Enterovirus infection and type 1 diabetes

Enteroviruses belong to the picornavirus family, and are small RNA viruses characterised by a single positive-strand genomic RNA. Serological studies have distinguished 66 human enterovirus serotypes. The enteroviruses have been classified into four groups: polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and echoviruses, but there are major overlaps between their biological properties. An association between Coxsackieviruses and type 1 diabetes has been suspected for more than 40 years, but the nature of the association remains controversial. The best evidence of enteroviral involvement in the pathogenesis of type 1 diabetes comes from animal studies and from the detection of viral proteins in the circulation of people with diabetes or the islets of those who died shortly after diagnosis. It remains unclear to what extent enteroviruses may induce autoimmunity, or simply represent opportunistic infection of already damaged cells. Transmission of enterovirus is reduced with improved hygiene, and there is therefore no simple viral explanation for the sustained rise in incidence of type 1 diabetes in affluent countries, but it has been argued that a falling rate of infection with delayed exposure to common viruses might result in more damaging consequences - the 'polio hypothesis'.

An introduction to enteroviruses

Enteroviruses contain a genome of approximately 7500 bases and are known to have a high mutation rate due to low-fidelity replication and frequent recombination. They infect millions of people each year, and are transmitted in epidemic fashion by respiratory secretions – saliva, sputum and nasal mucus – or by the faecal–oral route. Poliovirus was the most dreaded member of the family, but a range of clinical syndromes have been described following other types of enterovirus infection.

Enterovirus and diabetes

coxsackie B4 virus
coxsackie B4 virus

Enterovirus, or more specifically, coxsackievirus,[a] has long headed the list of possible viral causes of type 1 diabetes. The observation of a seasonal (spring and autumn) cycle in presentation of childhood diabetes suggested a role for viral infection, and laboratory investigation showed that diabetes could be induced in mice by the encephalomyocarditis virus and by coxsackie B4. It was assumed at the time that diabetes was the consequence of acute viral infection, and the first prospective investigation, the Bart's–Windsor family study, was established in the hope of catching the virus responsible in the weeks preceding onset of diabetes.

Evidence of enteroviral infection before autoimmunity develops

Studies in pregnancy: An aetiological role for viruses was suggested by case–control studies of mothers whose children subsequently developed type 1 diabetes. A Swedish study showed that such mothers were more likely to show serological evidence of enteroviral infection in pregnancy, although the fraction of cases with maternal infection was small.[1] A smaller study using a combination of PCR and IgM antibodies found evidence that enterovirus RNA was more common in the serum of mothers whose children later developed diabetes, but a subsequent study in Finland failed to confirm this.[2]

Evidence of enteroviral infection at clinical onset of diabetes

Viral antibody studies: Later clinical studies were based around the attempt to show an association between viral antibody titres, suggestive of recent viral infection, and new-onset diabetes.[3] Several studies suggested a link but systematic review of 26 case–control studies published between 1966 and 2001 found little evidence of a consistent association.[4] Furthermore, antibody studies may not discriminate between diabetogenic and neutral strains of virus, and differences between antibody responses or viral persistence in people with diabetes and controls may simply reflect patterns of immune responsiveness related to HLA type.[5] It thus seems unlikely that the question will be resolved by this type of analysis.

PCR-based studies Actual presence of the virus in the circulation is best detected by PCR techniques. A number of studies have reported detection of viral RNA in newly diagnosed or prediabetic children, most commonly coxsackie B4. PCR techniques have the limitation that the RNA sequences detected come from the untranslated part of the genome, and do not indicate the precise serotype, since this is based on variations in capsid proteins.[6] A recent meta-analysis of PCR-based studies (based on analysis of blood, stool or tissue) concluded that there are strong associations between diabetes-related autoimmunity (odds ratio 3.7, 95% CI 2.1–6.8) or clinical type 1 diabetes (odds ratio 9.8, 95% CI 5.5–17.4).[7] Potential criticisms of this analysis include the heterogeneity of methods used in these studies, failure to match cases and control for HLA type, and the suspicion of strong publication bias.

Enterovirus infection and human islets

Coxsackie viruses can infect isolated human pancreas,[8] and in situ hybridisation has provided evidence of enteroviral fragments in the beta cells of individuals with a recent diagnosis of type 1 diabetes. Immunostaining found evidence of the viral capsid protein VP-1 in 3/6 patients studied.[9] A later and larger study found VP-1 staining in 44/72 pancreases from people with type 1 diabetes, as against 3/50 controls. It should however be noted that this staining is not strain-specific. An accompanying Editorial points out the possibility of non-specific staining of other beta cell antigens, and concludes that this study could not be considered definitive.[10]

Evidence of recent infection in older individuals might simply mean that acute viral infection can precipitate clinical onset in preclinical cases of autoimmune diabetes, or more easily colonise the islets of those with established diabetes, thus excluding any fundamental role in causation of the disease. There is therefore a need to establish whether the viraemia reported by these studies is acute or persistent, and – if the latter – the age at which the virus was acquired.

