Innate Immune Activity Is Detected Prior to Seroconversion in Children With HLA-Conferred Type 1 Diabetes Susceptibility

Author:

Kallionpää Henna123,Elo Laura L.14,Laajala Essi1356,Mykkänen Juha1378,Ricaño-Ponce Isis9,Vaarma Matti10,Laajala Teemu D.1,Hyöty Heikki1112,Ilonen Jorma1314,Veijola Riitta15,Simell Tuula37,Wijmenga Cisca9,Knip Mikael3161718,Lähdesmäki Harri135,Simell Olli378,Lahesmaa Riitta13

Affiliation:

1. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland

2. Turku Doctoral Programme of Biomedical Sciences, Turku, Finland

3. The Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research, Helsinki, Finland

4. Biomathematics Research Group, Department of Mathematics, University of Turku, Turku, Finland

5. Department of Information and Computer Science, Aalto University School of Science, Aalto, Finland

6. The National Graduate School in Informational and Structural Biology, Turku, Finland

7. Department of Pediatrics, University of Turku, Turku, Finland

8. Department of Pediatrics, Turku University Hospital, Turku, Finland

9. Department of Genetics, University of Groningen, University Medical Centre, Groningen, the Netherlands

10. Department of Signal Processing, Tampere University of Technology, Tampere, Finland

11. Department of Virology, University of Tampere, Tampere, Finland

12. Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland

13. Immunogenetics Laboratory, University of Turku, Turku, Finland

14. Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland

15. Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland

16. Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

17. Folkhälsan Research Center, Helsinki, Finland

18. Department of Pediatrics, Tampere University Hospital, Tampere, Finland

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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