Responses of Coxsackievirus B4-Specific T-Cell Lines to 2C Protein—Characterization of Epitopes with Special Reference to the GAD65 Homology Region

Marttila, Jane; Juhela, S; Vaarala, Outi; Hyöty, Heikki; Roivainen, Merja; Hinkkanen, Ari; Vilja, Pekka; Simell, Olli; Ilonen, Jorma

doi:10.1006/viro.2001.0917

Cited by 36 publications

(24 citation statements)

References 36 publications

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“…In the autoimmune diabetes-prone NOD mouse (30), T cell cross-reactivity between the P2-C and GAD65 sequences was found, but CBV infection of NOD mice had no effect on T cell reactivity to the GAD65 peptide or on diabetes incidence (27). In humans with type 1 diabetes, CD4 + T cell clones generated to GAD65 258-266 showed no proliferation to CBV P2-C 35-43 (31), and three CD4 + T cell lines to CBV P2-C 35-43 did not proliferate to GAD65 peptides containing the PEVKEK motif (32). Furthermore, CD8…”

Section: Discussionmentioning

confidence: 99%

Evidence for Molecular Mimicry between Human T Cell Epitopes in Rotavirus and Pancreatic Islet Autoantigens

Honeyman

Stone

Falk³

et al. 2010

The Journal of Immunology

104

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In type 1 diabetes, insulin-producing β cells in the islets of the pancreas are destroyed by autoreactive T cells. Rotavirus (RV) has been implicated in the pathogenesis of type 1 diabetes. Peptides in VP7, a major immunogenic protein of RV, have high sequence similarity to T cell epitope peptides in the islet autoantigens tyrosine phosphatase-like insulinoma Ag 2 (IA2) and glutamic acid decarboxylase 65 (GAD65). We aimed to educe evidence for the hypothesis that molecular mimicry with RV promotes autoimmunity to islet autoantigens. Peptides in RV and their sequence-similar counterparts in IA2 and GAD65 were assayed for binding to HLA molecules associated with type 1 diabetes and for the ability to elicit T cell proliferative responses in HLA-typed individuals. T cells expanded or cloned to epitopes in IA2 or RV were then tested for cross-reactivity with these epitopes. Peptides in RV-VP7, similar to T cell epitopes in IA2 and GAD65, bound strongly to HLA-DRB1*04 molecules that confer susceptibility to type 1 diabetes and were also T cell epitopes in humans at risk for type 1 diabetes. The proliferative responses of T cells to the similar peptides in RV and islet autoantigens were significantly correlated. T cells expanded to the IA2 epitope could be restimulated to express IFN-γ by the similar peptide in RV-VP7, and T cell clones generated to this RV-VP7 peptide cross-reacted with the IA2 epitope. Our findings are consistent with the hypothesis that molecular mimicry with RV could promote autoimmunity to islet Ags.

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Section: Discussionmentioning

confidence: 99%

Evidence for Molecular Mimicry between Human T Cell Epitopes in Rotavirus and Pancreatic Islet Autoantigens

Honeyman

Stone

Falk³

et al. 2010

The Journal of Immunology

104

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“…Cellular immune responses are considered to be an obligatory part of the beta-cell damaging process. One possibility is immunological cross-reactivity between viral and betacell proteins, which has been investigated [54].…”

Section: Interferons and T-cell Responses To Enterovirusesmentioning

confidence: 99%

The role of viruses in human diabetes

Hyöty

2002

Diabetologia

219

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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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“…In addition, other immune-mediated mechanisms can contribute to the cell damage. Such mechanisms include immunological cross-reactivity between viral and host antigens (molecular mimicry) and possible induction of non-neutralizing anti-viral "enhancing" antibodies, which can lead to strong immune activation and worsen the pathogenesis [7,[18][19][20]. A hypothetical model of some key determinants of EV diabetogenicity is shown in Figure 1.…”

Section: Lessons From Other Enterovirus Diseases and The Pathogenesismentioning

confidence: 99%

“…Theoretically, the vaccine could cause beta-cell damage if it shares common antigenic structures with beta-cell proteins (molecular mimicry). Previous studies have suggested that such epitopes may exist both in beta-cell and EV proteins, but their role in the pathogenesis of T1D remains elusive [20]. Inactivated CBV vaccine does not exaggerate the development of diabetes in NOD mouse, and there are no indications that polio vaccines could cause diabetes [56].…”

Section: Safety Of the Vaccinementioning

confidence: 99%

Virus Infections as Potential Targets of Preventive Treatments for Type 1 Diabetes

Nurminen

Oikarinen²,

Hyöty

2012

Rev Diabet Stud

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Environmental factors play an important role in the pathogenesis of type 1 diabetes, and are attractive targets for preventive interventions. Several studies have shown that viruses can cause diabetes in animals, indicating their potential as candidates for environmental triggering agents. However, human studies have been hampered by the complex nature of the disease pathogenesis, leaving the question of viral etiology unanswered. Significant progress has recently been made in this field by searching for viruses within pancreatic tissue samples, and by carrying out prospective studies. Consequently, there is increasing evidence for a group of enteroviruses acting as possible environmental key triggers. In past studies, these viruses have been linked to type 1 diabetes. Recent studies have shown that they exert tropism to pancreatic islets, and that they are associated with the start of the beta-cell damaging process. Also, polymorphisms of the gene coding for the innate immune system sensor for enteroviruses (IFIH1) were found to modulate the risk of diabetes. Based on these findings, interest in the possible development of vaccines against these viruses has increased. However, even if enterovirus vaccines (polio vaccines) are effective and safe, we currently lack necessary information for the development of a vaccine against diabetogenic enteroviruses, e.g. regarding the identification of their specific serotypes and the causal relationship between these viruses and diabetes initiation. Ongoing research projects are currently addressing these questions, and will hopefully increase the consensus in this field. Also, new sequencing technologies will provide additional information about the whole virome, which could enable the discovery of new candidate viruses.

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Responses of Coxsackievirus B4-Specific T-Cell Lines to 2C Protein—Characterization of Epitopes with Special Reference to the GAD65 Homology Region

Cited by 36 publications

References 36 publications

Evidence for Molecular Mimicry between Human T Cell Epitopes in Rotavirus and Pancreatic Islet Autoantigens

Evidence for Molecular Mimicry between Human T Cell Epitopes in Rotavirus and Pancreatic Islet Autoantigens

The role of viruses in human diabetes

Virus Infections as Potential Targets of Preventive Treatments for Type 1 Diabetes

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