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Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted alpha-Enolase T Cell Epitope in Rheumatoid Arthritis
Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden..
Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Neuroimmunol Unit, Stockholm, Sweden.;Karolinska Inst, Dept Med Solna, Sci Life Lab, Stockholm, Sweden..
Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden..
Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden.;Karolinska Inst, Dept Med Solna, Sci Life Lab, Stockholm, Sweden..
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2016 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 494Article in journal (Refereed) Published
Abstract [en]

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 alpha-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified alpha-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.

Place, publisher, year, edition, pages
2016. Vol. 7, article id 494
Keyword [en]
rheumatoid arthritis, HLA-DR4/alpha-enolase, neo-antigen, CD4(+) T cell, autoimmunity, cytokines, crystal structures
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-310749DOI: 10.3389/fimmu.2016.00494ISI: 000387919500002PubMedID: 27895642OAI: oai:DiVA.org:uu-310749DiVA, id: diva2:1058153
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilSwedish Rheumatism Association
Note

Correction in: Frontiers in Immunology, Volume: 8, Article Number: 1236, DOI: 10.3389/fimmu.2017.01236

Available from: 2016-12-20 Created: 2016-12-19 Last updated: 2018-03-23Bibliographically approved

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