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

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.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
Humans
Child
Autoantibodies
Diabetes Mellitus, Type 1
Transcriptome
Autoimmunity/genetics
Insulin/metabolism
Enterovirus Infections/genetics
Islets of Langerhans/metabolism

Moradi, ElahehUniversity of Tampere (författare)
Salenius, KaroliinaUniversity of Tampere (författare)
Lehtipuro, SuviUniversity of Tampere (författare)
Häkkinen, TomiUniversity of Tampere (författare)
Laiho, Jutta EUniversity of Tampere (författare)
Oikarinen, SamiUniversity of Tampere (författare)
Randelin, SofiaUniversity of Tampere (författare)
Parikh, Hemang MUniversity of South Florida(Swepub:lu)he5472pa (författare)
Krischer, Jeffrey PUniversity of South Florida (författare)
Toppari, JormaUniversity of Turku (författare)
Lernmark, ÅkeLund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Celiac Disease and Diabetes Unit,Lund University Research Groups,Skåne University Hospital(Swepub:lu)endo-ale (författare)
Petrosino, Joseph FBaylor College of Medicine (författare)
Ajami, Nadim JBaylor College of Medicine (författare)
She, Jin-XiongJinfiniti Precision Medicine (författare)
Hagopian, William APacific Northwest Research Institute (författare)
Rewers, Marian J (författare)
Lloyd, Richard E (författare)
Rautajoki, Kirsi J (författare)
Hyöty, Heikki (författare)
Nykter, Matti (författare)
University of TampereUniversity of South Florida (creator_code:org_t)
TEDDY Study Group

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