title: A Critical Role for the Type I Interferon Receptor in Virus-Induced Autoimmune Diabetes in Rats.
abstract: The pathogenesis of human type 1 diabetes, characterized by immune-mediated damage of insulin-producing β-cells of pancreatic islets, may involve viral infection. Essential components of the innate immune antiviral response, including type I interferon (IFN) and IFN receptor-mediated signaling pathways, are candidates for determining susceptibility to human type 1 diabetes. Numerous aspects of human type 1 diabetes pathogenesis are recapitulated in the LEW.1WR1 rat model. Diabetes can be induced in LEW.1WR1 weanling rats challenged with virus or with the viral mimetic polyinosinic:polycytidylic acid (poly I:C). We hypothesized that disrupting the cognate type I IFN receptor (type I IFN α/β receptor [IFNAR]) to interrupt IFN signaling would prevent or delay the development of virus-induced diabetes. We generated IFNAR1 subunit-deficient LEW.1WR1 rats using CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-associated protein 9) genome editing and confirmed functional disruption of the Ifnar1 gene. IFNAR1 deficiency significantly delayed the onset and frequency of diabetes and greatly reduced the intensity of insulitis after poly I:C treatment. The occurrence of Kilham rat virus-induced diabetes was also diminished in IFNAR1-deficient animals. These findings firmly establish that alterations in innate immunity influence the course of autoimmune diabetes and support the use of targeted strategies to limit or prevent the development of type 1 diabetes.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Qaisar
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Suvana
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Glennice
authors.initials: G
authors.lastname: Ryan
authors.affiliation: Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Chaoxing
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Oikemus
authors.affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Brodsky
authors.affiliation: Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Rita
authors.initials: R
authors.lastname: Bortell
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA jennifer.wang@umassmed.edu.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Wang
mesh_terms: D000818:Animals; D064113:CRISPR-Cas Systems / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D005260:Female; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology; D007370:Interferon Type I / Q000378:metabolism; D008297:Male; D017992:Parvovirus / Q000235:genetics / Q000502:physiology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta