T cell Responses to Enterovirus Antigens and to β-cell Autoantigens in Unaffected Children Positive for IDDM-Associated Autoantibodies

Juhela, S; Hyöty, Heikki; Hinkkanen, Ari; Elliott, JF; Roivainen, Merja; Kulmala, Petri; Rahko, J; Knip, Mikael; Ilonen, Jorma

doi:10.1006/jaut.1999.0276

Cited by 29 publications

(24 citation statements)

References 42 publications

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“…Genetically-susceptible subjects with autoimmune markers of beta-cell damage (i. e., autoantibodies) develop Tcell responses against EV antigens and EV-infected cells [12,20,21]. The relation between antibodies detected and the increased prevalence of Coxsackievirus B (CVB) infection in recently-diagnosed diabetic patients compared with healthy subjects is, however, often inconsistent [6,10,14,18,19,21], as we also found in our previous studies [22±25].…”

supporting

confidence: 66%

“…The detection limit of this assay is 0.015 fg of viral RNA. The IgG and IgA class antibodies to CVB4 antigen and to a synthetic EV peptide were analysed using an enzyme immunoassay (EIA) method described previously [4,20] and IgM class antibodies using a heavy chain capture EIA using a panel of three EV antigens (CVB3, echovirus 11, and CVA16) [20]. These antibody assays were designed to detect antibodies in several EV serotypes.…”

Section: Infection Of Hela Cells With Coxsackievirus B (Cvb)mentioning

confidence: 99%

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Restricted TCR Vβ gene expression and enterovirus infection in Type I diabetes: a pilot study

et al. 2000

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Type I (insulin-dependent) diabetes mellitus is an autoimmune disease characterized by infiltrating lymphocytes in the Langerhans' islets and by destruction of insulin-producing beta cells [1]. Despite many years of intensive studies, the precise cause and mechanisms triggering the beta-cell-specific attack still remain undetermined. The less than 50 % concordance for the disease between monozygotic twins suggests, however, that a complex interplay occurs between genetic and non-genetic factors (i. e., environmental) [2,3]. In particular, epidemiological evidence supports a role for infectious agents in the development and/or progression of Type I diabetes [4±10].Although the possibility of a virus-mediated etiopathogenesis of Type I diabetes still remains a central point of discussion, certain viral infections, especially Diabetologia (2000) Abstract Aims/hypothesis. High frequencies of T-cell receptor (TCR) Vb7 + T cells were detected among the lymphocytes isolated from pancreatic islets of children at the onset of Type I (insulin-dependent) diabetes mellitus. We assessed whether a preferential expression of certain TCR Vb gene families could also be detected among the peripheral blood mononuclear cells from diabetic patients. Methods. T-cell receptor repertoires were evaluated by using a semi-quantitative RT-PCR-based technique and confirmed by FACS analysis in peripheral blood mononuclear cells from diabetic patients before, at and after onset of the disease. These patients were also tested for exposure to enteroviruses by RT-PCR and by measuring titres of enterovirus-specific antibodies of the IgA, IgG, and IgM classes. Results. T-cell receptor Vb7 gene family values were higher in recently-diagnosed diabetic patients (10.5 % 3.7) than in age-matched non-diabetic control subjects (5.1 % 1.6) (p < 0.001). In a timecourse analysis of people who developed diabetes during clinical monitoring (i. e., converters), T-cell receptor Vb7 gene expression showed values consistently above 10 % (p < 0.0005). Long-standing diabetic patients showed lower percentage of Vb7 expression compared to values measured at disease onset. In the longitudinal study of the converters, multiple acute enterovirus infections were also detected. These infections appeared to be temporally related to increased percentage of Vb7 gene transcripts. Conclusion/interpretation. The deviation in the T-cell receptor Vb repertoire among circulating T cells from diabetic patients seems to re-emphasize the importance of enterovirus infections in accelerating the progression of Type I diabetes. [Diabetologia (2000) 43: 1484±1497] Keywords Type I diabetes, etiology, autoimmunity, Coxsackievirus, T cell receptor.

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confidence: 66%

Section: Infection Of Hela Cells With Coxsackievirus B (Cvb)mentioning

confidence: 99%

Restricted TCR Vβ gene expression and enterovirus infection in Type I diabetes: a pilot study

et al. 2000

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“…The development of stronger responsiveness to enterovirusinfected cell lysates cannot be evaluated in the present study because the preclinical samples were not available from children with type 1 diabetes. However, we have previously shown that healthy children with diabetes-associated autoantibodies who represent early phases of prediabetes have stronger enterovirus-specific T-cell responses compared with healthy children without these autoantibodies (32). This reactivity was targeted to the CBV4-infected cell lysate antigen but not to purified enteroviruses, just like in the reactivity in this study.…”

Section: Discussionmentioning

confidence: 56%

T-cell responses to enterovirus antigens in children with type 1 diabetes.

et al. 2000

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Enterovirus infections, implicated in the pathogenesis of type 1 diabetes in a number of studies, may precipitate the symptoms of clinical diabetes and play a role in the initiation of the ␤-cell damaging process. The aim of this study was to evaluate whether cellular immune responses to enterovirus antigens are abnormal in children with type 1 diabetes. Lymphocyte proliferation responses to enterovirus antigens were analyzed in 41 children with new-onset type 1 diabetes, 23 children with type 1 diabetes for 4-72 months, and healthy control children in subgroups matched for HLA-DQB1 risk alleles, sex, and age. Children with diabetes for 4-72 months more often had T-cell responses to the Coxsackievirus B4-infected cell lysate antigen than children with new-onset diabetes (P < 0.01) or control children (P < 0.01). Responses to recombinant nonstructural protein 2C of Coxsackievirus B4 were also more frequent in children with type 1 diabetes for 4-72 months when compared with control subjects (P = 0.03), whereas the responses to purified Coxsackievirus B4 and recombinant VP0 protein, which did not contain nonstructural proteins, did not differ. These data suggest that T-cell responses to Coxsackievirus B4 proteins and particularly to the antigens containing the nonstructural proteins of the virus are increased in children with type 1 diabetes after the onset of the disease. However, in children with new-onset diabetes, responses were normal or even decreased. This phenomenon was specific for enteroviruses and could be caused by trapping of enterovirus-specific T-cells in the pancreas.

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“…These studies emphasize the potential importance of interferon-α as a factor linking virus infection with islet autoimmunity. Increased T-cell proliferation to enterovirus antigens has also been reported in Type I diabetic patients [51,52,53] which could reflect increased exposure to enteroviruses in these patients. Cellular immune responses are considered to be an obligatory part of the beta-cell damaging process.…”

Section: Interferons and T-cell Responses To Enterovirusesmentioning

confidence: 85%

The role of viruses in human diabetes

Hyöty

2002

Diabetologia

222

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Abstract. Viruses have long been considered a major environmental factor in the aetiology of Type I (insulin-dependent) diabetes mellitus and recent work has greatly confirmed and extended this role. In addition to the enteroviruses, there are several other viruses which, from time to time, have been considered potential causal agents for human diabetes. With the exception of rubella, their role is not clear.

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T cell Responses to Enterovirus Antigens and to β-cell Autoantigens in Unaffected Children Positive for IDDM-Associated Autoantibodies

Cited by 29 publications

References 42 publications

Restricted TCR Vβ gene expression and enterovirus infection in Type I diabetes: a pilot study

Restricted TCR Vβ gene expression and enterovirus infection in Type I diabetes: a pilot study

T-cell responses to enterovirus antigens in children with type 1 diabetes.

The role of viruses in human diabetes

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