Neonatal Type I diabetes associated with maternal echovirus 6 infection: a case report

Otonkoski, Timo; Roivainen, Merja; Vaarala, Outi; Dinesen, Bo; Leipälä, Jaana; Hovi, Tapani; Knip, Mikael

doi:10.1007/s001250051518

Cited by 81 publications

(59 citation statements)

References 12 publications

(14 reference statements)

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“…The effects of EV-6 on beta cells from different donors was somewhat more variable. Recently we described an infant who developed immune-mediated Type I diabetes in utero already and according to our serological analysis the pathogenic process might have been induced by echovirus 6 infection during pregnancy [20]. Another echovirus, EV-9 DM, was recently isolated from a 6-week-old girl with an acute onset of Type I diabetes [21] and according to our present results, high multiplicity infection by this isolate results in impaired beta-cell function.…”

Section: Discussionsupporting

confidence: 65%

“…The results suggest that several out of the 64 human enterovirus serotypes should be considered potentially diabetogenic [1,17]. Observational studies revealing post-enterovirus-epidemic peak incidences of Type I diabetes [18,19] and case reports [20,21] support this view. It is possible that the relative extent of diabetogenicity can vary within a serotype as genetic variation between field strains of a given enterovirus serotype is extensive.…”

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confidence: 93%

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Functional impairment and killing of human beta cells by enteroviruses: the capacity is shared by a wide range of serotypes, but the extent is a characteristic of individual virus strains

et al. 2002

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Aims/hypothesis. Direct infection of beta cells could explain the diabetogenic effect of enteroviruses. Primary adult human beta cells are susceptible to coxsackievirus infections, which could result in impaired beta-cell function or cell death (coxsackieviruses B3, B4, B5) or both, or no apparent immediate adverse effects (coxsackievirus A9). We extended these studies to additional enterovirus serotypes including several echoviruses, some of which have been associated clinically with the development of Type I (insulin-dependent) diabetes mellitus. Methods. The patterns and consequences of enterovirus infections were investigated in cultured adult human isolated islets. Cell type-specific infection and viability were assessed by immunocytochemical methods. Beta-cell function was studied by perifusion. Results. Poliovirus type 1/Mahoney, coxsackievirus A13, human parechovirus 1 and several echoviruses (serotypes 6, 7, 11) were capable of causing significant functional impairment (p<0.05) and beta-cell death. In contrast, echovirus serotypes 9 and 30 were not destructive. However, when several different field isolates of echovirus 30 were investigated, some of them were found to be clearly more destructive than the corresponding prototype strain. This was also true for echovirus 9. A strain isolated from a 6-week-old baby suffering from acute Type I diabetes was functionally more destructive than either of the echovirus 9 prototype strains. Conclusion/interpretation. These observations indicate that the capacity of an enterovirus to kill human beta cells or impair their function is not entirely defined by the serotype, but in addition by as yet unidentified characteristics of the virus strain involved. Moreover, any serotype could potentially be diabetogenic. [Diabetologia (2002) 45:693-702]

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 93%

Functional impairment and killing of human beta cells by enteroviruses: the capacity is shared by a wide range of serotypes, but the extent is a characteristic of individual virus strains

et al. 2002

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“…Table 3 HLA-DQα (position 52) and HLA-DQβ (position 57) susceptibility heterodimers: comparison between our study population, healthy subjects [9] and patients with Type I diabetes [9] Number of susceptibility Children with permanent diabetes Type I diabetes case-control study [9] Thus, even though we do not exclude the possibility of cases of autoimmune diabetes in very young infants, this seems to be a quite rare event in isolation. Diabetes with autoimmune phenomena is instead connected to complex syndrome(s) [3,15,16], sometimes associated to the presence of higher concentrations of autoimmune markers or histological evidence of insulitis [21] or both, or to viral infections [2].…”

Section: Markers Of Autoimmunity Children In the Eopdmentioning

confidence: 99%

“…Neonatal diabetes with onset in the first days of life and signs of beta-cell autoimmunity has been found associated with short-term maternal enterovirus infection [2] or autoimmune entercolitis [3], but the clinical features of such cases differ from those observed in subjects with diabetes occurring later after birth, which resemble Type I diabetes. On the other hand, a few reports link non autoimmune neonatal diabetes to congenital absence of islet of Langerhans [4], extremely rare genetic disorders or syndromes [5], and pancreatic agenesis [6].…”

