Abstract
Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by immune-mediated destruction of insulin-producing β-cells. The concordance rate for T1D in monozygotic twins is ≈30–50%, indicating that environmental factors also play a role in T1D development. Previous studies have demonstrated that enterovirus infections such as coxsackievirus type B (CVB) are associated with triggering T1D. Prior to autoantibody development in T1D, viral RNA and antibodies against CVB can be detected within the blood, stool, and pancreata. An innate pathogen recognition receptor, melanoma differentiation-associated protein 5 (MDA5), which is encoded by the IFIH1 gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms in IFIH1 alter the structure and function of MDA5 that may lead to exacerbated antiviral responses contributing to increased T1D-susceptibility. Binding of viral dsRNA via MDA5 induces synthesis of antiviral proteins such as interferon-alpha and -beta (IFN-α/β). Viral infection and subsequent IFN-α/β synthesis can lead to ER stress within insulin-producing β-cells causing neo-epitope generation, activation of β-cell-specific autoreactive T cells, and β-cell destruction. Therefore, an interplay between genetics, enteroviral infections, and antiviral responses may be critical for T1D development.
Highlights
Type 1 diabetes (T1D) is a chronic inflammatory autoimmune disease where pancreatic β-cells are destroyed by autoreactive T cells [1,2]
T1D riskand protection-associated single nucleotide polymorphisms (SNPs) in IFIH1 are present in the helicase, pincer, and C-terminal domain (CTD) regions of melanoma differentiation-associated protein 5 (MDA5) causing dysregulated IFNα/β synthesis and double-stranded RNA (dsRNA) binding
It remains unclear how these SNPs alter MDA5 structure and other unknown functions leading to T1D risk or protection
Summary
Type 1 diabetes (T1D) is a chronic inflammatory autoimmune disease where pancreatic β-cells are destroyed by autoreactive T cells [1,2]. Single nucleotide polymorphisms (SNPs) in immune response genes such as DDX58 (DExD/H-Box Helicase 58), TLR2 (Toll-like receptor 2), TLR3 (Toll-like receptor 3), TLR7 (Toll-like receptor 7), TYK2 (tyrosine kinase 2), and IFIH1 (Interferon Induced With Helicase C Domain 1) are implicated with T1D disease risk [13,14,15,16,17,18,19,20,21,22,23,24,25] Mutations in these innate sensors provide a key link between genetics and the environment for T1D initiation. This review article will discuss the collective contributions of CVB infections, the innate sensor MDA5, IFN-α/β, antiviral responses from pancreatic β-cells, and the immune system in T1D development
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