Coxsackie B virus infection and onset of childhood diabetes

Clements, G. B.; Galbraith, Daniel; Taylor, K. W.

doi:10.1016/s0140-6736(95)91270-3

Cited by 236 publications

(153 citation statements)

References 8 publications

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“…vp1 staining in islets was found in~10% of non-diabetic controls of all ages. This is consistent with studies showing that 4-5% of normal children had enteroviral RNA in their serum [4,7,8] and 11.8% had enteroviral RNA present in faecal samples [34,35]. Since a range of enteroviruses can infect human islets in vitro [12,36,37] it is possible that the pancreas is frequently colonised during an enteroviral infection.…”

Section: Discussionsupporting

confidence: 89%

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The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

et al. 2009

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Aims/hypothesis Evidence that the beta cells of human patients with type 1 diabetes can be infected with enterovirus is accumulating, but it remains unclear whether such infections occur at high frequency and are important in the disease process. We have now assessed the prevalence of enteroviral capsid protein vp1 (vp1) staining in a large cohort of autopsy pancreases of recent-onset type 1 diabetic patients and a range of controls. Methods Serial sections of paraffin-embedded pancreatic autopsy samples from 72 recent-onset type 1 diabetes patients and up to 161 controls were immunostained for insulin, glucagon, vp1, double-stranded RNA activated protein kinase R (PKR) and MHC class I. Results vp1-immunopositive cells were detected in multiple islets of 44 out of 72 young recent-onset type 1 diabetic patients, compared with a total of only three islets in three out of 50 neonatal and paediatric normal controls. vp1 staining was restricted to insulin-containing beta cells. Among the control pancreases, vp1 immunopositivity was also observed in some islets from ten out of 25 type 2 diabetic patients. A strong correlation was established between islet cell vp1 positivity and PKR production in insulin-containing islets of both type 1 and type 2 diabetic patients, consistent with a persistent viral infection of the islets. Conclusions/interpretation Immunoreactive vp1 is commonly found in the islets of recent-onset type 1 diabetes patients, but only rarely in normal paediatric controls. vp1 immunostaining was also observed in some islets of type 2 diabetes patients, suggesting that the phenomenon is not restricted to type 1 diabetes patients.

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Section: Discussionsupporting

confidence: 89%

“…Much of the evidence is circumstantial [1] but includes observations that antibodies against common Coxsackie B enteroviruses (CVB) and enteroviral RNA occur more frequently in the circulation of recent-onset type 1 diabetes patients than in controls [2][3][4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

et al. 2009

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“…On top of the strong genetic component, environmental factors contribute to type 1 diabetes epidemiology. Common enterovirus infections, probably together with other environmental factors, appear to have a role in triggering insulitis and eventually clinical type 1 diabetes [2][3][4][5][6][7]. Viral infection has recently been suggested as the causative agent for the new form of 'type 1-like' diabetes mellitus in Japan [8].…”

Section: Introductionmentioning

confidence: 99%

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

et al. 2005

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Aims/hypothesis: It is thought that enterovirus infections initiate or facilitate the pathogenetic processes leading to type 1 diabetes. Exposure of cultured human islets to cytolytic enterovirus strains kills beta cells after a protracted period, suggesting a role for secondary virusinduced factors such as cytokines. Methods: To clarify the molecular mechanisms involved in virus-induced beta cell destruction, we analysed the global pattern of gene expression in human islets. After 48 h, RNA was extracted from three independent human islet preparations infected with coxsackievirus B5 or exposed to interleukin 1β (50 U/ml) plus interferon γ (1,000 U/ml), and gene expression profiles were analysed using Affymetrix HG-U133A gene chips, which enable simultaneous analysis of 22,000 probe sets. Results: As many as 13,077 genes were detected in control human islets, and 945 and 1293 single genes were found to be modified by exposure to viral infection and the indicated cytokines, respectively. Four hundred and eighty-four genes were similarly modified by the cytokines and viral infection. Conclusions/ interpretation: The large number of modified genes observed emphasises the complex responses of human islet cells to agents potentially involved in insulitis. Notably, both cytokines and viral infection significantly (p<0.02) increased the expression of several chemokines, the cytokine IL-15 and the intercellular adhesion molecule ICAM-1, which might contribute to the homing and activation of mononuclear cells in the islets during infection and/or an early autoimmune response. The present results provide novel insights into the molecular mechanisms involved in viral-and cytokine-induced human beta cell dysfunction and death.

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“…One favoured idea is based on molecular mimicry [1,23,25,26] whereby the critical event is infection with a virus or micro-organism that displays to the immune system a protein resembling a constituent of the body sufficiently closely so that the response is cross-reactive with an autologous molecule (self). The coxsackie B4 virus has been particularly incriminated in IDDM, according to seasonality of the disease onset; sequence similarity between GAD and virus proteins [1,23,25]; identification of viral sequences in serum of children at onset of disease [27]; and a high frequency of serological evidence of enterovirus exposure both in utero and in childhood [28]. On the other hand, the concept of molecular mimicry is not sustained by the failure of monoclonal antibodies to recognize sequences of GAD [29], nor does it explain why autoimmune responses to GAD specifically occur in beta cells.…”

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confidence: 99%