Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes

Sarah J. Richardson, Teresa Rodriguez-Calvo, Ivan C. Gerling, Clayton E. Mathews, John S. Kaddis, Mark A. Russell, Marie Zeissler, Pia Leete, Lars Krogvold, Knut Dahl-Jørgensen, Matthias von Herrath, Alberto Pugliese, Mark A. Atkinson, Noel G. Morgan

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Aims/hypothesis: 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. Methods: 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. Results: 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. Conclusions/interpretation: 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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalDiabetologia
DOIs
StateAccepted/In press - Aug 9 2016

Fingerprint

Histocompatibility Antigens Class I
HLA Antigens
Type 1 Diabetes Mellitus
Islets of Langerhans
STAT1 Transcription Factor
Insulin
RNA
Pancreas
Protein Isoforms
Tissue Donors
Laser Capture Microdissection
Viruses
Insulin-Secreting Cells
Artifacts
Proteins
Up-Regulation
Hormones
Gene Expression

Keywords

  • DiViD
  • HLA class I
  • HLA-F
  • Islet cell
  • nPOD
  • Pancreas
  • STAT1
  • Type 1 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Richardson, S. J., Rodriguez-Calvo, T., Gerling, I. C., Mathews, C. E., Kaddis, J. S., Russell, M. A., ... Morgan, N. G. (Accepted/In press). Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia, 1-11. https://doi.org/10.1007/s00125-016-4067-4

Islet cell hyperexpression of HLA class I antigens : a defining feature in type 1 diabetes. / Richardson, Sarah J.; Rodriguez-Calvo, Teresa; Gerling, Ivan C.; Mathews, Clayton E.; Kaddis, John S.; Russell, Mark A.; Zeissler, Marie; Leete, Pia; Krogvold, Lars; Dahl-Jørgensen, Knut; von Herrath, Matthias; Pugliese, Alberto; Atkinson, Mark A.; Morgan, Noel G.

In: Diabetologia, 09.08.2016, p. 1-11.

Research output: Contribution to journalArticle

Richardson, SJ, Rodriguez-Calvo, T, Gerling, IC, Mathews, CE, Kaddis, JS, Russell, MA, Zeissler, M, Leete, P, Krogvold, L, Dahl-Jørgensen, K, von Herrath, M, Pugliese, A, Atkinson, MA & Morgan, NG 2016, 'Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes', Diabetologia, pp. 1-11. https://doi.org/10.1007/s00125-016-4067-4
Richardson SJ, Rodriguez-Calvo T, Gerling IC, Mathews CE, Kaddis JS, Russell MA et al. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia. 2016 Aug 9;1-11. https://doi.org/10.1007/s00125-016-4067-4
Richardson, Sarah J. ; Rodriguez-Calvo, Teresa ; Gerling, Ivan C. ; Mathews, Clayton E. ; Kaddis, John S. ; Russell, Mark A. ; Zeissler, Marie ; Leete, Pia ; Krogvold, Lars ; Dahl-Jørgensen, Knut ; von Herrath, Matthias ; Pugliese, Alberto ; Atkinson, Mark A. ; Morgan, Noel G. / Islet cell hyperexpression of HLA class I antigens : a defining feature in type 1 diabetes. In: Diabetologia. 2016 ; pp. 1-11.
@article{aee52d45371a4a9ab6d4be4a53872bdd,
title = "Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes",
abstract = "Aims/hypothesis: 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. Methods: 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. Results: 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. Conclusions/interpretation: 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.",
keywords = "DiViD, HLA class I, HLA-F, Islet cell, nPOD, Pancreas, STAT1, Type 1 diabetes",
author = "Richardson, {Sarah J.} and Teresa Rodriguez-Calvo and Gerling, {Ivan C.} and Mathews, {Clayton E.} and Kaddis, {John S.} and Russell, {Mark A.} and Marie Zeissler and Pia Leete and Lars Krogvold and Knut Dahl-J{\o}rgensen and {von Herrath}, Matthias and Alberto Pugliese and Atkinson, {Mark A.} and Morgan, {Noel G.}",
year = "2016",
month = "8",
day = "9",
doi = "10.1007/s00125-016-4067-4",
language = "English (US)",
pages = "1--11",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",

}

TY - JOUR

T1 - Islet cell hyperexpression of HLA class I antigens

T2 - a defining feature in type 1 diabetes

AU - Richardson, Sarah J.

AU - Rodriguez-Calvo, Teresa

AU - Gerling, Ivan C.

AU - Mathews, Clayton E.

AU - Kaddis, John S.

AU - Russell, Mark A.

AU - Zeissler, Marie

AU - Leete, Pia

AU - Krogvold, Lars

AU - Dahl-Jørgensen, Knut

AU - von Herrath, Matthias

AU - Pugliese, Alberto

AU - Atkinson, Mark A.

AU - Morgan, Noel G.

PY - 2016/8/9

Y1 - 2016/8/9

N2 - Aims/hypothesis: 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. Methods: 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. Results: 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. Conclusions/interpretation: 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.

AB - Aims/hypothesis: 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. Methods: 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. Results: 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. Conclusions/interpretation: 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.

KW - DiViD

KW - HLA class I

KW - HLA-F

KW - Islet cell

KW - nPOD

KW - Pancreas

KW - STAT1

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=84981244952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84981244952&partnerID=8YFLogxK

U2 - 10.1007/s00125-016-4067-4

DO - 10.1007/s00125-016-4067-4

M3 - Article

C2 - 27506584

AN - SCOPUS:84981244952

SP - 1

EP - 11

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

ER -