title: Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes.
abstract: Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it.
  
  
  
  Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays.
  
  
  
  Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of β2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both 'classical' HLA class I isoforms (i.e. HLA-ABC) as well as a 'non-classical' HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5. However, it was strongly associated with increased STAT1 expression in all three cohorts. Islet hyperexpression of HLA class I molecules occurred in the insulin-containing islets of patients with recent-onset type 1 diabetes and was also detectable in many patients with disease duration of up to 11 years, declining thereafter.
  
  
  
  Islet cell HLA class I hyperexpression is not an artefact, but is a hallmark in the immunopathogenesis of type 1 diabetes. The response is closely associated with elevated expression of STAT1 and, together, these occur uniquely in patients with type 1 diabetes, thereby contributing to their selective susceptibility to autoimmune-mediated destruction.
authors: Islet Biology Exeter (IBEx), Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Building (Level 4), Barrack Road, Exeter, EX2 5DW, UK. s.richardson@exeter.ac.uk.
authors: Sarah J
authors: SJ
authors: Richardson
authors: La Jolla Institute for Allergy and Immunology, San Diego, CA, USA.
authors: Teresa
authors: T
authors: Rodriguez-Calvo
authors: Department of Medicine, University of Tennessee, Memphis, TN, USA.
authors: Ivan C
authors: IC
authors: Gerling
authors: Department of Pathology, University of Florida, Gainesville, FL, USA.
authors: Clayton E
authors: CE
authors: Mathews
authors: Department of Information Sciences, City of Hope, Duarte, CA, USA.
authors: John S
authors: JS
authors: Kaddis
authors: Islet Biology Exeter (IBEx), Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Building (Level 4), Barrack Road, Exeter, EX2 5DW, UK.
authors: Mark A
authors: MA
authors: Russell
authors: Islet Biology Exeter (IBEx), Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Building (Level 4), Barrack Road, Exeter, EX2 5DW, UK.
authors: Marie
authors: M
authors: Zeissler
authors: Islet Biology Exeter (IBEx), Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Building (Level 4), Barrack Road, Exeter, EX2 5DW, UK.
authors: Pia
authors: P
authors: Leete
authors: Paediatric Department, Oslo University Hospital, Oslo, Norway.|Faculty of Medicine, University of Oslo, Oslo, Norway.
authors: Lars
authors: L
authors: Krogvold
authors: Paediatric Department, Oslo University Hospital, Oslo, Norway.|Faculty of Medicine, University of Oslo, Oslo, Norway.
authors: Knut
authors: K
authors: Dahl-Jørgensen
authors: La Jolla Institute for Allergy and Immunology, San Diego, CA, USA.
authors: Matthias
authors: M
authors: von Herrath
authors: Diabetes Research Institute, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: Alberto
authors: A
authors: Pugliese
authors: Department of Pathology, University of Florida, Gainesville, FL, USA.
authors: Mark A
authors: MA
authors: Atkinson
authors: Islet Biology Exeter (IBEx), Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Building (Level 4), Barrack Road, Exeter, EX2 5DW, UK. n.g.morgan@exeter.ac.uk.
authors: Noel G
authors: NG
authors: Morgan
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010179:Pancreas / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D007328:Insulin; D050794:STAT1 Transcription Factor
keywords: DiViD; HLA class I; HLA-F; Islet cell; Pancreas; STAT1; Type 1 diabetes; nPOD