title: Coxsackie-adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes.
abstract: OBJECTIVE
  One of the theories connecting enterovirus (EV) infection of human islets with type 1 diabetes (T1D) is the development of a fertile field in the islets. This implies induction of appropriate proteins for the viral replication such as the coxsackie-adenovirus receptor (CAR). The aim of this study was to investigate to what extent CAR is expressed in human islets of Langerhans, and what conditions that would change the expression.
  
  
  METHODS
  Immunohistochemistry for CAR was performed on paraffin-embedded pancreatic tissue from patients with T1D (n=9 recent onset T1D, n=4 long-standing T1D), islet autoantibody-positive individuals (n=14) and non-diabetic controls (n=24) individuals. The expression of CAR was also examined by reverse transcription PCR on microdissected islets (n=5), exocrine tissue (n=5) and on explanted islets infected with EV or exposed to chemokines produced by EV-infected islet cells.
  
  
  RESULTS
  An increased frequency of patients with T1D and autoantibody-positive individuals expressed CAR in the pancreas (p<0.039). CAR staining was detected more frequently in pancreatic islets from patients with T1D and autoantibody-positive subjects (15/27) compared with (6/24) non-diabetic controls (p<0.033). Also in explanted islets cultured in UV-treated culture medium from coxsackievirus B (CBV)-1-infected islets, the expression of the CAR gene was increased compared with controls. Laser microdissection of pancreatic tissue revealed that CAR expression was 10-fold higher in endocrine compared with exocrine cells of the pancreas. CAR was also expressed in explanted islets and the expression level decreased with time in culture. CBV-1 infection of explanted islets clearly decreased the expression of CAR (p<0.05). In contrast, infection with echovirus 6 did not affect the expression of CAR.
  
  
  CONCLUSIONS
  CAR is expressed in pancreatic islets of patients with T1D and the expression level of CAR is increased in explanted islets exposed to proinflammatory cytokines/chemokines produced by infected islets. T1D is associated with increased levels of certain chemokines/cytokines in the islets and this might be the mechanism behind the increased expression of CAR in TID islets.
authors.affiliation: Department of Immunology, Genetics and Pathology , Uppsala University, The Rudbeck Laboratory , Uppsala, Uppland , Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Hodik
authors.affiliation: Department of Immunology, Genetics and Pathology , Uppsala University, The Rudbeck Laboratory , Uppsala, Uppland , Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Anagandula
authors.affiliation: Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Fuxe
authors.affiliation: Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo and Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Krogvold
authors.affiliation: Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo and Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Dahl-Jørgensen
authors.affiliation: Department of Virology, University of Tampere, Tampere, Finland; FimlabLaboratories, Pirkanmaa Hospital District, Tampere, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Hyöty
authors.affiliation: Autoimmunity Unit, Department of Clinical Sciences , Skåne University Hospital, Lund University , Malmo , Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Sarmiento
authors.affiliation: Department of Immunology, Genetics and Pathology , Uppsala University, The Rudbeck Laboratory , Uppsala, Uppland , Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Frisk
keywords: Islet of Langerhans; Receptor(s); Type 1; Virus