title: Innate immune activity is detected prior to seroconversion in children with HLA-conferred type 1 diabetes susceptibility.
abstract: The insult leading to autoantibody development in children who will progress to develop type 1 diabetes (T1D) has remained elusive. To investigate the genes and molecular pathways in the pathogenesis of this disease, we performed genome-wide transcriptomics analysis on a unique series of prospective whole-blood RNA samples from at-risk children collected in the Finnish Type 1 Diabetes Prediction and Prevention study. We studied 28 autoantibody-positive children, out of which 22 progressed to clinical disease. Collectively, the samples covered the time span from before the development of autoantibodies (seroconversion) through the diagnosis of diabetes. Healthy control subjects matched for date and place of birth, sex, and HLA-DQB1 susceptibility were selected for each case. Additionally, we genotyped the study subjects with Immunochip to identify potential genetic variants associated with the observed transcriptional signatures. Genes and pathways related to innate immunity functions, such as the type 1 interferon (IFN) response, were active, and IFN response factors were identified as central mediators of the IFN-related transcriptional changes. Importantly, this signature was detected already before the T1D-associated autoantibodies were detected. Together, these data provide a unique resource for new hypotheses explaining T1D biology.
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FinlandTurku Doctoral Programme of Biomedical Sciences, Turku, FinlandThe Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Kallionpää
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FinlandBiomathematics Research Group, Department of Mathematics, University of Turku, Turku, Finland.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Elo
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FinlandThe Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, FinlandDepartment of Information and Computer Science, Aalto University School of Science, Aalto, FinlandThe National Graduate School in Informational and Structural Biology, Turku, Finland.
authors.forename: Essi
authors.initials: E
authors.lastname: Laajala
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FinlandThe Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, FinlandDepartment of Pediatrics, University of Turku, Turku, FinlandDepartment of Pediatrics, Turku University Hospital, Turku, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Mykkänen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre, Groningen, the Netherlands.
authors.forename: Isis
authors.initials: I
authors.lastname: Ricaño-Ponce
authors.affiliation: Department of Signal Processing, Tampere University of Technology, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Vaarma
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors.forename: Teemu D
authors.initials: TD
authors.lastname: Laajala
authors.affiliation: Department of Virology, University of Tampere, Tampere, FinlandFimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Hyöty
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, FinlandDepartment of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.affiliation: The Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, FinlandDepartment of Pediatrics, University of Turku, Turku, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Simell
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre, Groningen, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: The Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, FinlandChildren's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandFolkhälsan Research Center, Helsinki, FinlandDepartment of Pediatrics, Tampere University Hospital, Tampere, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FinlandThe Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, FinlandDepartment of Information and Computer Science, Aalto University School of Science, Aalto, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.affiliation: The Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, FinlandDepartment of Pediatrics, University of Turku, Turku, FinlandDepartment of Pediatrics, Turku University Hospital, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FinlandThe Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, Finland riitta.lahesmaa@btk.fi.
authors.forename: Riitta
authors.initials: R
authors.lastname: Lahesmaa
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D059467:Transcriptome
chemical_list: D001323:Autoantibodies; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen