5NI9

Crystal structure of HLA-DRB1*04:01 with the alpha-enolase peptide 326-340

Summary for 5NI9

• Entry DOI: 10.2210/pdb5ni9/pdb
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-4 beta chain, Alpha-enolase, ... (7 entities in total)
• Functional Keywords: hla-dr, enolase, arthritis, antigen presentation, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 47170.09

Authors

Gerstner, C.,Dubnovitsky, A. (deposition date: 2017-03-23, release date: 2018-06-13, Last modification date: 2024-11-13)

Primary citation

Pieper, J.,Dubnovitsky, A.,Gerstner, C.,James, E.A.,Rieck, M.,Kozhukh, G.,Tandre, K.,Pellegrino, S.,Gebe, J.A.,Ronnblom, L.,Sandalova, T.,Kwok, W.W.,Klareskog, L.,Buckner, J.H.,Achour, A.,Malmstrom, V.
Memory T cells specific to citrullinated alpha-enolase are enriched in the rheumatic joint.
J. Autoimmun., 92:47-56, 2018

PubMed Abstract: 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-enolase 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-enolase 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 eno were similar in synovial fluid and peripheral blood, while in contrast, the frequency of T cells recognizing cit-eno 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-enolase 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-enolase were found at elevated frequencies implicating that neo-antigen formation is critical for breach of tolerance.

PubMed: 29853344
DOI: 10.1016/j.jaut.2018.04.004

Experimental method

X-RAY DIFFRACTION (1.33 Å)