions/interpretation
CVB1 infections may contribute to the initiation of islet autoimmunity being particularly important in the insulin-driven autoimmune process.
Keywords
Coxsackievirus 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 antibodiesAbbreviations
- CAR
Coxsackie and adenovirus receptor
- CVB
Coxsackievirus group B
- GADA
GAD65 autoantibody
- IAA
Insulin autoantibody
- ICA
Islet cell antibody
- DIPP
Type 1 Diabetes Prediction and Prevention
Notes
Acknowledgements
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.
Contribution statement
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.
Funding
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.
Supplementary material
References
- 1.Arvan P, Pietropaolo M, Ostrov D, Rhodes CJ (2012) Islet autoantigens: structure, function, localization, and regulation. Cold Spring Harb Perspect Med 2:a007658Google Scholar
- 2.Eizirik DL, Colli ML, Ortis F (2009) The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol 5:219–226CrossRefPubMedGoogle Scholar
- 3.Kutlu B, Burdick D, Baxter D et al (2009) Detailed transcriptome atlas of the pancreatic beta cell. BMC Med Genet 2:3-8794-2-3Google Scholar
- 4.Wang C, Mao R, Van de Casteele M, Pipeleers D, Ling Z (2007) Glucagon-like peptide-1 stimulates GABA formation by pancreatic beta-cells at the level of glutamate decarboxylase. Am J Physiol Endocrinol Metab 292:E1201–E1206CrossRefPubMedGoogle Scholar
- 5.Ilonen J, Hammais A, Laine AP et al (2013) Patterns of beta-cell autoantibody appearance and genetic associations during the first years of life. Diabetes 62:3636–3640CrossRefPubMedCentralPubMedGoogle Scholar
- 6.Krischer JP, Lynch KF, Schatz DA et al (2015) The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia 58:980–987CrossRefPubMedCentralPubMedGoogle Scholar
- 7.Laitinen OH, Honkanen H, Pakkanen O et al (2014) Coxsackievirus B1 is associated with induction of beta-cell autoimmunity that portends type 1 diabetes. Diabetes 63:446–455CrossRefPubMedGoogle Scholar
- 8.Oikarinen S, Tauriainen S, Hober D et al (2014) Virus antibody survey in different European populations indicates risk association between coxsackievirus B1 and type 1 diabetes. Diabetes 63:655–662CrossRefPubMedGoogle Scholar
- 9.Nanto-Salonen K, Kupila A, Simell S et al (2008) Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 372:1746–1755CrossRefPubMedGoogle Scholar
- 10.Ilonen J, Kiviniemi M, Lempainen J et al (2016) Genetic susceptibility to type 1 diabetes in childhood - estimation of HLA class II associated disease risk and class II effect in various phases of islet autoimmunity. Pediatr Diabetes 17(Suppl 22):8–16CrossRefPubMedGoogle Scholar
- 11.Knip M, Virtanen SM, Seppa K et al (2010) Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 363:1900–1908CrossRefPubMedCentralPubMedGoogle Scholar
- 12.World Health Organization. Department of Noncommunicable Disease Surveillance. (1999) Definition, diagnosis and classification of diabetes mellitus and its complications : report of a WHO consultation. Part 1, Diagnosis and classification of diabetes mellitus. World Health Organization, Department of Noncommunicable Disease Surveillance, GenevaGoogle Scholar
- 13.Lonnrot M, Lynch KF, Elding Larsson H et al (2017) Correction to: respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study. Diabetologia 61:254CrossRefGoogle Scholar
- 14.Oikarinen M, Tauriainen S, Honkanen T et al (2008) Analysis of pancreas tissue in a child positive for islet cell antibodies. Diabetologia 51:1796–1802CrossRefPubMedGoogle Scholar
- 15.Sarmiento L, Frisk G, Anagandula M, Cabrera-Rode E, Roivainen M, Cilio CM (2013) Expression of innate immunity genes and damage of primary human pancreatic islets by epidemic strains of Echovirus: implication for post-virus islet autoimmunity. PLoS One 8:e77850CrossRefPubMedCentralPubMedGoogle Scholar
- 16.Frisk G, Diderholm H (2000) Tissue culture of isolated human pancreatic islets infected with different strains of coxsackievirus B4: assessment of virus replication and effects on islet morphology and insulin release. Int J Exp Diabetes Res 1:165–175CrossRefPubMedCentralPubMedGoogle Scholar
- 17.Hodik M, Anagandula M, Fuxe J et al (2016) Coxsackie-adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes. BMJ Open Diabetes Res Care 4:e000219CrossRefPubMedCentralPubMedGoogle Scholar
- 18.Jenson AB, Rosenberg HS, Notkins AL (1980) Pancreatic islet-cell damage in children with fatal viral infections. Lancet 2:354–358PubMedGoogle Scholar
- 19.Ujevich MM, Jaffe R (1980) Pancreatic islet cell damage. Its occurrence in neonatal coxsackievirus encephalomyocarditis. Arch Pathol Lab Med 104:438–441PubMedGoogle Scholar
- 20.Dotta F, Censini S, van Halteren AG et al (2007) Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A 104:5115–5120CrossRefPubMedCentralPubMedGoogle Scholar
