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Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structural basis of cross-reactivity of anti-citrullinated protein antibodies Changrong Ge , Bingze Xu , Bibo Liang , Erik Lönnblom , Susanna L. Lundström , Roman A. Zubarev , Burcu Ayoglu , Peter Nilsson , Thomas Skogh , Alf Kastbom , Vivianne Malmström , Lars Klareskog , René E. M. Toes , Theo Rispens , Doreen Dobritzsch , Rikard Holmdahl Arthritis & Rheumatology DOI: 10.1002/art.40698 Diamond Proposal Number(s): [8492, 11265] Show Abstract ▼ Abstract: OBJECTIVES: Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis. Here we addressed the molecular basis of the specificity and cross-reactivity of ACPAs from patients with rheumatoid arthritis (RA). METHODS: Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc and characterized for glycosylation using mass-spectrometry and cross-reactivity using Biacore and Luminex immunoassay. Crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with three different citrullinated peptides were solved using x-ray crystallography. The prevalence of autoantibodies reactive against three of the citrullinated peptides that also interact with E4, was investigated by Luminex immunoassay in two Swedish cohorts of RA patients. RESULTS: Analysis of the crystal structures of a monoclonal ACPA in complex with citrullinated peptides revealed key residues of several complementarity-determining regions (CDR) that recognize the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of autoantibodies in two large cohorts of RA patients. CONCLUSIONS: The data show for the first time how ACPA, derived from human RA, recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation of the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.	Aug 2018

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I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography

Structural basis of cross-reactivity of anti-citrullinated protein antibodies