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A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis.
Arthritis Rheumatol. 2016 05; 68(5):1124-35.AR

Abstract

OBJECTIVE

Antibodies against citrullinated type II collagen (Cit-CII) are common in the sera and synovial fluid of patients with rheumatoid arthritis (RA); however, the known T cell epitope of CII is not dependent on citrullination. The aim of this study was to identify and functionally characterize the Cit-CII-restricted T cell epitopes that are relevant to RA.

METHODS

Peripheral blood mononuclear cells (PBMCs) from HLA-DRB1*10:01-positive patients with RA and healthy donors were stimulated in vitro with candidate CII peptides. CD154 up-regulation was measured as a marker of antigen-specific activation, and anti-HLA-DR-blocking experiments confirmed HLA restriction. Cytokine production was measured using a Luminex technique. Direct peptide-binding assays using HLA-DRB1*10:01 and HLA-DRB1*04:01 monomeric proteins were performed. The T cell receptor (TCR) β-chain of CD154-enriched antigen-specific T cells was analyzed using high-throughput sequencing.

RESULTS

A novel Cit-CII peptide was identified based on its ability to activate CD4+ T cells from HLA-DRB1*10:01-positive individuals. When stimulated in vitro, Cit-CII autoreactive T cells produced proinflammatory cytokines. Cit-CII(311-325) bound (with low affinity) to HLA-DRB1*10:01 but not to HLA-DRB1*04:01, while the native form was unable to bind either protein. In addition, highly expanded clones were identified in the TCRβ repertoire of Cit-CII(311-325) -stimulated PBMCs.

CONCLUSION

These results illustrate the ability of the citrullination process to create T cell epitopes from CII, a cartilage-restricted protein that is relevant to RA pathogenesis. The exclusive binding of Cit-CII(311-325) to HLA-DRB1*10:01 suggests that recognition of citrullinated epitopes might vary between individuals carrying different RA-associated HLA-DR molecules.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Chemin K
Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
Pollastro S
Amsterdam Rheumatology and Immunology Center, and Academic Medical Center, Amsterdam, The Netherlands.
James E
Benaroya Research Institute at Virginia Mason, Seattle, Washington.
Ge C
Karolinska Institute, Stockholm, Sweden.
Albrecht I
Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
Herrath J
Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
Gerstner C
Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
Tandre K
Uppsala University, Uppsala, Sweden.
Sampaio Rizzi T
Amsterdam Rheumatology and Immunology Center, and Academic Medical Center, Amsterdam, The Netherlands.
Rönnblom L
Uppsala University, Uppsala, Sweden.
Catrina A
Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
Holmdahl R
Karolinska Institute, Stockholm, Sweden.
Klareskog L
Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
de Vries N
Amsterdam Rheumatology and Immunology Center, and Academic Medical Center, Amsterdam, The Netherlands.
Malmström V
Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.

MeSH

AdultAgedArthritis, RheumatoidCase-Control StudiesCitrullineCollagen Type IICytokinesEpitopes, T-LymphocyteFemaleHLA-DRB1 ChainsHigh-Throughput Nucleotide SequencingHumansIn Vitro TechniquesLeukocytes, MononuclearMaleMiddle AgedReceptors, Antigen, T-Cell, alpha-betaSequence Analysis, DNA

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26713667

Citation

Chemin, Karine, et al. "A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis." Arthritis & Rheumatology (Hoboken, N.J.), vol. 68, no. 5, 2016, pp. 1124-35.
Chemin K, Pollastro S, James E, et al. A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(5):1124-35.
Chemin, K., Pollastro, S., James, E., Ge, C., Albrecht, I., Herrath, J., Gerstner, C., Tandre, K., Sampaio Rizzi, T., Rönnblom, L., Catrina, A., Holmdahl, R., Klareskog, L., de Vries, N., & Malmström, V. (2016). A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis. Arthritis & Rheumatology (Hoboken, N.J.), 68(5), 1124-35. https://doi.org/10.1002/art.39553
Chemin K, et al. A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(5):1124-35. PubMed PMID: 26713667.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis. AU - Chemin,Karine, AU - Pollastro,Sabrina, AU - James,Eddie, AU - Ge,Changrong, AU - Albrecht,Inka, AU - Herrath,Jessica, AU - Gerstner,Christina, AU - Tandre,Karolina, AU - Sampaio Rizzi,Thais, AU - Rönnblom,Lars, AU - Catrina,Anca, AU - Holmdahl,Rikard, AU - Klareskog,Lars, AU - de Vries,Niek, AU - Malmström,Vivianne, PY - 2015/09/18/received PY - 2015/12/15/accepted PY - 2015/12/30/entrez PY - 2015/12/30/pubmed PY - 2017/7/8/medline SP - 1124 EP - 35 JF - Arthritis & rheumatology (Hoboken, N.J.) JO - Arthritis Rheumatol VL - 68 IS - 5 N2 - OBJECTIVE: Antibodies against citrullinated type II collagen (Cit-CII) are common in the sera and synovial fluid of patients with rheumatoid arthritis (RA); however, the known T cell epitope of CII is not dependent on citrullination. The aim of this study was to identify and functionally characterize the Cit-CII-restricted T cell epitopes that are relevant to RA. METHODS: Peripheral blood mononuclear cells (PBMCs) from HLA-DRB1*10:01-positive patients with RA and healthy donors were stimulated in vitro with candidate CII peptides. CD154 up-regulation was measured as a marker of antigen-specific activation, and anti-HLA-DR-blocking experiments confirmed HLA restriction. Cytokine production was measured using a Luminex technique. Direct peptide-binding assays using HLA-DRB1*10:01 and HLA-DRB1*04:01 monomeric proteins were performed. The T cell receptor (TCR) β-chain of CD154-enriched antigen-specific T cells was analyzed using high-throughput sequencing. RESULTS: A novel Cit-CII peptide was identified based on its ability to activate CD4+ T cells from HLA-DRB1*10:01-positive individuals. When stimulated in vitro, Cit-CII autoreactive T cells produced proinflammatory cytokines. Cit-CII(311-325) bound (with low affinity) to HLA-DRB1*10:01 but not to HLA-DRB1*04:01, while the native form was unable to bind either protein. In addition, highly expanded clones were identified in the TCRβ repertoire of Cit-CII(311-325) -stimulated PBMCs. CONCLUSION: These results illustrate the ability of the citrullination process to create T cell epitopes from CII, a cartilage-restricted protein that is relevant to RA pathogenesis. The exclusive binding of Cit-CII(311-325) to HLA-DRB1*10:01 suggests that recognition of citrullinated epitopes might vary between individuals carrying different RA-associated HLA-DR molecules. SN - 2326-5205 UR - https://www.unboundmedicine.com/medline/citation/26713667/A_Novel_HLA_DRB1_10:01_Restricted_T_Cell_Epitope_From_Citrullinated_Type_II_Collagen_Relevant_to_Rheumatoid_Arthritis_ DB - PRIME DP - Unbound Medicine ER -