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Citrullinated Aggrecan Epitopes as Targets of Autoreactive CD 4+ T Cells in Patients With Rheumatoid Arthritis
Author(s) -
Rims Cliff,
Uchtenhagen Hannes,
Kaplan Mariana J.,
CarmonaRivera Carmelo,
Carlucci Philip,
Mikecz Katalin,
Markovics Adrienn,
Carlin Jeffrey,
Buckner Jane H.,
James Eddie A.
Publication year - 2019
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40768
Subject(s) - aggrecan , epitope , antigen , antibody , immunology , rheumatoid arthritis , t cell , microbiology and biotechnology , arthritis , immunogenicity , medicine , immune system , biology , osteoarthritis , pathology , alternative medicine , articular cartilage
Objective Recognition of citrullinated antigens such as vimentin, fibrinogen, and α‐enolase is associated with rheumatoid arthritis ( RA ). Emerging data suggest that the matrix protein aggrecan is also recognized as a citrullinated antigen. This study was undertaken to directly visualize Cit‐aggrecan–specific T cells and characterize them in patients with RA . Methods Citrullinated aggrecan peptides with likely DRB 1*04:01 binding motifs were predicted using a previously published scanning algorithm. Peptides with detectable binding were assessed for immunogenicity by HLA tetramer staining, followed by single cell cloning. Selectivity for citrullinated peptide was assessed by tetramer staining and proliferation assays. Ex vivo tetramer staining was then performed to assess frequencies of aggrecan‐specific T cells in peripheral blood. Finally, disease association was assessed by comparing T cell frequencies in RA patients and controls and correlating aggrecan‐specific T cells with levels of aggrecan‐specific antibodies. Results We identified 6 immunogenic peptides, 2 of which were the predominant T cell targets in peripheral blood. These 2 epitopes were citrullinated at HLA binding residues and shared homologous sequences. RA patients had significantly higher frequencies of Cit‐aggrecan–specific T cells than healthy subjects. Furthermore, T cell frequencies were significantly correlated with antibodies against citrullinated aggrecan. Conclusion Our findings indicate that T cells that recognize citrullinated aggrecan are present in patients with RA and correlate with antibodies that target this same antigen. Consequently, aggrecan‐specific T cells and antibodies are potentially relevant markers that could be used to monitor patients with RA or at‐risk subjects.