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Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
Karolinska Inst, Sweden.
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2019 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 71, no 2, p. 210-221Article in journal (Refereed) Published
Abstract [en]

Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized 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 serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 71, no 2, p. 210-221
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:liu:diva-154566DOI: 10.1002/art.40698ISI: 000457458100005PubMedID: 30152126OAI: oai:DiVA.org:liu-154566DiVA, id: diva2:1290503
Note

Funding Agencies|Swedish Strategic Science Foundation; Knut and Alice Wallenberg Foundation; Swedish Research Council; Guangdong province [201001Y04675344]; EU Innovative Medicine Initiative (BeTheCure grant); European Community Seventh Framework Programme (FP7/2007-2013) under BioStruct-X [283570]

Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20

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Skogh, ThomasKastbom, Alf
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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Rheumatology
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