Innate Viral Receptor Signaling Determines Type 1 Diabetes Onset

Abstract

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.

Keywords: MDA5; RIG-I-like receptors; autoimmunity; coxsackievirus B; innate immunity; toll-like receptors; type 1 diabetes; type I and III interferon.

Figure 1

Summary of toll-like receptor (TLR)- and RIG-I-like receptors virus-associated ligands and the relationship between interferon (IFN) expression, genetic susceptibility, and autoimmunity. Upon ligand binding, cytosolic MDA5 and RIG-I receptors induce activation of the adaptor molecule, VISA (also called MAVS, IPS1, and CARDIF), endosomally located toll-like receptor 3 (TLR3) recruits TRIF (also known as TICAM), and TLR2, -4, -6, -7, -8, and -9 interact with myeloid differentiation primary response protein 88 (MYD88) in order to provide IFN expression stimulation in the cell nucleus. IFN induces expression of various interferon-stimulated genes (ISGs) which perform positive feedback on IFN genes. IFN is released from the cell to establish an antiviral state in surrounding cells and act in an autocrine and paracrine manner by binding to its cell surface receptors, IFNAR1/2 and IFNλR. Individuals exhibiting heightened genetic susceptibility to type I diabetes (T1D) can have increased basal and pathogen-elicited expression of IFN causing the immune system to skew toward a self-reactive state. Conversely, significantly diminished IFN expression would render a host unable to mount a proper response to virus infection. Thus balance of receptor stimulation between autoimmunity and virus hypersusceptibility is tightly regulated and pathogenic stimuli which exacerbates inflammation in genetically susceptible individuals may result in loss of tolerance.

Figure 2

Model for persistent versus acute infections in pancreas for promoting type I diabetes (T1D). Virus infections induce proinflammatory signaling in resident and infiltrating antigen-presenting cells of the pancreas. Persistent infections whereby viral products including enteroviral 5′ terminally deleted double-stranded RNA are maintained in tissue microenvironments to produce low-grade inflammatory signaling. Alternatively, acute infections may result in unregulated positive feedback mechanisms which produce chronic inflammation even after the virus is cleared.