Anti‐viral innate immunity: Is it where type 1 diabetes really begins?

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Type 1 diabetes (T1D) is a common multifactorial autoimmune disease resulting from the destruction of insulin-producing β-cells in the pancreas as a consequence of dysregulated immune responses. 1 In the past few years, there has been a flurry of discoveries and advancements in our understanding of the immunopathogenic mechanisms at the basis of T1D development and progression. Despite genetic predisposition to T1D being considered a key risk factor, exogenous agents are now extensively thought to be responsible for the recent increase in the disease. 1 Accumulating evidence strongly supports the role of viral infections in the pathogenesis of autoimmune diabetes as one of the initial determinants that trigger β-cell destruction by autoreactive T lymphocytes. 1,2 In particular, the coxsackievirus B (CVB) is increasingly recognized as a smoking gun for T1D development. 1 While research studies point to a role of the adaptive immune response in T1D pathogenesis, with the prevalent view that cytotoxic T cells are directly involved in the tissue damage, there is growing appreciation that innate immunity is critical for initiating the early events leading up to the autoimmune process upon viral infections. 3,4 Innate immune cells physiologically reside in the endocrine pancreas where they recognise pathogens and give rise to the sequel of primary immune responses to warrant microbial clearance and tissue homoeostasis. 5 Nevertheless, it is possible that defects in sensing viruses, associated with impaired host immune responses, trigger β-cell autoimmunity in genetically susceptible individuals. In support of this concept, a recent study by Pedersen and co-workers revealed that single-nucleotide polymorphisms in genes of the innate anti-viral immune system are associated with T1D onset. 6 In particular, these researchers observed that multiple IFNstimulated genes, such as the 2 0 -5 0 oligoadenylate synthetase family of genes, are elevated in new-onset T1D, thus might cause inflammation in the islets and progression to diabetes. 6 In this context, it is possible to hypothesise that persistent pancreatic infections by T1D- Pioneering studies in a non-obese diabetic mouse model have demonstrated that macrophages also strongly contribute to the establishment of a pro-inflammatory microenvironment, which sustains the activation of islet-specific autoreactive T lymphocytes 10 ( Figure 1). As a relevant example, upon CVB4 infection, β-cells upregulated the surface markers of cellular stress (e.g., death receptor 4) and are engulfed by resident macrophages, with consequent production of pro-inflammatory cytokines and the presentation of pancreatic self-antigens 11 (Figure 1). An additional mechanism through which macrophages contribute to T1D development includes the production of IL-1β, tumour necrosis factor (TNF)-α, and reactive oxidation species, which directly destroy virus-infected β-cells with the subsequent spread of intracellular epitopes. 12,13 These cytokines, together with type I IFNs, classically known for interfering with the viral infection, have been implicated in the early stages of T1D autoimmunity by further enhancing IL-1β and IL-18 production by macrophages. 5 In this regard, recent experimental evidence revealed that in vivo inactivation and/or deletion of the type I IFN pathway in macrophages can prevent T1D onset, 14 supporting the key pathogenic role of this innate immune pathway in T1D development.
Other crucial players of the innate immune system influencing T1D pathogenesis are NK cells, the main lymphocyte subset that confers early protection against viruses, by killing infected cells.
Indeed, it has been shown that autoimmunity against pancreatic islets can also originate from the direct cytolytic activity of NK cells towards β-cells persistently infected with CVB4 15 (Figure 1). Furthermore, βcell apoptosis mediated by NK cells leads to epitope spreading, which together with IFN-γ production triggers the activation of self-reactive T cells. 15 Notably, additional studies have reported a low frequency of

F I G U R E 1 Schematic representation of the pathogenic interplay among viral infection, innate immune cell response and T cells in type 1 diabetes (T1D). Upon infection by coxsackievirus B4 in pancreatic tissue, the innate cells (i.e., macrophages, dendritic cells [DCs], and natural killer [NK] cells) activate the anti-viral immune response by producing several pro-inflammatory cytokines and direct kill the infected cells.
DCs present β-cell-derived proteins and/or viral antigens to autoreactive T cells. MHC, Major Histocompatibility Complex; TCR, T Cell Receptor.
NK cells, aberrant signalling of their activation receptor NKG2D and impaired cytolytic activity, especially towards pancreatic β-cells persistently infected with CVB4. 15 As a hypothesis, defective cytotoxicity of NK cells towards CVB4-infected cells might contribute to the persistence of the virus, thus triggering T1D development. 15 In this Commentary, we highlighted the importance of the interplay between innate immunity and viral infections as a key piece Nevertheless, limited effectiveness of these molecules against β-cell mass decline has been observed, although short-term transient inhibition of the IL-8 receptors improved metabolic control (i.e., HbA1c). 23 It is possible that at the time of the clinical intervention (i.e., T1D onset), aberrant innate immune cells have already triggered specific anti-pancreatic adaptive immune responses. Nonetheless, heterogeneity in the disease pathogenesis, also due to different T1D patient endotypes, 24 may represent a major barrier to therapeutic efforts. Thus, it is reasonable to hypothesise that an early intervention direct on innate immunity in autoantibody-positive at-risk subjects or specific vaccination against the major T1D-associated virus could be helpful to control the disease development.
The requirement for an efficient line of attack against T1D development is growing; therefore, it is essential to revisit and explore new approaches beyond the current concepts. Indeed, antiviral strategies are now under investigation to prevent or clear persistent CVB infection 25,26 with a view to halting T1D development; however, they are still in the experimental phase or clinical trials. Overall, preventing the altered anti-viral innate immune response through specific vaccines and drugs might open new frontiers of therapy to control and/or prevent autoimmune diabetes and would be definitive proof of their causal role in triggering T1D.

AUTHOR CONTRIBUTIONS
All the authors contributed substantively to the design, writing, and editing of the commentary and approved the final version submitted for publication.