Epitopes described in "Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients."

Article Authors:Omri Snir; Mary Rieck; John A Gebe; Betty B Yue; Crystal A Rawlings; Gerald Nepom; Vivianne Malmström; Jane H Buckner
Article Title:Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients.
Reference Detail
Reference ID:1022455
Abstract:OBJECTIVE: Antibodies toward the citrullinated form of the synovial antigen vimentin are specific for rheumatoid arthritis (RA) and are associated with HLA-DRB1*0401. This suggests that T cells specific for peptides derived from citrullinated vimentin presented in the context of HLA-DRB1*0401 may contribute to the etiopathogenesis of RA. The aim of this study was to identify immunodominant epitopes from citrullinated vimentin presented by HLA-DRB1*0401 and to characterize the resulting T cell responses. METHODS: We first predicted an HLA-binding T cell epitope from citrullinated vimentin based on the binding motif of HLA-DRB1*0401 and then confirmed its affinity. A class II major histocompatibility complex (MHC) tetramer loaded with the citrullinated form of vimentin aa 59-78 (cit-vimentin aa 59-78) was constructed and used to screen for specific T cells in HLA-DRB1*0401-transgenic mice, patients with RA, and healthy control subjects. Additionally, the cytokine output following cit-vimentin aa 59-78 challenge was analyzed in patients and healthy control subjects by multicolor flow cytometry and Luminex-based analysis. RESULTS: The citrullinated form of vimentin aa 59-78 bound to HLA-DRB1*0401, but the native form could not. Subsequently, cit-vimentin aa 59-78-specific T cells were detected in immunized mice and in the periphery of both HLA-DR*0401-positive healthy control subjects and HLA-DR*0401-positive patients with RA, using class II MHC tetramers, CD154 up-regulation, and intracellular cytokine measurements. As demonstrated in cell culture supernatants, the production of cytokines (predominantly interferon-) in response to cit-vimentin aa 59-78 was significantly higher in patients compared with controls. CONCLUSION: Here, we describe a posttranslational modification of an RA candidate autoantigen toward which HLA-DRB1*0401-restricted T cells can be detected in both patients with RA and healthy controls but for which a proinflammatory response is observed uniquely in patients with RA.
Affiliations:Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Reference Type:Literature
PubMed ID:21567378
Journal:Arthritis Rheum
Journal Volume:63
Article Pages:2873-83
Journal ISSN:0004-3591
Article Chemical List:Epitopes, T-Lymphocyte;HLA-DRB1 Chains;HLA-DRB1*04:01 antigen;Peptides, Cyclic;Vimentin
Article MeSH List:Adult; Animals; Arthritis, Rheumatoid(immunology); Epitopes, T-Lymphocyte(immunology); HLA-DRB1 Chains(immunology); Humans; Mice; Mice, Transgenic; Peptides, Cyclic(immunology); T-Lymphocytes(immunology); Vimentin(immunology)
Curation Last Updated:2015-06-07 20:06:29