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Identifying potential targets for Epstein-Barr virus-associated molecular mimicry in T cell-mediated autoimmunity of multiple sclerosis

Tschochner, M., Leary, S. and Nolan, D. (2011) Identifying potential targets for Epstein-Barr virus-associated molecular mimicry in T cell-mediated autoimmunity of multiple sclerosis. In: 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, 19 – 22 October 2011, Amsterdam, Netherlands.

Link to Published Version: https://doi.org/10.1177/1352458511422300
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Abstract

Background: Susceptibility to Multiple Sclerosis (MS) is conferred by immune system associated genes. In particular, carriage of class II human leukocyte antigen (HLA)-DRB1*1501 has been identified as a major MS risk allele. Additionally, it has been shown that Epstein-Barr virus (EBV) nuclear antigen1 (EBNA1)-specific CD4+ T cells are selectively expanded in MS patients, and can cross-recognize MS-associated myelin antigens.

Goals: We therefore sought to identify potential epitopes that can act as molecular mimicry molecules between immune dominant viral epitopes and antigens in the human brain that may be involved in the initiation and maintenance of central nervous system (CNS) autoimmune T-cell responses associated with MS using computational analysis.

Methods: HLA binding algorithms (NetMHCIIpan) were utilized to identify potential class II HLA epitopes, using a set of EBV EBNA-1 protein sequences (EMBL) and a dataset of CNS proteins enriched for axoglial proteins (human protein reference database (HPRD.org) and Dhaunchak et al., Glia, 2010). Amongst these, potential cross-reactive epitopes of strong and weak HLA binders as well as epitopes sharing the majority of peptide amino acid residues, in particular within the epitope core HLA-binding sequence, were identified.

Results: We identified 16 proteins in the CNS protein dataset with predicted HLA-DRB1*1501-restricted epitopes and shared specificities with EBNA-1 peptides. We identified 58 different putative 15-mer class II HLA epitopes that could be grouped in 7 different clusters, sharing the same core position in EBNA-1, showing potential cross-reactivity between EBNA-1 binders and the analysed CNS protein dataset. The top cross-recognized epitope sequences were all located in the C-terminal part of the EBNA-1 gene and were confined to four discrete regions (EBNA-1 residues 477-483, 512-518, 527-529, 557-558). With this prediction algorithm, the core sequence of previously published DRB1*1501 epitope AEGLRALLARSHVER was also identified.

Discussion: We have identified several novel potential epitopes within CNS proteins that were selected for their capacity to bind HLA-DRB1*1501 and to share this propensity with the EBNA-1 protein. Further functional analysis of these potentially cross-reactive viral and host epitopes will be undertaken in order to further characterise potential relationships between latent EBV infection and MS pathogenesis.

Publication Type: Conference Item
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Publisher: Sage Publications
Copyright: © SAGE Publications
URI: http://researchrepository.murdoch.edu.au/id/eprint/37429
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