title: RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes.
abstract: OBJECTIVE
  The contribution of innate immunity responsible for aggressive β-cell destruction in human fulminant type 1 diabetes is unclear.
  
  
  METHODS
  Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes.
  
  
  RESULTS
  RIG-I was strongly expressed in β-cells in all three pancreata infected with enterovirus. Melanoma differentiation-associated gene-5 was hyperexpressed in islet cells, including β- and α-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN)-α and IFN-β were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-γ, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC-class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid-receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in β-cells. Serum levels of IFN-γ were markedly increased in patients with fulminant type 1 diabetes.
  
  
  CONCLUSIONS
  These findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive β-cell toxicity in fulminant type 1 diabetes.
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Aida
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Nishida
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tanaka
authors.forename: Taro
authors.initials: T
authors.lastname: Maruyama
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.forename: Takuya
authors.initials: T
authors.lastname: Awata
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimura
authors.forename: Soichi
authors.initials: S
authors.lastname: Takizawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Ichijo
authors.forename: Daiichiro
authors.initials: D
authors.lastname: Akiyama
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Furuya
authors.forename: Akio
authors.initials: A
authors.lastname: Kawaguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneshige
authors.forename: Jun
authors.initials: J
authors.lastname: Itakura
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Endo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016923:Cell Death / Q000276:immunology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D004769:Enterovirus Infections / Q000276:immunology / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D020382:Interleukin-18; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D016899:Interferon-beta; D007371:Interferon-gamma; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1