Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection

Jake Lin, Elaheh Moradi, Karoliina Salenius, Suvi Lehtipuro, Tomi Häkkinen, Jutta E. Laiho, Sami Oikarinen, Sofia Randelin, Hemang M. Parikh, Jeffrey P. Krischer, Jorma Toppari, Åke Lernmark, Joseph F. Petrosino, Nadim J. Ajami, Jin-Xiong She, William A. Hagopian, Marian J. Rewers, Richard E. Lloyd, Kirsi J. Rautajoki (), Heikki Hyöty () and Matti Nykter ()
Additional contact information
Jake Lin: Tampere University and Tays Cancer Centre
Elaheh Moradi: Tampere University and Tays Cancer Centre
Karoliina Salenius: Tampere University and Tays Cancer Centre
Suvi Lehtipuro: Tampere University and Tays Cancer Centre
Tomi Häkkinen: Tampere University and Tays Cancer Centre
Jutta E. Laiho: Tampere University
Sami Oikarinen: Tampere University
Sofia Randelin: Tampere University and Tays Cancer Centre
Hemang M. Parikh: University of South Florida
Jeffrey P. Krischer: University of South Florida
Jorma Toppari: University of Turku
Åke Lernmark: Lund University CRC, Skåne University Hospital
Joseph F. Petrosino: Baylor College of Medicine
Nadim J. Ajami: Baylor College of Medicine
Jin-Xiong She: Jinfiniti Precision Medicine, Inc.
William A. Hagopian: Pacific Northwest Research Institute
Marian J. Rewers: University of Colorado
Richard E. Lloyd: Baylor College of Medicine
Kirsi J. Rautajoki: Tampere University and Tays Cancer Centre
Heikki Hyöty: Tampere University
Matti Nykter: Tampere University and Tays Cancer Centre

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Although the genetic basis and pathogenesis of type 1 diabetes have been studied extensively, how host responses to environmental factors might contribute to autoantibody development remains largely unknown. Here, we use longitudinal blood transcriptome sequencing data to characterize host responses in children within 12 months prior to the appearance of type 1 diabetes-linked islet autoantibodies, as well as matched control children. We report that children who present with insulin-specific autoantibodies first have distinct transcriptional profiles from those who develop GADA autoantibodies first. In particular, gene dosage-driven expression of GSTM1 is associated with GADA autoantibody positivity. Moreover, compared with controls, we observe increased monocyte and decreased B cell proportions 9-12 months prior to autoantibody positivity, especially in children who developed antibodies against insulin first. Lastly, we show that control children present transcriptional signatures consistent with robust immune responses to enterovirus infection, whereas children who later developed islet autoimmunity do not. These findings highlight distinct immune-related transcriptomic differences between case and control children prior to case progression to islet autoimmunity and uncover deficient antiviral response in children who later develop islet autoimmunity.

Date: 2023
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DOI: 10.1038/s41467-023-42763-9

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