Molecular mimicry in diabetes mellitus: the homologous domain in coxsackie B virus protein 2C and islet autoantigen GAD 65 is highly conserved in the coxsackie B-like enteroviruses and binds to the diabetes associated HLA-DR3 molecule

Vreugdenhil, Gienke R.; Geluk, Annemieke; Ottenhoff, Tom H. M.; Melchers, Willem J. G.; Roep, Bart O.; Galama, J.M.D.

doi:10.1007/s001250050864

Cited by 87 publications

(61 citation statements)

References 53 publications

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“…Enteroviruses may also trigger autoimmunity via presentation of self-molecules in an inflammatory context (bystander activation) (124) and/or by molecular mimicry (125)(126)(127). Cross-reactivities with viral proteins were reported for autoantibody (128)(129)(130)(131)(132)(133)(134) and T cell responses (73,132,(135)(136)(137)(138)(139)(140)(141)(142)(143)(144) with GAD65, IA-2, and insulin autoantigens. β Cell inflammation and ER stress promote β cell dysfunction and immunogenicity, and protein misfolding is associated with abnormal autoantigen presentation (145)(146)(147).…”

Section: Modified T Cell Autoantigens (Neoepitopes)mentioning

confidence: 99%

Autoreactive T cells in type 1 diabetes

Pugliese¹

2017

Journal of Clinical Investigation

300

226

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Section: Modified T Cell Autoantigens (Neoepitopes)mentioning

confidence: 99%

Autoreactive T cells in type 1 diabetes

Pugliese¹

2017

Journal of Clinical Investigation

300

226

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“…If mimicry were an initiating event, a major autoantigenic epitope of GAD65 should correspond to the region of similarity shared by CBV and GAD65. This appears to hold for T lymphocyte epitopes of GAD65, because peptides corresponding to the PEVKEK region from both GAD and CBV can bind to the permissive HLA molecule DR3 (14) and can stimulate T lymphocytes from subjects with newly diagnosed or presymptomatic type 1 diabetes (15). Furthermore, antisera from rabbits immunized with synthetic peptides encompassing the PEVKEK region of CBV can cross-react with GAD65 by ELISA (16).…”

Section: G Lutamic Acid Decarboxylase (Gad)mentioning

confidence: 99%

Conformational Epitopes on the Diabetes Autoantigen GAD65 Identified by Peptide Phage Display and Molecular Modeling

Myers

Davies

Tong

et al. 2000

The Journal of Immunology

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The major diabetes autoantigen, glutamic acid decarboxylase (GAD65), contains a region of sequence similarity, including six identical residues PEVKEK, to the P2C protein of coxsackie B virus, suggesting that cross-reactivity between coxsackie B virus and GAD65 can initiate autoimmune diabetes. We used the human islet cell mAbs MICA3 and MICA4 to identify the Ab epitopes of GAD65 by screening phage-displayed random peptide libraries. The identified peptide sequences could be mapped to a homology model of the pyridoxal phosphate (PLP) binding domain of GAD65. For MICA3, a surface loop containing the sequence PEVKEK and two adjacent exposed helixes were identified in the PLP binding domain as well as a region of the C terminus of GAD65 that has previously been identified as critical for MICA3 binding. To confirm that the loop containing the PEVKEK sequence contributes to the MICA3 epitope, this loop was deleted by mutagenesis. This reduced binding of MICA3 by 70%. Peptide sequences selected using MICA4 were rich in basic or hydroxyl-containing amino acids, and the surface of the GAD65 PLP-binding domain surrounding Lys358, which is known to be critical for MICA4 binding, was likewise rich in these amino acids. Also, the two phage most reactive with MICA4 encoded the motif VALxG, and the reverse of this sequence, LAV, was located in this same region. Thus, we have defined the MICA3 and MICA4 epitopes on GAD65 using the combination of phage display, molecular modeling, and mutagenesis and have provided compelling evidence for the involvement of the PEVKEK loop in the MICA3 epitope.

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“…The cellular immune responses to the non-structural 2C protein have largely been studied due to homology with the diabetesassociated auto-antigen glutamic acid decarboxylase 65 (GAD65), which has led to the concept of molecular mimicry between enteroviruses and human proteins as an explanation for the evolution of type 1 diabetes in childhood (Ellis et al, 2005;Varela-Calvino et al, 2000, 2004Vreugdenhil et al, 1998). However, T-cell epitopes in the structural viral proteins (VPs) of CV-B4 have also been described.…”

Section: Introductionmentioning

confidence: 99%

Elicitation of T-cell responses by structural and non-structural proteins of coxsackievirus B4

Bengs

Marttila

Susi

et al. 2015

Journal of General Virology

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Coxsackievirus B4 (CV-B4) belongs to the genus Enterovirus within the family Picornaviridae. To investigate target proteins recognized by T-cells in human enterovirus B infections, virus-encoded structural [VP0 (VP4 and VP2), VP1, VP3] and non-structural (2A, 2B, 2C, 3C and 3D) proteins were expressed and purified in Escherichia coli. Peripheral blood of 19 healthy adult donors was used to create enterovirus-specific T-cell lines by repeated stimulation with CV-B4 cell lysate antigen. T-cell lines responded in individual patterns, and responses to all purified proteins were observed. The most often recognized enteroviral protein was VP0, which is the fusion between the most conserved structural proteins, VP4 and VP2. T-cell responses to VP0 were detected in 15 of the 19 (79 %) donor lines. Non-structural 2C protein was recognized in 11 of the 19 (58 %) lines, and 11 of the 19 (58 %) lines also had a response to 3D protein. Furthermore, responses to other non-structural proteins (2A, 2B and 3C) were also detected. T-cell responses did not correlate clearly to the individual HLA-DR-DQ phenotype or the history of past coxsackie B virus infections of the donors.

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Molecular mimicry in diabetes mellitus: the homologous domain in coxsackie B virus protein 2C and islet autoantigen GAD 65 is highly conserved in the coxsackie B-like enteroviruses and binds to the diabetes associated HLA-DR3 molecule

Cited by 87 publications

References 53 publications

Autoreactive T cells in type 1 diabetes

Autoreactive T cells in type 1 diabetes

Conformational Epitopes on the Diabetes Autoantigen GAD65 Identified by Peptide Phage Display and Molecular Modeling

Elicitation of T-cell responses by structural and non-structural proteins of coxsackievirus B4

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