Enteroviruses and T1D: Is It the Virus, the Genes or Both which Cause T1D

Abstract

<jats:p>Type 1 diabetes (T1D) is a chronic autoimmune disorder that results from the selective destruction of insulin-producing β-cells in the pancreas. Up to now, the mechanisms triggering the initiation and progression of the disease are, in their complexity, not fully understood and imply the disruption of several tolerance networks. Viral infection is one of the environmental factors triggering diabetes, which is initially based on the observation that the disease’s incidence follows a periodic pattern within the population. Moreover, the strong correlation of genetic susceptibility is a prerequisite for enteroviral infection associated islet autoimmunity. Epidemiological data and clinical findings indicate enteroviral infections, mainly of the coxsackie B virus family, as potential pathogenic mechanisms to trigger the autoimmune reaction towards β-cells, resulting in the boost of inflammation following β-cell destruction and the onset of T1D. This review discusses previously identified virus-associated genetics and pathways of β-cell destruction. Is it the virus itself which leads to β-cell destruction and T1D progression? Or is it genetic, so that the virus may activate auto-immunity and β-cell destruction only in genetically predisposed individuals?</jats:p>

Type 1 Diabetes: Interferons and the Aftermath of Pancreatic Beta-Cell Enteroviral Infection

“…TLR3 typically resides in the endosomal compartment and is predominantly restricted to immune cells [ 64 ]. Consistent with this (and noting that the evidence remains equivocal [ 65 ]), we have not been able to detect TLR3 by immunohistochemistry in human beta cells [ 5 ]. By contrast, MDA5 and RIG-I both sense dsRNA species present in the cytoplasm of most cells [ 64 ].…”

Commentary: A Human Pluripotent Stem Cell-Based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids

“…The concept of virus associated diabetes is not new. Already back in 1926, Franklin Adams observed that severe T1D breaks out “immediately after such an infection”, and this has been later confirmed in many large studies ( 16 ). There is a large body of evidence for enteroviral infection initiating the auto-immune response and subsequent β-cell destruction in genetically predisposed individuals, where a viral response is boosted through massive production of pro-inflammatory cytokines.…”

“…Decorated with a high concentration of pattern recognition receptors, i.e., TLR3/4, RIG-I, MDA-5, and with IL-1R1, and especially vulnerable to inflammatory destruction, the β-cell undergoes apoptosis in response to inflammation, metabolic control derails and diabetes develops. In parallel, the virus initiated interferon response accelerates hyperexpression of surface HLA-I molecules and thus activation of auto-reactive T-cells and auto-immunity against β-cells ( 16 ). Also, β-cell failure in T2D has been associated with chronic subclinical inflammation and elevated cytokines and chemokines, especially IL-1β, IL-6, and CXCL10 levels in proximity to the islet are initiator for β-destruction, dysfunction, and metabolic deterioration ( Figure 1B ) ( 16 , 17 ).…”

Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

“…The finish DIPP cohort revealed the appearance of islet autoantibodies in a seasonal pattern, with IA following the seasonality of viral infection [45]. A combination of factors in addition to viral infection, including higher inflammation, altered diet, reduced exercise and reduced vitamin D levels have been suggested to influence seasonality of T1D and other autoimmune diseases [120,121].…”