title: Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes.
abstract: OBJECTIVE
  Fulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated beta-cell failure are unclear.
  
  
  METHODS
  Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2-5 days after onset of fulminant type 1 diabetes. We examined islet cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility complex (MHC) expressions in the pancreata using immunohistochemical analyses and RT-PCR.
  
  
  RESULTS
  Immunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3 receptor-bearing T-cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-gamma and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including beta-cells and alpha-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells.
  
  
  CONCLUSIONS
  These results strongly suggest the presence of a circuit for the destruction of beta-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-gamma and CXCL10 in beta-cells. CXCL10 secreted from beta-cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-gamma in the islets, not only damaging beta-cells but also accelerating CXCL10 generation in residual beta-cells and thus further activating cell-mediated autoimmunity until all beta-cells have been destroyed.
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tanaka
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Nishida
authors.forename: Kaoru
authors.initials: K
authors.lastname: Aida
authors.forename: Taro
authors.initials: T
authors.lastname: Maruyama
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
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: Takahashi
authors.forename: Daiichiro
authors.initials: D
authors.lastname: Akiyama
authors.forename: Sayaka
authors.initials: S
authors.lastname: Arai-Yamashita
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: Ryohei
authors.initials: R
authors.lastname: Katoh
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Endo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000328:Adult; D000368:Aged; D001344:Autopsy; D036022:Capsid Proteins / Q000235:genetics; D054357:Chemokine CXCL10 / Q000097:blood / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000276:immunology / Q000473:pathology*; D016883:Diabetic Ketoacidosis / Q000235:genetics / Q000473:pathology; D004769:Enterovirus Infections / Q000097:blood / Q000150:complications* / Q000276:immunology; D017809:Fatal Outcome; D005260:Female; D006681:HLA-D Antigens / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D054367:Receptors, CXCR3 / Q000235:genetics*
chemical_list: C515187:CXCR3 protein, human; D036022:Capsid Proteins; D054357:Chemokine CXCL10; D006681:HLA-D Antigens; D015395:Histocompatibility Antigens Class I; D012367:RNA, Viral; D054367:Receptors, CXCR3