Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Abstract

Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.

IgA-Type Enterovirus Antibodies Are Increased among Adults and Children with Recently Diagnosed Type 1 Diabetes

“…Because there was no difference in IgG antibody prevalence between the T1D and control cases, we propose that both participants with T1D and controls had had similar exposure to earlier IgG antibody-inducing EV contacts [ 24 ]. On the contrary, IgA EV antibodies may indicate a recent or lasting mucosal infection [ 3 ]. Mucosal EV infection can lead to functional and structural changes resulting in islet autoimmunity development [ 3 ].…”

“…On the contrary, IgA EV antibodies may indicate a recent or lasting mucosal infection [ 3 ]. Mucosal EV infection can lead to functional and structural changes resulting in islet autoimmunity development [ 3 ]. Therefore, we can conclude that the difference in IgA seroprevalence in the adult group suggests that EV infection might be similarly involved in adulthood-onset T1D development, as it triggers childhood-onset T1D.…”

“…Which of the known EV strains is involved in it remains open. Because there are several candidate EV strains for the aetiology of T1D [ 3 , 28 , 29 ], our approach to use a common peptide antigen to assess recent EV exposure is the most appropriate option. Of course, to confirm the association between EV and adult-onset T1D, viral RNA, and protein, such as VP1, investigations of the pancreatic tissue should be performed in cases of recently diagnosed adulthood diabetes.…”

“…However, a previous Finnish study has shown that this high risk genotype was only detected in 21% of T1D cases [ 2 ]. It has also been suggested that environmental factors such as low vitamin intake, cow's milk exposure, breastfeeding, toxins, high birth weight, gut microbiome, and viruses are triggers for onset of the disease [ 1 , 3 ].…”

Virus Infection Causes Dysbiosis to Promote Type 1 Diabetes Onset

“…Both clinical and epidemiological studies show that infections of Coxsackievirus B (CVB) and other enteric viruses play a role in precipitating autoimmunity in T1D-susceptible individuals (8)(9)(10)(11)(12). CVB is an enterovirus with a single-stranded RNA genome that is typically transferred via the fecal-oral route in humans.…”