ACPA-positive rheumatoid arthritis (RA) is associated with distinct HLA-DR alleles and immune responses to many citrullinated self-antigens. Herein we investigated the T cell epitope confined within α-enolase326-340 in the context of HLA-DRB1*04:01 and assessed the corresponding CD4+ T cells in both the circulation and in the rheumatic joint. Comparative crystallographic analyses were performed for the native and citrullinated α-enolase326-340 peptides in complex with HLA-DRB1*04:01. HLA-tetramers assembled with either the native or citrullinated peptide were used for ex vivo and in vitro assessment of α−enolase-specific T cells in peripheral blood, synovial fluid and synovial tissue by flow cytometry. The native and modified peptides take a completely conserved structural conformation within the peptide-binding cleft of HLA-DRB1*04:01. The citrulline residue-327 was located N-terminally, protruding towards TCRs. The frequencies of T cells recognizing native eno326-340 were similar in synovial fluid and peripheral blood, while in contrast, the frequency of T cells recognizing cit-eno326-340 was significantly elevated in synovial fluid compared to peripheral blood (3.6-fold, p = 0.0150). Additionally, citrulline-specific T cells with a memory phenotype were also significantly increased (1.6-fold, p = 0.0052) in synovial fluid compared to peripheral blood. The native T cell epitope confined within α-enolase326-340 does not appear to lead to complete negative selection of cognate CD4+ T cells. In RA patient samples, only T cells recognizing the citrullinated version of α-enolase326-340 were found at elevated frequencies implicating that neo-antigen formation is critical for breach of tolerance.
Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint / J. Pieper, A. Dubnovitsky, C. Gerstner, E.A. James, M. Rieck, G. Kozhukh, K. Tandre, S. Pellegrino, J.A. Gebe, L. Rönnblom, T. Sandalova, W.W. Kwok, L. Klareskog, J.H. Buckner, A. Achour, V. Malmström. - In: JOURNAL OF AUTOIMMUNITY. - ISSN 0896-8411. - 92(2018 Aug), pp. 47-56.
|Titolo:||Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint|
|Parole Chiave:||Autoimmunity; Citrullination; Crystal structure; HLA class II tetramers|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Data di pubblicazione:||ago-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.jaut.2018.04.004|
|Appare nelle tipologie:||01 - Articolo su periodico|