Sequence homology with an identical PEVKEK motif exists between coxsackie B4 and the islet antigen GAD65,[11] suggesting the possibility of molecular mimicry, but reports of immune cross-reactivity are conflicting. Further suggestive evidence of acute vs persistent viral infection comes from cytokine studies in the newly diagnosed. The most potent antiviral cytokines are interferons-α and –β. These form part of the early innate response to viral infection, and high levels therefore suggest recent infection. Autopsy reports have shown that interferon-α was expressed on the surface of beta cells, but not other islet endocrine cells, in patients who died soon after diagnosis of diabetes.[12] Raised circulating levels of interferon-α have also been reported in the serum of newly diagnosed patients, but might simply reflect the proinflammatory milieu that exists at that stage of the disease.

There is at present conflicting evidence as to the role of early viral exposure in the pathogenesis of type 1 diabetes.[13] Despite a mass of circumstantial evidence relating to serological changes suggestive of recent viral exposure in the newly diagnosed, no reliable conclusions can be drawn at this stage. PCR evidence of viraemia before or around the time of diagnosis continues to accumulate, but is hard to interpret. Large-scale prospective studies from birth using improved methods of investigation should eventually resolve some of these issues.[14]

On present evidence, viral infection can only be implicated in a minority of cases of type 1 diabetes, and cannot explain the relentless linear rise in incidence noted from many parts of the world. It has however been proposed, by analogy with poliovirus, that delayed exposure to enterovirus may determine the clinical outcome.[15] Polio may once have been a harmless virus encountered by all children early in infancy; problems arose with improving hygiene, which resulted to first exposure later in life and the emergence of paralytic polio. This suggestion links viral infection to the hygiene hypothesis, but is unproved; polio investigators have even doubted the relevance of the hypothesis to polio!

References

  1. ^ Dahlquist GG et al. Enteroviral RNA and IgM antibodies in early pregnancy and risk for childhood-onset IDDM in offspring. Diabetes Care 1999;22:364–65

  2. ^ Lönnrot M et al. Enterovirus infection as a risk factor for β-cell autoimmunity in a prospectively observed birth cohort. The Finnish Diabetes Prediction and Prevention Study. Diabetes 2000;49:1314–31

  3. ^ Gamble D et al. Viral antibodies in diabetes mellitus. BMJ 1969;3(5671):627–30

  4. ^ Green J et al. Coxsackie B virus serology and type 1 diabetes a systematic review of published case–control studies. Diabetic Medicine 2004;21:507–14

  5. ^ Graves PM et al. The role of enteroviral infections in the development of IDDM. Limitations of current approaches. Diabetes 1997;46:161–8

  6. ^ Hyöty H, Taylor KW. The role of viruses in human diabetes. Diabetologia 2002;45:1353–61

  7. ^ Yeung WC et al. Enterovirus infection and type 1 diabetes systematic review and meta-analysis of observational molecular studies. BMJ 2011;342:d35

  8. ^ Jaidane H et al. Enteroviruses and type 1 towards a better understanding of the relationship. Rev Med Virol 2010;20:265–80

  9. ^ Dotta F et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A 2007;104:5115–20

  10. ^ Roivainen M, Klingel K. Role of enteroviruses in the pathogenesis of type 1 diabetes. Diabetologia 2009;52:995–6

  11. ^ Atkinson M et al. Cellular immunity to to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J Clin Invest 1994;94:2125–212

  12. ^ Foulis AK et al. A search for evidence of viral infection in pancreases of newly diagnosed patients with IDDM. Diabetologia 1997;40:53–61

  13. ^ Gale EAM, Atkinson M. A piece of nucleic acid surrounded by controversy - coxsackievirus and the causes of type 1 diabetes. Diabetic Medicine 2004;21:503–6

  14. ^ Nathanson N, Martin JR. The epidemiology of polio - enigmas surrounding its appearance, epidemicity and disappearance. Am J Epidemiol 1979;110:672–92

  15. ^ Lonnrot M et al. Enterovirus antibodies in relation to islet cell antibodies in two populations with high and low incidence of type 1 diabetes. Diabetes Care 1999;22:2086–88.

Footnotes

  1. ^ Coxsackie virus is named after Coxackie, a town on the Hudson River in New York State.

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