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Type I Interferon Is a Catastrophic Feature of the Diabetic Islet Microenvironment.

ABSTRACT: A detailed understanding of the molecular pathways and cellular interactions that result in islet beta cell (? cell) destruction is essential for the development and implementation of effective therapies for prevention or reversal of type 1 diabetes (T1D). However, events that define the pathogenesis of human T1D have remained elusive. This gap in our knowledge results from the complex interaction between genetics, the immune system, and environmental factors that precipitate T1D in humans. A link between genetics, the immune system, and environmental factors are type 1 interferons (T1-IFNs). These cytokines are well known for inducing antiviral factors that limit infection by regulating innate and adaptive immune responses. Further, several T1D genetic risk loci are within genes that link innate and adaptive immune cell responses to T1-IFN. An additional clue that links T1-IFN to T1D is that these cytokines are a known constituent of the autoinflammatory milieu within the pancreas of patients with T1D. The presence of IFN?/? is correlated with characteristic MHC class I (MHC-I) hyperexpression found in the islets of patients with T1D, suggesting that T1-IFNs modulate the cross-talk between autoreactive cytotoxic CD8+ T lymphocytes and insulin-producing pancreatic ? cells. Here, we review the evidence supporting the diabetogenic potential of T1-IFN in the islet microenvironment.

SUBMITTER: Newby BN

PROVIDER: S-EPMC5604085 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Type I Interferon Is a Catastrophic Feature of the Diabetic Islet Microenvironment.

Newby Brittney N BN Mathews Clayton E CE

Frontiers in endocrinology 20170914

A detailed understanding of the molecular pathways and cellular interactions that result in islet beta cell (β cell) destruction is essential for the development and implementation of effective therapies for prevention or reversal of type 1 diabetes (T1D). However, events that define the pathogenesis of human T1D have remained elusive. This gap in our knowledge results from the complex interaction between genetics, the immune system, and environmental factors that precipitate T1D in humans. A li ...[more]

PMID: 28959234

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Project description:Aims/hypothesisHuman 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.MethodsPancreas 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.ResultsHyperexpression 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/interpretationIslet 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.

Project description:Pericytes (PCs) are multipotent contractile cells that wrap around the endothelial cells to maintain the blood vessel's functionality and integrity. The hyperglycemia associated with Type 2 diabetes mellitus (T2DM) was shown to impair the function of PCs and increase the risk of diabetes complications. In this study, we aimed to investigate the deleterious effect of the diabetic microenvironment on the regenerative capacities of human PCs. PCs isolated from human adipose tissue were cultured in the presence or absence of serum collected from diabetic patients (DS). The functionality of PCs was analysed after 6, 14, and 30 days. Microscopic examination of PCs cultured in DS (DS-PCs) showed increased aggregate formation and altered surface topography with hyperbolic invaginations. Compared to PCs cultured in normal serum (NS-PCs), DS-PCs showed more fragmented mitochondria and thicker nuclear membrane. DS caused impaired angiogenic differentiation of PCs as confirmed by tube formation, decreased VEGF-A and IGF-1 gene expression, upregulated TSP1, PF4, actin related protein 2/3 complex and downregulated COL21A1 protein expression. These cells suffered higher apoptotis and showed higher expression of Clic4, apoptosis facilitator BCl-2-like protein serine/threonine protein phosphatase, and Caspase-7 proteins. DS-PCs showed dysregulated DNA repair genes CDKN1A, SIRT1, XRCC5 and TERF2 and up-regulation of the pro-inflammatory genes ICAM1, IL-6, and TNF-α. DS treated cells also showed disruption in the expression of the focal adhesion and binding proeins TSP1, TGF- β, fibronectin and PCDH7. DS-PCs showed resistance mechanisms upon exposure to diabetic microenvironment by maitining the intracellular ROS level and upregulation of ECM organizing proteins vinculin, IQGAP1, and tubulin beta chain.These data show that the diabetic microenvironment exert a deleterious effect on the regenerative capacities of human adipose tissue-derived PCs, and may thus have possible implications on the vascular complications of type-2 diabetes mellitus. Nevertheless, their protective mechanisms when initially exposed to DS could provide a promising cellular therapy for T2DM.

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Type I Interferon Is a Catastrophic Feature of the Diabetic Islet Microenvironment.

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Type I Interferon Is a Catastrophic Feature of the Diabetic Islet Microenvironment.

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