Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

Abstract

A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-γ/interleukin-1β or IFN-α.

Revealing enterovirus infection in chronic human disorders: An integrated diagnostic approach

“…EV capsid antigens are expressed in cardiomyocytes of subjects with chronic cardiomyopathy 14, 46, 51, 52 , as well as in pancreatic beta cells 53–55 and lymphoid cells of diabetic patients 29, 56 . Notably, Norwegian investigators succeeded in detecting EV infection in pancreata of type 1 diabetics at the clinical onset 9, 57 . Taken together, the results of the above studies suggest that EV persistence and organ damage are causally related.…”

Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

“…The CD8 + T cells were tissue resident memory T cells (T RM ) (CD8 + CD69 + CD103 + ), but without expression of mRNA species associated with acute cytotoxicity or inflammation [55•]. In contrast, interferon-stimulated genes and CXCL10 were shown to be upregulated in the islet core as compared to peri-islet tissue [56•]. …”

Pancreatic islet inflammation: an emerging role for chemokines

“…Blocking CXCL10 activity with neutralizing antibodies prevented re-infiltration of pancreatic islets after a course of anti-CD3 therapy (Lasch, et al 2015). Because T-cells primed with autoantigens typically produce and secrete IFN-γ, targeted upregulation of CXCL10 by IFN-γ signaling in β-cells is likely contributing to T1D disease pathology (Burke, et al 2013a; Burke et al 2016; Lundberg, et al 2016). The enhanced transcription of the CXCL10 gene is also consistent with heightened STAT1 activity in islet β-cells (Burke et al 2013a; Lundberg et al 2016).…”