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Type 1 Interferonopathies and Link to T1D
Type I IFNs and Type 1 IFN-Opathies: Implications for T cell Responses?
As previously mentioned, T1D is historically characterized as a T-cell mediated disease. Here, we extend our discussions to suggest that the established IFN response that precedes T1D onset, together with viral-induced type 1 IFN-opathy in the pancreas and microenvironment of the islet, serves to fine-tune subsequent T cell responses during T1D. Several lines of research have demonstrated correlations of IFNs and T cells, supporting our proposal. Specifically, concurrent publications by Crouse et al. and Xu et al. have shown that, within the context of viral infections in mice, signalling through the type I IFN receptor (IFNAR) promoted survival of CD8 T gdc-0980 and prevented their killing by NK cells (Crouse et al., 2014; Xu et al., 2014). Importantly, a paper by Curtsinger et al. found that, in addition to influencing CD8 T cells through CD4 T helper cells and cytokines such as interleukin-5, type I IFNs could directly interact with CD8 T cells. Type I IFNs could provide the third signal (in addition to antigen stimulation, and costimulatory molecules) needed for complete CD8 T cell expansion and activation of cytolytic functions (Curtsinger et al., 2005). For example, when CD8T cells from OT-1 mice were exposed to antigen, costimulatory signals, and IFNα, there was increased clonal expansion, increased lytic activity, and increased interferon-gamma secretion by the CD8 T cells compared to antigen and costimulatory signals alone. Conversely, cells from OT-1/IFNAR-deficient mice had reduced functionality (Curtsinger et al., 2005). Together with the previously proven capacity of type I IFNs to promote survival of activated T cells (Marrack et al., 1999), Curtsinger et al.\'s findings imply that persistent/chronic infections in the pancreas could be providing the continued IFN signal needed for autoreactive T cells to overcome the tolerance threshold and become pathogenic during T1D.
Treatment Avenues
Altogether, our review suggests a two-phase affect of virus and IFN in T1D. The first phase is the probable initiation or propagation of cellular immune responses including cytotoxic T lymphocyte and macrophage activation in the islet microenvironment, either initiated or expanded by virus and IFN response. In the second phase of T1D, after onset, there is a loss of cellular immunity but a persistence of beta cells with insulin as well as virus. When considering treatment options for T1D, use of anti-IFN receptor antibodies to remove IFN negative influences upon beta cell function could prove effective in targeting the second phase of disease development. Indeed, biological research and development companies have been conducting trials with a potential monoclonal antibody against the type I IFN receptor (IFNAR) for the treatment of lupus, with potential crossover to other autoimmune diseases such as T1D (Hultquist, 2015). While the prospect of using anti-IFNAR monoclonal antibodies is promising, considering persistent/chronic viral infections as contributors to establishment and/or pathogenesis of T1D provides exciting alternatives for more targeted treatment options, such as antivirals. One avenue of scrutiny involves the removal of virus/PAMPs to subvert signalling through host PRRs, hence interrupting continual production of IFNs and subsequent inflammatory processes. As research continues to demonstrate an association between viruses and T1D, investigating the use of antiviral treatments is increasingly proving necessary. Also, continued research into viral infections and the inflammatory pathways during T1D may provide a crucial platform for the consideration of off-target effects of vaccines and how vaccines can be used to prevent the development of T1D. Within the scope of vaccine development, a recent preclinical study by Larsson et al. demonstrated that a non-adjuvanted, formalin-inactivated prototype vaccine against Coxsackievirus B1 was indeed efficacious and safe in NOD mice. Vaccination led to significantly higher titers of anti-Coxsackievirus B1 neutralising antibodies, accompanied by significantly reduced viral titers in the blood and pancreas, when compared to mock-treatment. Importantly, while infection accelerated diabetes onset in non-vaccinated prediabetic NOD mice, there was no acceleration of disease in vaccinated mice (Larsson et al., 2015). Larsson et al.\'s paper reinforces the association of enteroviruses like Coxsackieviruses with T1D but also supports the proposition for the removal of virus/PAMPS in investigating treatment options for T1D.