Deficiency in Type I Interferon Signaling Prevents the Early Interferon–Induced Gene Signature in Pancreatic Islets but Not Type 1 Diabetes in NOD Mice

Abstract

Type I interferons (IFNs) have been implicated in the initiation of islet autoimmunity and development of type 1 diabetes. To directly test their involvement, we generated NOD mice deficient in type I IFN receptors (NOD.IFNAR1 2/2). Expression of the type I IFN-induced genes Mx1, Isg15, Ifit1, Oas1a, and Cxcr4 was detectable in NOD islets as early as 1 week of age. Of these five genes, expression of Isg15, Ifit1, Oas1a, and Mx1 peaked at 3-4 weeks of age, corresponding with an increase in Ifna mRNA, declined at 5-6 weeks of age, and increased again at 10-14 weeks of age. Increased IFN-induced gene expression was ablated in NOD.IFNAR1 2/2 islets.Loss of Toll-like receptor 2 (TLR2) resulted in reduced islet expression of Mx1 at 2 weeks of age, but TLR2 or TLR9 deficiency did not change the expression of other IFN-induced genes in islets compared with wild-type NOD islets. We observed increased b-cell major histocompatibility complex class I expression with age in NOD and NOD.IFNAR1 2/2 mice. NOD.IFNAR1 2/2 mice developed insulitis and diabetes at a similar rate to NOD controls. These results indicate type I IFN is produced within islets in young mice but is not essential for the initiation and progression of diabetes in NOD mice. Type 1 diabetes is caused by the autoimmune destruction of insulin-producing b-cells. Human type 1 diabetes and the NOD mouse are characterized by infiltration of immune cells into pancreatic islets. In NOD mice, myeloid cells are observed from ;3-4 weeks of age (1-5), followed by an influx of b-cell-specific T cells that cause b-cell death. Diabetes occurs after 15 weeks of age. Type I interferon (IFN) has been associated with the development of autoimmune diabetes in humans and mice. Elevated IFN-a mRNA transcripts were observed in the pancreata and islets of deceased diabetic patients (6). b-Cells from type 1 diabetic individuals with hyperexpression of HLA class I contained immunoreactive 8). Transgenic mice expressing IFN-a in b-cells developed insulitis and diabetes, but the severity was dependent on the genetic background, suggesting IFN-a

The role of islet antigen presenting cells and the presentation of insulin in the initiation of autoimmune diabetes in the NOD mouse

“…In our colony, the first detectable upregulation of interferon genes was Ifnb1 at 4 weeks followed by Ifna at 6 weeks and Ifng at 8 weeks. Other groups have reported the upregulation of type I interferons in both the pancreatic lymph nodes and islets of NOD mice during the 3-4 week time period, although the timing seems to vary between colonies (86-87). …”

“…This issue remains very confusing to the field. Neutralization of the type I interferon receptor with antibodies decreased diabetes incidence, but genetic ablation of the receptor had no effect (87). Removal of the type II interferon receptor had no effect in one study and led to a reduction of diabetes in females and an increase in diabetes in males in another (88, 89).…”

Viral infections in type 1 diabetes mellitus — why the β cells?

“…Transient blockade of either the type I interferon receptor or expression of Ifn-α by dendritic cells before the onset of insulitis markedly decreases the incidence of diabetes mellitus in NOD mice 94,95 . By contrast, NOD mice lacking a functional type I interferon receptor develop diabetes mellitus at the same rate as wild-type NOD mice 96 . A possible interpretation of these apparently contradictory findings is that viral infection and the subsequent production of type I interferons favours autoimmunity (and eventually T1DM) if the expression of interferons is induced at early and critical points during the development of this condition.…”

Is Type 1 Diabetes “Going Viral”?

“…Further, recent data have also shown that mice with elevated expression of MDA5 exhibit increased systemic autoimmune disease (13,14). However, although identification of IFN I transcriptional signatures and increased IFN I expression has implicated a role for IFN I in diabetes in mice, loss of IFN I signaling did not affect diabetes induction (15). This implies that the IFN I signature itself is not causal to the disease process; rather, the signature reflects an ongoing and underlying causal process, i.e., virus infection.…”