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.

Autoreactive T cells in type 1 diabetes

“…This observation was confirmed with various methodologies in multiple patient cohorts (26) (Figure 2). Hyperexpression of HLA-I molecules helps explain the predominance of CD8 + T cells in insulitis.…”

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

“…Our present data, however, suggest that the roles of STAT1 and STAT2 are not redundant in beta cells, as the observed increase in STAT1 activation is not sufficient to compensate for the lack of STAT2. A very recent study has shown that HLA hyperexpression is strongly correlated with STAT1 expression in beta cellcontaining islets from type 1 diabetes patients [1]. STAT2 was not investigated in this study.…”

“…Furthermore, histological analysis and other approaches have identified higher expression of type I IFNs in islets from patients with type 1 diabetes [7][8][9][10], and self-reactive antibodies targeting type I IFNs are associated with protection against type 1 diabetes in patients with an autoimmune syndrome [20]. Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I [1,2], ER stress [3,37] and beta cell apoptosis [6], and we presently show that IFNα induces or contributes to these three phenomena in human beta cells.…”

“…Three hallmarks of the pancreatic islets in early human type 1 diabetes and in mouse models of the disease are overexpression of HLA class I [1,2], presence of markers of endoplasmic reticulum (ER) stress [3][4][5] and beta cell apoptosis [6]. The mediator(s) of these phenomena, however, remain(s) to be defined.…”

Narrowing in on the anti-β cell-specific T cells: looking ‘where the action is’

“…Cellular heterogeneity of B cells infiltrating the islets can be correlated with β-cell destruction, insulin-containing islets, and age of onset of T1D [38,40 ▪ ]. Interestingly, the hyperexpression of Human Leukocyte Antigen (HLA) Class I by pancreatic β cells [26,39,41,42 ▪ ,43] is associated with T1D, but can be heterogeneous in expression; this was seen as well even in those individuals with serum autoantibody, but without a clinical diagnosis of T1D [44]. However, the role of hyperexpression of HLA class I in T1D pathology remains under investigation.…”