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Antibodies to cartilage oligomeric matrix protein are pathogenic in mice and may be clinically relevant in rheumatoid arthritis

DOI: 10.1002/art.42072 DOI Help

Authors: Changrong Ge (Karolinska Institutet) , Dongmei Tong (Karolinska Institute) , Erik Lönnblom (Karolinska Institute) , Bibo Liang (Karolinska Institute) , Weiwei Cai (Karolinska Institute) , Cecilia Fahlquist-Hagert (Karolinska Institute) , Taotao Li (Karolinska Institute) , Alf Kastbom (Linköping University) , Inger Gjertsson (University of Gothenburg) , Doreen Dobritzsch (Uppsala University) , Rikard Holmdahl (Karolinska Institute; Southern Medical University; University of Turku)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Arthritis & Rheumatology

State: Published (Approved)
Published: January 2022
Diamond Proposal Number(s): 8492

Open Access Open Access

Abstract: Objectives: Cartilage oligomeric matrix protein (COMP) is an autoantigen in rheumatoid arthritis and experimental arthritis models. We aimed to investigate the structure, function and relevance of anti-COMP antibodies. Methods: The pathogenicity of monoclonal anti-COMP antibodies in mice was investigated by passive transfer experiments and interaction with cartilage by immunohistochemical staining. The interaction of the monoclonal antibody 15A11 in complex with its specific COMP epitope P6 was determined by X-ray crystallography. The modulation of the binding to 15A11 by calcium ions was studied by ELISA and the surface plasma resonance technique. The clinical relevance and value of serum IgG specific for the COMP P6 epitope and its citrullinated variants were evaluated in a large Swedish cohort of RA patients. Results: The murine monoclonal anti-COMP antibody 15A11 induced arthritis in naïve mice. The crystal structure of 15A11-P6 complex explained how the antibody could bind to COMP, which can be modulated by calcium ions. Moreover, serum IgGs specific for the COMP P6 peptide and its citrullinated variants were detectable at significantly higher levels in RA patients compared to the healthy controls and correlated with a higher disease activity score. Conclusions: We provide the structural basis for binding a pathogenic anti-COMP antibody to cartilage. The recognized epitope can be citrullinated and levels of antibodies to this epitope are elevated in RA patients and correlate with higher disease activity, implicating a pathogenic role of anti-COMP antibodies in a subset of RA patients.

Journal Keywords: cartilage oligomeric matrix protein; autoantibody; arthritogenicity; ACPA; rheumatoid arthritis

Diamond Keywords: Rheumatoid Arthritis

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 27/01/2022 09:35

Documents:
Arthritis Rheumatology - 2022 - Ge - Antibodies to cartilage oligomeric matrix protein are pathogenic in mice and may be.pdf

Discipline Tags:

Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)