Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors

Abstract

The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells.

Detection of Antiviral Tissue Responses and Increased Cell Stress in the Pancreatic Islets of Newly Diagnosed Type 1 Diabetes Patients: Results From the DiViD Study

“…Thus, it is possible that they could represent a population of dedifferentiating or nascent beta cells that either have lost, or not yet acquired, insulin immunopositivity. This observation in samples from the DiViD cases, using a different antibody against MDA5 (ab4544, Abcam), has recently been published ( 25 ). These two findings identifies a potentially important concept, which will require further verification in subsequent studies.…”

Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?

“…In line with this hypothesis, gene expression of the pattern recognition receptor IFH1 -a T1D candidate gene encoding MDA5, a helicase involved in the recognition of viral double-stranded RNA 51,52 -is much higher in human α-cells than in β-cells 33 , supporting the observation that α-cells clear viruses more effectively than do β-cells 53 . This difference in MDA5 expression was confirmed by histological studies showing that human α-cells from both normoglycaemic donors and T1D donors have a higher expression of MDA5 than β-cells from these donors 54 .…”

Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review)

“…This difference appears to make β-cells more susceptible to the establishment of persistent low-grade viral infections. MDA5 is increased in patients with new-onset T1DM, possibly because of elevated inflammatory conditions ( 77 ).…”