Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis
Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from α-en...
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Frontiers Media S.A.
2016-11-01
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Series: | Frontiers in Immunology |
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Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2016.00494/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Christina Gerstner Anatoly Dubnovitsky Anatoly Dubnovitsky Charlotta Sandin Genadiy Kozhukh Genadiy Kozhukh Hannes Uchtenhagen Hannes Uchtenhagen Eddie A. James Johan Rönnelid Anders Jimmy Ytterberg Anders Jimmy Ytterberg Jennifer Pieper Evan Reed Karolina Tandre Mary Rieck Roman A. Zubarev Lars Rönnblom Tatyana Sandalova Tatyana Sandalova Jane H. Buckner Adnane Achour Adnane Achour Vivianne Malmström |
spellingShingle |
Christina Gerstner Anatoly Dubnovitsky Anatoly Dubnovitsky Charlotta Sandin Genadiy Kozhukh Genadiy Kozhukh Hannes Uchtenhagen Hannes Uchtenhagen Eddie A. James Johan Rönnelid Anders Jimmy Ytterberg Anders Jimmy Ytterberg Jennifer Pieper Evan Reed Karolina Tandre Mary Rieck Roman A. Zubarev Lars Rönnblom Tatyana Sandalova Tatyana Sandalova Jane H. Buckner Adnane Achour Adnane Achour Vivianne Malmström Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis Frontiers in Immunology rheumatoid arthritis HLA-DR4/α-enolase neo-antigen CD4+ T cell autoimmunity cytokines |
author_facet |
Christina Gerstner Anatoly Dubnovitsky Anatoly Dubnovitsky Charlotta Sandin Genadiy Kozhukh Genadiy Kozhukh Hannes Uchtenhagen Hannes Uchtenhagen Eddie A. James Johan Rönnelid Anders Jimmy Ytterberg Anders Jimmy Ytterberg Jennifer Pieper Evan Reed Karolina Tandre Mary Rieck Roman A. Zubarev Lars Rönnblom Tatyana Sandalova Tatyana Sandalova Jane H. Buckner Adnane Achour Adnane Achour Vivianne Malmström |
author_sort |
Christina Gerstner |
title |
Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis |
title_short |
Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis |
title_full |
Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis |
title_fullStr |
Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis |
title_full_unstemmed |
Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis |
title_sort |
functional and structural characterization of a novel hla-drb1*04:01-restricted α-enolase t cell epitope in rheumatoid arthritis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2016-11-01 |
description |
Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from α-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified α-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue. |
topic |
rheumatoid arthritis HLA-DR4/α-enolase neo-antigen CD4+ T cell autoimmunity cytokines |
url |
http://journal.frontiersin.org/article/10.3389/fimmu.2016.00494/full |
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doaj-0896a9add6fe43039b24b4c4429423b12020-11-25T01:02:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242016-11-01710.3389/fimmu.2016.00494224418Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid ArthritisChristina Gerstner0Anatoly Dubnovitsky1Anatoly Dubnovitsky2Charlotta Sandin3Genadiy Kozhukh4Genadiy Kozhukh5Hannes Uchtenhagen6Hannes Uchtenhagen7Eddie A. James8Johan Rönnelid9Anders Jimmy Ytterberg10Anders Jimmy Ytterberg11Jennifer Pieper12Evan Reed13Karolina Tandre14Mary Rieck15Roman A. Zubarev16Lars Rönnblom17Tatyana Sandalova18Tatyana Sandalova19Jane H. Buckner20Adnane Achour21Adnane Achour22Vivianne Malmström23Rheumatology Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenNeuroimmunology Unit, Department of Clinical Neurosciences, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenScience for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, SwedenRheumatology Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenRheumatology Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenScience for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, SwedenRheumatology Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenTranslational Research program, BRI at Virginia Mason, Seattle, WA, USATetramer Core, BRI at Virginia Mason, Seattle, WA, USADepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenRheumatology Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenRheumatology Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenRheumatology Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenScience for Life Laboratory, Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, SwedenTranslational Research program, BRI at Virginia Mason, Seattle, WA, USADepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenScience for Life Laboratory, Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, SwedenDepartment of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, SwedenTranslational Research program, BRI at Virginia Mason, Seattle, WA, USAScience for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, SwedenDepartment of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, SwedenRheumatology Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenAntibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from α-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified α-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue.http://journal.frontiersin.org/article/10.3389/fimmu.2016.00494/fullrheumatoid arthritisHLA-DR4/α-enolaseneo-antigenCD4+ T cellautoimmunitycytokines |