Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies

Yeung, Wing-Chi G; Rawlinson, William D.; Craig, Maria E.

doi:10.1136/bmj.d35

Cited by 436 publications

(405 citation statements)

References 56 publications

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“…25,26 In this context, our data are consistent with the recently published metaanalysis of 33 prevalence studies suggesting that enterovirus infection is common among patients with T1D. 27 Our microarray data provided additional evidence to support the notion that viral infection may have contributed to the onset of T1D in the two quadruplets. Notably, cellular anti-viral responses were more prominent in the diabetic sisters where the antiviral signalling of interferons was the most significantly affected pathway.…”

Section: Discussionsupporting

confidence: 90%

Case report: type 1 diabetes in monozygotic quadruplets

et al. 2011

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Type 1 diabetes (T1D) is an autoimmune disease characterized by the lack of insulin due to an autoimmune destruction of pancreatic beta cells. Here, we report a unique case of a family with naturally conceived quadruplets in which T1D was diagnosed in two quadruplets simultaneously. At the same time, the third quadruplet was diagnosed with the pre-diabetic stage. Remarkably, all four quadruplets were positive for anti-islet cell antibodies, GAD65 and IA-A2. Monozygotic status of the quadruplets was confirmed by testing 14 different short tandem repeat polymorphisms. Serological examination confirmed that all quadruplets and their father suffered from a recent enteroviral infection of EV68-71 serotype. To assess the nature of the molecular pathological processes contributing to the development of diabetes, immunocompetent cells isolated from all family members were characterized by gene expression arrays, immune-cell enumerations and cytokine-production assays. The microarray data provided evidence that viral infection, and IL-27 and IL-9 cytokine signalling contributed to the onset of T1D in two of the quadruplets. The propensity of stimulated immunocompetent cells from non-diabetic members of the family to secrete high level of IFN-a further corroborates this conclusion. The number of T regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was found diminished in all family members. Thus, this unique family is a prime example for the support of the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity is 'fertilized' and precipitated by a viral infection leading to a fully blown T1D.

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Section: Discussionsupporting

confidence: 90%

Case report: type 1 diabetes in monozygotic quadruplets

et al. 2011

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“…Epidemiological studies have suggested that infections with enteroviruses, in particular those of the coxsackie B virus (CVB) serotypes, may be linked to islet autoimmunity and development of type 1 diabetes [1][2][3][4][5]. Other observations suggesting that infections with these viruses have a causative role in diabetes development come from studies that found enteroviruses more frequently in pancreases [6][7][8] and, in some studies, also gut biopsies [9][10][11], from patients with type 1 diabetes compared with healthy controls.…”

Section: Introductionmentioning

confidence: 89%

“…Based upon the observations linking enterovirus infections to the development of type 1 diabetes [1][2][3][4][5], it would be expected that such infections are more common in countries with a high disease incidence compared with those with an intermediate or low incidence. In contrast to this assumption, epidemiological studies conducted in different geographical regions of Europe have demonstrated that the frequency of enterovirus infections in the background population shows an inverse correlation to the incidence of type 1 diabetes [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice

et al. 2013

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Aims/hypothesis Enterovirus (e.g. Coxsackie B virus serotypes [CVBs]) infections may be associated with development of type 1 diabetes. Studies conducted in several European countries have, however, shown an inverse correlation between the incidence of type 1 diabetes and the prevalence of enterovirus infections. These findings could in part be explained by an extension of the poliovirus hypothesis, suggesting that the absence of maternally transferred antibodies protecting offspring from early infection increases the risk for diabetes development. Experimental evidence supporting this hypothesis in type 1 diabetes is, however, lacking. As maternally transferred protection from infection is a crucial component of the extended poliovirus hypothesis, we here tested the hypothesis that previously infected females transfer protection against infection and diabetes to offspring.Methods The induction of CVB-specific maternal antibodies and transfer of protection from virus infection, replication and development of virus-induced diabetes to offspring was assessed using NOD and Socs1-transgenic NOD mice. Results Infected mice produced neutralising antibodies to CVB. Offspring from infected females were positive for neutralising antibodies and were strongly protected from both infection and experimental diabetes. Conclusions/interpretation Our study shows that maternally transferred antibodies protect offspring from enterovirus infection and virus-induced diabetes. This suggests that the absence of maternally provided protection increases the risk for severe outcomes after an enterovirus infection in offspring. Moreover, our findings may have implications for the design of prospective studies aimed at investigating the possible role of enterovirus infections in the aetiology of human type 1 diabetes.

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“…Enteroviral components have been more frequently detected in blood of T1D patients, and a meta-analysis has reported a strong association between EV detection, especially CV-B, and T1D. 3 The presence of EV protein in the pancreas of T1D patients has been observed. 4 Prospective studies confirmed the link between EV and the development of pancreas islet autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Anti-coxsackievirus B4 (CV-B4) enhancing activity of serum associated with increased viral load and pathology in mice reinfected with CV-B4

et al. 2016

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In previous studies it was shown that inoculation of Swiss albino mice with CV-B4 E2 resulted in the production of serum IgG capable of enhancing the CV-B4 E2 infection of murine spleen cells cultures. To investigate whether such an enhancing activity of serum can play a role in vivo, we decided to study the CV-B4 E2 infection in mice exposed to successive inoculations of virus. In Swiss albino mice infected with CV-B4 E2 at the age of 21 days, anti-CV-B4 E2 neutralizing and enhancing activities of their serum peaked after 55 d. In contrast, mice inoculated at the age of 55 d expressed much lower activities. Despite the neutralizing activity of serum, CV-B4 E2 inoculated a second time to 55 day-old animals spread into the host. At the age of 72 and 89 d the levels of viral RNA and infectious particles were higher in organs of animals exposed to 2 successive infections compared with animals infected once at the age of 21 d or 55 d. In animals with 2 successive inoculations of CV-B4 E2 there was a relationship between the anti-CV-B4 E2 enhancing activity of serum and the level of viral RNA in organs and an enhancement of pathology was observed as displayed by histological analysis of pancreas and hyperglycaemia. Altogether our data strongly suggest that an anti-CV-B4 E2 enhancing activity in the host can play a role in the outcome of a secondary infection with this virus.

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Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies

Cited by 436 publications

References 56 publications

Case report: type 1 diabetes in monozygotic quadruplets

Case report: type 1 diabetes in monozygotic quadruplets

Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice

Anti-coxsackievirus B4 (CV-B4) enhancing activity of serum associated with increased viral load and pathology in mice reinfected with CV-B4

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