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confidence: 99%

Permanent diabetes mellitus in the first year of life

et al. 2002

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Aims/hypothesis. The pathogenesis of permanent diabetes mellitus diagnosed early in life is heterogeneous and, in most cases, not known. We aimed at identifying markers differentiating between non-autoimmune and autoimmune diabetes. Methods. The clinical, genetic and epidemiological features of 111 diabetic patients (62 males) who received insulin within 12 months of life were studied. Results. The epidemic curve by age of diabetes onset revealed two subsets of patients at a cutoff of 180 days. In the group with diabetes onset before 180 days ("early onset" permanent diabetes) the analysis of HLA susceptibility heterodimers (available for 21 individuals) showed that 76% had a "protective" HLA genotype for Type I (insulin-dependent) diabetes mellitus as compared to 11.9% (5/42) of the later onset group. Accordingly, "early onset" children were less likely to have autoimmunity markers (4 out of 26 tested) than children with onset after 180 days (13 out 20 tested) (15.4% vs. 65.0%, p<0.01). Of note, 19 out of 20 (or the 95%) patients who were born on the island of Sardinia, an Italian region where the incidence of Type I diabetes is six times higher than continental Italy (33/100000/year vs 5/100000/year), were included in the later onset group (>180 days). Small-for-date birthweight, a possible sign of reduced foetal insulin secretion, was more common in the "early onset" group (OR=9.9, 95%-CI 2.6-38.6). Conclusion/interpretation. These results, obtained in the largest population-based cohort of diabetic infants hitherto reported, suggest that "early onset" permanent diabetes cases differ from later onset cases and that most of them do not have an autoimmune pathogenesis. [Diabetologia (2002) 45:798-804]

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“…Vertical transmission of CV-B associated with foetal thymus infection has been reported [Iwasaki et al, 1985;Lozovskaia et al, 1997]. In addition, it has been shown that enterovirus infections in utero may induce b-cell autoimmunity [Otonkoski et al, 2000], and that CV-B4 infection during pregnancy was a risk factor for childhood-onset type 1 diabetes [Dahlquist et al, 1995;Hyöty et al, 1995].…”

Section: Introductionmentioning

confidence: 97%

Coxsackievirus B4 infection of murine foetal thymus organ cultures

Brilot

Jaïdane

Geenen

et al. 2008

Journal of Medical Virology

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The infection of foetal thymus with coxsackievirus B4 (CV-B4) E2 has been studied ex vivo by using CD-1 mice on foetal day 14, as a ready source of organs for experimentation to investigate the hypothesis of the role of thymic viral infections in the pathogenesis of type 1 diabetes. The replication of CV-B4 E2 in murine foetal thymus organ cultures has been demonstrated by evaluating the levels of positive-and negativestranded viral RNA in cells by using a real-time quantitative RT-PCR method and by determining titres of infectious viral particles in culture supernatants for 7 days post-infection (p.i.). Staining of tissue sections with an anti-cytokeratin antibody and haematoxylin-eosin showed that CV-B4 infection had no visible effect on cell survival and organ integrity. Cell counts in mock-and virus-infected foetal thymus organ cultures increased from day 1 through day 7, and live cell numbers were comparable in both conditions as shown by Trypan blue exclusion test and 7-amino-actinomycin D staining of thymocytes. Compared with controls on day 7 p.i., cytofluorometric analyses on cells from CV-B4 E2-infected foetal thymus organ cultures displayed a marked increase in the percentage of the most immature CD3 À CD4 À CD8 À thymocytes, and a decrease in the percentage of immature CD3 À CD4 þ CD8 þ cells, together with an increase in the percentage of mature CD3 þ CD4 þ and CD3 þ CD8 þ cells. These data show that CV-B4 E2 disturbs T-cell maturation and differentiation processes in infected murine foetal thymus organ cultures and provide evidence of a suitable system to investigate the effect of viruses in T-cell differentiation.

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Neonatal Type I diabetes associated with maternal echovirus 6 infection: a case report

Cited by 81 publications

References 12 publications

Functional impairment and killing of human beta cells by enteroviruses: the capacity is shared by a wide range of serotypes, but the extent is a characteristic of individual virus strains

Functional impairment and killing of human beta cells by enteroviruses: the capacity is shared by a wide range of serotypes, but the extent is a characteristic of individual virus strains

Permanent diabetes mellitus in the first year of life

Coxsackievirus B4 infection of murine foetal thymus organ cultures

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