Enterovirus infection is associated with an increased risk of childhood type 1 diabetes in Taiwan: a nationwide population-based cohort study

Lin, Hsiao Chuan; Wang, Chung Hsing; Tsai, Fuu Jen; Hwang, Kao Pin; Chen, Walter; Lin, Cheng Chieh; Li, Tsai‐Chung

doi:10.1007/s00125-014-3400-z

Cited by 36 publications

(28 citation statements)

References 47 publications

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“…Since these studies were based on parental reporting of infection, causative agents were not identified. In contrast, a large population-based study of >1 million cases and controls from Taiwan demonstrated that enterovirus infection before 18 years of age was associated with an increased risk of subsequent type 1 diabetes (adjusted HR 1.5) [25]. Such studies cannot determine whether the associations between early infections and IA or type 1 diabetes reflect increased exposure to viruses or an underlying susceptibility to virus infection due to a dysregulated immune response [59].…”

Section: Childhood Infectionsmentioning

confidence: 97%

Early-life factors contributing to type 1 diabetes

et al. 2019

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The incidence of type 1 diabetes has increased since the mid-twentieth century at a rate that is too rapid to be attributed to genetic predisposition alone. While the disease can occur at any age, mounting evidence from longitudinal cohort studies of at-risk children indicate that type 1 diabetes associated autoantibodies can be present from the first year of life, and that those who develop type 1 diabetes at a young age have a more aggressive form of the disease. This corroborates the hypothesis that environmental exposures in early life contribute to type 1 diabetes risk, whether related to maternal influences on the fetus during pregnancy, neonatal factors or later effects during infancy and early childhood. Studies to date show a range of environmental triggers acting at different time points, suggesting a multifactorial model of genetic and environmental factors in the pathogenesis of type 1 diabetes, which integrally involves a dialogue between the immune system and pancreatic beta cells. For example, breastfeeding may have a weak protective effect on type 1 diabetes risk, while use of an extensively hydrolysed formula does not. Additionally, exposure to being overweight pre-conception, both in utero and postnatally, is associated with increased risk of type 1 diabetes. Epidemiological, clinical and pathological studies in humans support a role for viral infections, particularly enteroviruses, in type 1 diabetes, but definitive proof is lacking. The role of the early microbiome and its perturbations in islet autoimmunity and type 1 diabetes is the subject of investigation in ongoing cohort studies. Understanding the interactions between environmental exposures and the human genome and metagenome, particularly across ethnically diverse populations, will be critical for the development of future strategies for primary prevention of type 1 diabetes.

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Section: Childhood Infectionsmentioning

confidence: 97%

Early-life factors contributing to type 1 diabetes

et al. 2019

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“…Since then, many other epidemiological and clinical investigations have been conducted in birth cohorts of children at genetic risk of type 1 diabetes to address the role of enteroviruses in the initiation and acceleration of islet autoimmunity [ 5 – 8 ]. The results have not always been concordant, in part due to methodological limitations and inadequacies of sampling timing and frequency; however, the weight of the evidence, derived from multiple countries, clearly supports an association between enteroviruses and type 1 diabetes [ 9 , 10 ]. This is supported by studies reporting that: (1) maternal viral infection in pregnancy, including enteroviral, is linked to type 1 diabetes risk in the offspring, as confirmed by a meta-analysis of ten studies (2992 participants, both mothers and offspring) [ 11 ]; (2) detection of enteroviruses in stools [ 12 ] and circulating antivirus neutralising antibodies [ 13 ] precedes the appearance of islet autoantibodies by several months in children at increased genetic risk for type 1 diabetes; and (3) faster progression to type 1 diabetes occurs in autoantibody-positive children with enterovirus RNA in their blood [ 6 ].…”

Section: Epidemiological and Genetic Studies Implicate Enteroviruses mentioning

confidence: 99%

Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes

et al. 2019

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In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.

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“…The most common hypothesis is that microbial infections initiate and/or exacerbate islet inflammation in genetically susceptible individuals ( 38 , 39 ). For instance, T1D is associated with enteroviruses such as coxsackievirus B1 ( 40 – 44 ). Viral infection of β cells may result in direct cytolysis and/or elicit local inflammation that initiates and/or drives autoimmunity ( 45 – 47 ).…”

Section: Introductionmentioning

confidence: 99%

Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response

2017

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Inflammation is typically induced in response to a microbial infection. The release of proinflammatory cytokines enhances the stimulatory capacity of antigen-presenting cells, as well as recruits adaptive and innate immune effectors to the site of infection. Once the microbe is cleared, inflammation is resolved by various mechanisms to avoid unnecessary tissue damage. Autoimmunity arises when aberrant immune responses target self-tissues causing inflammation. In type 1 diabetes (T1D), T cells attack the insulin producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by in part altering central and peripheral tolerance inducing events. This results in the development and expansion of β cell-specific effector T cells (Teff) which mediate islet inflammation. Unlike protective immunity where inflammation is terminated, autoimmunity is sustained by chronic inflammation. In this review, we will highlight the key events which initiate and sustain T cell-driven pancreatic islet inflammation in nonobese diabetic mice and in human T1D. Specifically, we will discuss: (i) dysregulation of thymic selection events, (ii) the role of intrinsic and extrinsic factors that enhance the expansion and pathogenicity of Teff, (iii) defects which impair homeostasis and suppressor activity of FoxP3-expressing regulatory T cells, and (iv) properties of β cells which contribute to islet inflammation.

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Enterovirus infection is associated with an increased risk of childhood type 1 diabetes in Taiwan: a nationwide population-based cohort study

Cited by 36 publications

References 47 publications

Early-life factors contributing to type 1 diabetes

Early-life factors contributing to type 1 diabetes

Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes

Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response

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