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  • Importantly Marro et al used a viral mouse model to

    2018-10-23

    Importantly, Marro et al. used a viral mouse model to demonstrate that progression to T1D can be directly modulated through IFN-α signaling. In their model, Rip-LCMV, C57Bl/6 mice expressed a transgene of the lymphocytic choriomeningitis virus (LCMV) glycoprotein under the control of the rat insulin promoter only within the islets. Subsequent infection with LCMV led to the development of diabetes in these mice (Marro et al., 2017). Marro and colleagues showed that administration of ceramidase against IFN- α-β receptor (IFNAR) and IFN-α species, but not IFN-β, prevented the virally-induced development of diabetes in the Rip-LCMV mice (Marro et al., 2017). These findings provided further support for the involvement of IFN driven inflammation in diabetes development. Concurrently, two independent longitudinal studies have been following a cohort of German and Finnish children with genetically determined predisposition to T1D. These cohorts are part of the BABYDIET and DIPP studies, respectively. In the DIPP study, subjects (n=28) are matched with autoantibody-negative controls based on date/place of birth, sex, and HLA genotype. The BABYDIET study includes 109 genetically susceptible children, along with 49 individuals recently diagnosed with T1D (disease duration of at least 3years), 15 adult individuals with longstanding T1D, 93 healthy adult volunteers, and 25 patients with SLE. Within the course of these studies, peripheral blood is collected from participants and microarray analysis is performed on RNA from PBMCs or whole blood to determine transcriptional profiles. Both studies reported presence of an IFN signature before the detection of autoantibodies in the children. The number of subjects who manifested the IFN signature was small, likely owing to the localized nature of the process or affects of chronic IFN response as well as age-related changes. However, despite these differences and the fact magnitude of the IFN signature varied among the susceptible children, recent onset diabetic cases and individuals with longstanding diabetes, their overall IFN signature overlapped with what was already reported for SLE patients and the signature was not observed in healthy controls (Ferreira et al., 2014; Kallionpää et al., 2014). The BABYDIET and DIPP cohorts constitute two epidemiologically relevant landmark studies that support the early involvement of an IFN response during T1D. Moreover, these reports of IFN response are directly in line with other studies demonstrating hyper-expression/dysregulation of MHC-I molecules in human pancreases during T1D (Foulis et al., 1987a). Specifically, Richardson et al. (2016) provided strong evidence for involvement of MHC-I molecules (both at the protein and the RNA level) and inflammatory pathway during T1D. Using human samples from nPOD (network for pancreatic organ donors with diabetes), the Diabetes Virus Detection study, and from a collection of recent-onset T1D samples from the United Kingdom, Richardson et al. demonstrated that classical and non-classical MHC-I hyper-expression is pertinent to patients with T1D but not the controls (Richardson et al., 2016). Marroqui and colleagues also reported comparable effects of IFN-α on MHC-I overexpression in human beta cells (Marroqui et al., 2017). Meanwhile, it is important to mention that Richardson et al.\'s and Marroqui et al.\'s studies are contradictory to an earlier report by Skog et al. (2015). Skog et al.\'s investigations did not conclusively define any considerable differences in MHC-I expression between T1D patients and non-T1D patients (Skog et al., 2015). These discrepancies further attest to the multifaceted complexity of T1D development and may indeed be a testament to the heterogeneity of T1D presentation. Finally, the concept that IFNs can play a crucial role in T1D is also supported by numerous reports of T1D development following IFN-α therapy for viral hepatitis, often associated with other autoimmune disorders as well. Some of these reports have recently been reviewed (Zornitzki et al., 2015). Altogether these aforementioned reports establish a strongly relevant basis for more extensive incorporation of inflammatory pathways in attempts to explain the pathogenesis of T1D and proposition of alternative treatment options.