title: Enterovirus Exposure Uniquely Discriminates Type 1 Diabetes Patients with a Homozygous from a Heterozygous Melanoma Differentiation-Associated Protein 5/Interferon Induced with Helicase C Domain 1 A946T Genotype.
abstract: In children at risk for type 1 diabetes, innate immune activity is detected before seroconversion. Enterovirus infections have been linked to diabetes development, and a polymorphism (A946T) in the innate immune sensor recognizing enterovirus RNA, interferon-induced with helicase C domain 1/melanoma differentiation-associated protein 5, predisposes to disease. We hypothesized that the strength of innate antienteroviral responses is affected in autoimmune type 1 diabetes patients and linked to the A946T polymorphism. We compared induction of interferon-stimulated genes (ISGs) in peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) in healthy individuals and diabetes patients upon stimulation with enterovirus, enterovirus-antibody complexes, or ligands mimicking infection in relation to the A946T polymorphism. Overall, PBMCs of diabetes patients and healthy donors showed comparable ISG induction upon stimulation. No differences were observed in DCs. Interestingly, the data imply that the magnitude of responses to enterovirus and enterovirus-antibody complexes in PBMCs is critically influenced by the A946T polymorphism and elevated in heterozygotes compared to TT homozygous individuals in autoimmune diabetes patients, but not healthy controls. These data imply an intrinsic difference in the responses to enterovirus and enterovirus-antibody complexes in diabetes patients carrying a TT risk genotype compared to heterozygotes that may influence control of enterovirus clearance.
authors.affiliation: 1 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Schulte
authors.affiliation: 1 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gielen
authors.affiliation: 1 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Esther D
authors.initials: ED
authors.lastname: Kers-Rebel
authors.affiliation: 1 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Amy C
authors.initials: AC
authors.lastname: Prosser
authors.affiliation: 2 Department of Medicine HS, Karolinska Institutet , The Center for Infectious Medicine, Stockholm, Sweden .
authors.forename: Katharina
authors.initials: K
authors.lastname: Lind
authors.affiliation: 2 Department of Medicine HS, Karolinska Institutet , The Center for Infectious Medicine, Stockholm, Sweden .
authors.forename: Malin
authors.initials: M
authors.lastname: Flodström-Tullberg
authors.affiliation: 3 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.affiliation: 3 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Lammy D
authors.initials: LD
authors.lastname: Elving
authors.affiliation: 1 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004770:Enterovirus / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors / Q000096:biosynthesis; D000072640:Interferon-Induced Helicase, IFIH1 / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D007155:Immunologic Factors; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1