Heritable susceptibility of the autoimmune disorder, type 1 diabetes (T1D), only partially equates for the incidence of the disease. Significant evidence attributes several environmental stressors, such as vitamin D deficiency, gut microbiome, dietary antigens, and most notably virus infections in triggering the onset of T1D in these genetically susceptible individuals. Extensive epidemiological and clinical studies have provided credibility to this causal relationship. Infection by the enterovirus, coxsackievirus B, has been closely associated with onset of T1D and is considered a significant etiological agent for disease induction. Recognition of viral antigens via innate pathogen-recognition receptors induce inflammatory events which contribute to autoreactivity of pancreatic self-antigens and ultimately the destruction of insulin-secreting beta cells. The activation of these specific innate pathways and expression of inflammatory molecules, including type I and III interferon, prime the immune system to elicit either a protective regulatory response or a diabetogenic effector response. Therefore, sensing of viral antigens by retinoic acid-inducible gene I-like receptors and toll-like receptors may be detrimental to inducing autoreactivity initiated by viral stress and resulting in T1D.

Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA) in adults, though the nature of the relationship remains unknown. Herein, we examine the contribution of viral infection to the severity of arthritis in mice. We provide the first evidence that latent gammaherpesvirus infection enhances clinical arthritis, modeling EBV's role in RA. Mice latently infected with a murine analog of EBV, gammaherpesvirus 68 (gHV68), develop more severe collagen-induced arthritis and a Th1-skewed immune profile reminiscent of human disease. We demonstrate that disease enhancement requires viral latency and is not due to active virus stimulation of the immune response. Age-associated B cells (ABCs) are associated with several human autoimmune diseases, including arthritis, though their contribution to disease is not well understood. Using ABC knockout mice, we provide the first evidence that ABCs are mechanistically required for viral enhancement of disease, thereby establishing that ABCs are impacted by latent gammaherpesvirus infection and provoke arthritis.

In addition to genetic predisposition, environmental determinants contribute to a complex etiology leading to onset of type 1 diabetes (T1D). Multiple studies have established the gut as an important site for immune modulation that can directly impact development of autoreactive cell populations against pancreatic self-antigens. Significant efforts have been made to unravel how changes in the microbiome function as a contributor to autoimmune responses and can serve as a biomarker for diabetes development. Large-scale longitudinal studies reveal that common environmental exposures precede diabetes pathology. Virus infections, particularly those associated with the gut, have been prominently identified as risk factors for T1D development. Evidence suggests recent-onset T1D patients experience pre-existing subclinical enteropathy and dysbiosis leading up to development of diabetes. The start of these dysbiotic events coincide with detection of virus infections. Thus viral infection may be a contributing driver for microbiome dysbiosis and disruption of intestinal homeostasis prior to T1D onset. Ultimately, understanding the cross-talk between viral infection, the microbiome, and the immune system is key for the development of preventative measures against T1D.

Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual “diabetogenic” microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4+ T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D.

The first Fresh Ideas, Foundational Experiments (FIFE): Immunology and Diabetes symposia workshop took place in 2016 and exemplified the active interest of a number of several investigators interested the global rise in the incidence of type 1 diabetes (T1D). This increase does not correlate with genetic drift and indicates that environmental exposures are playing an increasingly significant role. Despite major biomedical and technological advances in diagnosis and treatment, treatments are frequently insufficient as they do not inhibit the progression of the underlying autoimmune response and often fail to prevent life-threatening complications. T1D is the result of autoimmune destruction of the insulin-producing beta cells of the pancreas, and the precise, mechanistic contribution of the immune system to disease pathogenesis and progression remains to be fully characterized. Ultimately, the combinatorial effect of concurrent factors, including beta cell fragility, exogenous stressors, and genetic priming of the innate and adaptive immune system, work together to induce T1D autoimmunity. Thus, T1D is the result of immunological defects and environmental pathogens, requiring the sustained attention of collaborative research teams such as FIFE: I & D with varied perspectives, unified by the universally held goal of finding a sustainable, life-long cure. Herein, the authors provide perspective on various fields in T1D research highlighted by speakers participating in the inaugural FIFE symposium.

In combination with genetic determinants, susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D) is established by various environmental factors including infection, microbial dysbiosis, antibiotic use, and vitamin D deficiency. Studies have implicated infection with certain viruses such as coxsackievirus B (CVB) to be an important cofactor associated with diabetes development and pathogenesis. Infections may be an instigating factor to alter the microbiome and this microbial change may be sufficient to skew immune populations and promote autoimmunity. Mucosa-associated invariant T (MAIT) cell populations have been shown to be altered leading up to diabetes onset in patients and mice. These cells are activated by microbial products in the gut to promote intestinal integrity, but they can also take on a more inflammatory phenotype and participate in autoimmune responses in the pancreas. Ultimately, there exists a significant potential for cross-talk between CVB infection, the microbiome, and gut-resident immune cells impacting T1D susceptibility. We have found CVB infection not only promotes onset of T1D in non-obese diabetic (NOD) mice but also causes dysbiosis which resembles that of a spontaneously diabetic NOD mouse. Introducing this new infection-induced microbial composition into naïve mice through the use of fecal microbiome transfers (FMTs) can accelerate T1D onset and alter immune profiles in the gut as well as the pancreas. Furthermore, MAIT populations are altered by this “diabetogenic” microbiome and also respond directly to CVB infection. Together our data highlights the role of virus infection and its ability to affect the gut microbiome and immune homeostasis to contribute to T1D development.

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