br Experimental Evidence for an Interferon Signature

Experimental Evidence for an Interferon Signature in T1D IFNα is known to stimulate expression of class I major histocompatibility complex (MHC-I) molecules at the surface of exposed cells. Hyper-expression of MHC-I molecules on islets along with detection of IFNα in pancreases of T1D patients compared to non-diabetic patients was an early suggestion that IFNs may be pathogenic (Huang et al., 1995; Foulis et al., 1987b). This hypothesis was also supported by earlier experiments in mice and rats indicating the potential nefarious role of type I IFNs in mammals (Gresser et al., 1980). Since then, many teams have led investigations into the role of IFNs in the pathogenesis of T1D using both human samples and mouse models such as the non-obese diabetic (NOD) mouse. Consequently, T1D has been related to the IFN signature discussed above, further supporting a role for inflammation as an initial triggering event during T1D. However, it is noteworthy that human data for an interferon signature is limited and this is likely due to the limited expression in the microenvironment of the islet. Comparisons of gene expression profiles in pancreatic lymph node CD4+ T annexin v of NOD mice (which spontaneously develop diabetes ~12weeks of age) and NOD/BDC2.5 T cell receptor transgenic mice (where more than 90% of T cell receptors are islet-antigen reactive and the mice develop diabetes ~3weeks of age) identified the up-regulation of IFN-stimulated genes in the mice. mRNA expression for IFN-stimulated genes included IFIT1, IFIT3, ISG15, and OAS1. Moreover, the up-regulated IFN-stimulated genes positively correlated with age of the mice where levels were higher in 6week-old mice compared to 2week-old mice (Li et al., 2008). Similarly, Planas et al. reported a data set of whole genome transcription profiles of human T1D pancreases and purified islets, which revealed an overall overexpression of both innate immunity and IFN-responsive genes (Planas et al., 2010). Even though the study by Planas and colleagues only included a small population (4 T1D patient pancreases and 7 non-T1D pancreases), the findings represented a valuable platform for organ-specific transcriptomic analysis in T1D and established a significant ground for additional large-scale investigations of locally relevant inflammation. A study, by Diana et al., analyzing initiation of diabetes in the NOD mice and the non-autoimmune prone C57Bl/6 and BALB/c mice observed IFNα and IFNα-stimulated gene products in NOD mice only (Diana et al., 2013). Additionally, the study established plasmacytoid dendritic cells (pDCs) as crucial players in the IFN signature in NOD mice, since depletion of pDCs in 2week-old NOD mice delayed development of diabetes up to 30weeks. While Diana et al.\'s work supports the case for IFN-α as a pivotal component for the IFN signature, we should underline that pDCs are also potent secretors of type III IFNs (Ank et al., 2008). Therefore, the positive effect of pDC depletion may not be explained solely through IFNα. Similarly, another study encompassing microarray analysis and qPCR examined chronological changes in gene expression in pancreatic islets of NOD mice from 2weeks of age until development of diabetes ~20weeks and up. To strengthen their examination, the researchers also used non-diabetic NOD. mice which lack a functional repertoire of adaptive T and B cells. The results demonstrated a unique age-correlated IFN signature in the NOD mice that was not present in the NOD., implying that the absence of B and T cells negatively affects the induction of an IFN signature. Notably, at two weeks of age, there were no discernable differences in immune responses between NOD and NOD. mice. Overall, the study suggests a synergistic interaction between innate and adaptive arms of the immune response for the establishment of inflammation and an IFN signature overtime, attesting to the multifactorial complexity of T1D development (Carrero et al., 2013).