Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity

doi:10.1007/s00125-016-4177-z

. 2017 Mar;60(3):424-431.

doi: 10.1007/s00125-016-4177-z. Epub 2017 Jan 9.

Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity

Hanna Honkanen¹, Sami Oikarinen^{2

3}, Noora Nurminen², Olli H Laitinen^{4

5}, Heini Huhtala⁶, Jussi Lehtonen², Tanja Ruokoranta⁴, Minna M Hankaniemi^{4

5}, Valérie Lecouturier⁷, Jeffrey W Almond⁷, Sisko Tauriainen⁸, Olli Simell^{9

10}, Jorma Ilonen¹¹, Riitta Veijola¹², Hanna Viskari^{2

13}, Mikael Knip^{14

15

16

17}, Heikki Hyöty^{2

3}

Affiliations

¹ Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland. hanna.honkanen@uta.fi.
² Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland.
³ Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
⁴ Vactech Ltd, Tampere, Finland.
⁵ BioMediTech, University of Tampere, Tampere, Finland.
⁶ School of Health Sciences, University of Tampere, Tampere, Finland.
⁷ Sanofi-Pasteur, Marcy L'Etoile, France.
⁸ Department of Virology, University of Turku, Turku, Finland.
⁹ Department of Pediatrics and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
¹⁰ Department of Pediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland.
¹¹ Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
¹² Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
¹³ Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
¹⁴ Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
¹⁵ Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
¹⁶ Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
¹⁷ Folkhälsan Research Center, Helsinki, Finland.

PMID: 28070615
DOI: 10.1007/s00125-016-4177-z

Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity

Hanna Honkanen et al. Diabetologia. 2017 Mar.

. 2017 Mar;60(3):424-431.

doi: 10.1007/s00125-016-4177-z. Epub 2017 Jan 9.

Authors

Affiliations

¹ Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland. hanna.honkanen@uta.fi.
² Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland.
³ Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
⁴ Vactech Ltd, Tampere, Finland.
⁵ BioMediTech, University of Tampere, Tampere, Finland.
⁶ School of Health Sciences, University of Tampere, Tampere, Finland.
⁷ Sanofi-Pasteur, Marcy L'Etoile, France.
⁸ Department of Virology, University of Turku, Turku, Finland.
⁹ Department of Pediatrics and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
¹⁰ Department of Pediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland.
¹¹ Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
¹² Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
¹³ Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
¹⁴ Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
¹⁵ Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
¹⁶ Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
¹⁷ Folkhälsan Research Center, Helsinki, Finland.

PMID: 28070615
DOI: 10.1007/s00125-016-4177-z

Abstract

Aims/hypothesis: This case-control study was nested in a prospective birth cohort to evaluate whether the presence of enteroviruses in stools was associated with the appearance of islet autoimmunity in the Type 1 Diabetes Prediction and Prevention study in Finland.

Methods: Altogether, 1673 longitudinal stool samples from 129 case children who turned positive for multiple islet autoantibodies and 3108 stool samples from 282 matched control children were screened for the presence of enterovirus RNA using RT-PCR. Viral genotype was detected by sequencing.

Results: Case children had more enterovirus infections than control children (0.8 vs 0.6 infections per child). Time-dependent analysis indicated that this excess of infections occurred more than 1 year before the first detection of islet autoantibodies (6.3 vs 2.1 infections per 10 follow-up years). No such difference was seen in infections occurring less than 1 year before islet autoantibody seroconversion or after seroconversion. The most frequent enterovirus types included coxsackievirus A4 (28% of genotyped viruses), coxsackievirus A2 (14%) and coxsackievirus A16 (11%).

Conclusions/interpretation: The results suggest that enterovirus infections diagnosed by detecting viral RNA in stools are associated with the development of islet autoimmunity with a time lag of several months.

Keywords: Enterovirus; Genotyping; RT-PCR; Stool samples; Type 1 diabetes.

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References

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[1] Pediatr Diabetes. 2016 Jul;17 Suppl 22:8-16 - PubMed

[2] Pediatr Diabetes. 2016 Jul;17 Suppl 22:8-16 - PubMed

[3] J Med Virol. 2002 Dec;68(4):544-57 - PubMed

[4] J Med Virol. 2002 Dec;68(4):544-57 - PubMed

[5] Lancet. 2008 Nov 15;372(9651):1746-55 - PubMed

[6] Lancet. 2008 Nov 15;372(9651):1746-55 - PubMed

[7] J Med Virol. 2012 Jun;84(6):923-30 - PubMed

[8] J Med Virol. 2012 Jun;84(6):923-30 - PubMed

[9] Diabetes. 2011 Jan;60(1):276-9 - PubMed

[10] Diabetes. 2011 Jan;60(1):276-9 - PubMed

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Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity

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Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity

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