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GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis


Planas, Raquel; Santos, Radleigh; Tomas-Ojer, Paula; Cruciani, Carolina; Lutterotti, Andreas; Faigle, Wolfgang; Schaeren-Wiemers, Nicole; Espejo, Carmen; Eixarch, Herena; Pinilla, Clemencia; Martin, Roland; Sospedra, Mireia (2018). GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis. Science Translational Medicine, 10(462):eaat4301.

Abstract

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4<jats:sup>+</jats:sup> T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–<jats:sc>l</jats:sc>-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4<jats:sup>+</jats:sup> T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-<jats:sc>l</jats:sc>-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.

Abstract

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4<jats:sup>+</jats:sup> T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–<jats:sc>l</jats:sc>-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4<jats:sup>+</jats:sup> T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-<jats:sc>l</jats:sc>-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:General Medicine
Language:English
Date:10 October 2018
Deposited On:06 Dec 2018 13:45
Last Modified:06 Dec 2018 13:48
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
OA Status:Green
Publisher DOI:https://doi.org/10.1126/scitranslmed.aat4301
PubMed ID:30305453

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