Abstract
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 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 IFNα/β 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 β cells. Here, we review the evidence supporting the diabetogenic potential of T1-IFN in the islet microenvironment.
Highlights
Type 1 diabetes (T1D) results from an autoimmune-mediated attack that targets insulin (INS)-secreting pancreatic beta (β) cells
We find upregulation of transcripts critically required for the MHC class I (MHC-I) antigen processing and presentation
It is well appreciated that the immune system plays a critical role in diminishing β cell mass, precipitating the onset of persistent hyperglycemia
Summary
Type 1 diabetes (T1D) results from an autoimmune-mediated attack that targets insulin (INS)-secreting pancreatic beta (β) cells. Numerous additional loci outside of the HLA region summate the remaining genetic risk for diabetes development, the individual odds ratios conferred by these regions are modest [11, 12] Several of these genes are thought to influence tolerance mechanisms facilitating the escape of autoreactive T cells into the periphery. Compelling evidence in primary human islets reveals that presence of the homozygous risk allele decreases the autonomous innate response to Coxsackievirus B3 [73] These data suggest that the A946T risk variant in IFIH1 may act as a double-edged sword, predisposing β cells to persistent enteroviral infection while concurrently promoting deleterious T1-IFN production in and around the islet microenvironment
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