- 21.Richardson SJ, Leete P, Bone AJ, Foulis AK, Morgan NG (2013) Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1. Diabetologia 56:185–193CrossRefPubMedGoogle Scholar
- 22.Krogvold L, Edwin B, Buanes T et al (2015) Detection of a low-grade enteroviral infection in the islets of langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes 64:1682–1687CrossRefPubMedGoogle Scholar
- 23.Klingel K, Hohenadl C, Canu A et al (1992) Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. Proc Natl Acad Sci U S A 89:314–318CrossRefPubMedCentralPubMedGoogle Scholar
- 24.Andreoletti L, Hober D, Becquart P et al (1997) Experimental CVB3-induced chronic myocarditis in two murine strains: evidence of interrelationships between virus replication and myocardial damage in persistent cardiac infection. J Med Virol 52:206–214CrossRefPubMedGoogle Scholar
- 25.Klingel K, Stephan S, Sauter M et al (1996) Pathogenesis of murine enterovirus myocarditis: virus dissemination and immune cell targets. J Virol 70:8888–8895PubMedCentralPubMedGoogle Scholar
- 26.Chapman NM, Kim KS, Drescher KM, Oka K, Tracy S (2008) 5′ terminal deletions in the genome of a coxsackievirus B2 strain occurred naturally in human heart. Virology 375:480–491CrossRefPubMedCentralPubMedGoogle Scholar
- 27.Kim KS, Tracy S, Tapprich W et al (2005) 5′-terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA. J Virol 79:7024–7041CrossRefPubMedCentralPubMedGoogle Scholar
- 28.Oka K, Oohira K, Yatabe Y et al (2005) Fulminant myocarditis demonstrating uncommon morphology—a report of two autopsy cases. Virchows Arch 446:259–264CrossRefPubMedGoogle Scholar
- 29.Ashton MP, Eugster A, Walther D et al (2016) Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin. Sci Rep 6:32899CrossRefPubMedCentralPubMedGoogle Scholar
- 30.Landau BJ, Whittier PS, Finkelstein SD et al (1990) Induction of heterotypic virus resistance in adult inbred mice immunized with a variant of Coxsackievirus B3. Microb Pathog 8:289–298CrossRefPubMedGoogle Scholar
- 31.Kutubuddin M, Simons J, Chow M (1992) Identification of T-helper epitopes in the VP1 capsid protein of poliovirus. J Virol 66:3042–3047PubMedCentralPubMedGoogle Scholar
- 32.Mahon BP, Katrak K, Mills KH (1992) Antigenic sequences of poliovirus recognized by T cells: serotype-specific epitopes on VP1 and VP3 and cross-reactive epitopes on VP4 defined by using CD4+ T-cell clones. J Virol 66:7012–7020PubMedCentralPubMedGoogle Scholar
- 33.Katrak K, Mahon BP, Minor PD, Mills KH (1991) Cellular and humoral immune responses to poliovirus in mice: a role for helper T cells in heterotypic immunity to poliovirus. J Gen Virol 72(Pt 5):1093–1098CrossRefPubMedGoogle Scholar
- 34.Beck MA, Tracy SM (1989) Murine cell-mediated immune response recognizes an enterovirus group-specific antigen(s). J Virol 63:4148–4156PubMedCentralPubMedGoogle Scholar
- 35.Wang KG, Sun LZ, Jubelt B, Waltenbaugh C (1989) Cell-mediated immune responses to poliovirus. I. Conditions for induction, characterization of effector cells, and cross-reactivity between serotypes for delayed hypersensitivity and T cell proliferative responses. Cell Immunol 119:252–262CrossRefPubMedGoogle Scholar
- 36.Drescher KM, von Herrath M, Tracy S (2015) Enteroviruses, hygiene and type 1 diabetes: toward a preventive vaccine. Rev Med Virol 25:19–32CrossRefPubMedGoogle Scholar
- 37.Yoon JW, Austin M, Onodera T, Notkins AL (1979) Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 300:1173–1179CrossRefPubMedGoogle Scholar
- 38.Lukashev AN, Lashkevich VA, Ivanova OE, Koroleva GA, Hinkkanen AE, Ilonen J (2005) Recombination in circulating human enterovirus B: independent evolution of structural and non-structural genome regions. J Gen Virol 86:3281–3290CrossRefPubMedGoogle Scholar
- 39.Hamalainen S, Nurminen N, Ahlfors H et al (2014) Coxsackievirus B1 reveals strain specific differences in plasmacytoid dendritic cell mediated immunogenicity. J Med Virol 86:1412–1420CrossRefPubMedGoogle Scholar
- 40.Anagandula M, Richardson SJ, Oberste MS et al (2014) Infection of human islets of langerhans with two strains of Coxsackie B virus serotype 1: assessment of virus replication, degree of cell death and induction of genes involved in the innate immunity pathway. J Med Virol 86:1402–1411CrossRefPubMedGoogle Scholar
- 41.Viskari HR, Koskela P, Lonnrot M et al (2000) Can enterovirus infections explain the increasing incidence of type 1 diabetes? Diabetes Care 23:414–416CrossRefPubMedGoogle Scholar
- 42.Honkanen H, Oikarinen S, Nurminen N et al (2017) Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity. Diabetologia 60:424–431CrossRefPubMedGoogle Scholar
- 43.Oikarinen S, Martiskainen M, Tauriainen S et al (2011) Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes 60:276–279CrossRefPubMedGoogle Scholar
- 44.Sedgwick P (2014) Nested case-control studies: advantages and disadvantages. BMJ 348:g1532CrossRefGoogle Scholar