title: Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity.
abstract: 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.
  
  
  
  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.
  
  
  
  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%).
  
  
  
  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.
authors.affiliation: Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland. hanna.honkanen@uta.fi.
authors.forename: Hanna
authors.initials: H
authors.lastname: Honkanen
authors.affiliation: Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland.|Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Oikarinen
authors.affiliation: Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Nurminen
authors.affiliation: Vactech Ltd, Tampere, Finland.|BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Olli H
authors.initials: OH
authors.lastname: Laitinen
authors.affiliation: School of Health Sciences, University of Tampere, Tampere, Finland.
authors.forename: Heini
authors.initials: H
authors.lastname: Huhtala
authors.affiliation: Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Lehtonen
authors.affiliation: Vactech Ltd, Tampere, Finland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Ruokoranta
authors.affiliation: Vactech Ltd, Tampere, Finland.|BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Minna M
authors.initials: MM
authors.lastname: Hankaniemi
authors.affiliation: Sanofi-Pasteur, Marcy L'Etoile, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lecouturier
authors.affiliation: Sanofi-Pasteur, Marcy L'Etoile, France.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Almond
authors.affiliation: Department of Virology, University of Turku, Turku, Finland.
authors.forename: Sisko
authors.initials: S
authors.lastname: Tauriainen
authors.affiliation: Department of Pediatrics and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.|Department of Pediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.affiliation: Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland.|Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Viskari
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.|Department of Pediatrics, Tampere University Hospital, Tampere, Finland.|Folkhälsan Research Center, Helsinki, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: Department of Virology, University of Tampere, PL100, 33014, Tampereen yliopisto, Finland.|Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Hyöty
mesh_terms: D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D004770:Enterovirus / Q000276:immunology* / Q000472:pathogenicity*; D005243:Feces / Q000821:virology*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction
keywords: Enterovirus; Genotyping; RT-PCR; Stool samples; Type 1 diabetes