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Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage

DOI: 10.1172/jci.insight.93688 DOI Help

Authors: Changrong Ge (Karolinska Institutet) , Dongmei Tong (Karolinska Institutet; Southern Medical University) , Bibo Liang (Karolinska Institutet; Southern Medical University) , Erik Lönnblom (Karolinska Institutet) , Nadine Schneider (University Hospital Frankfurt Goethe University) , Cecilia Hagert (University of Turku) , Johan Viljanen (Uppsala University) , Burcu Ayoglu (KTH Royal Institute of Technology) , Roma Stawikowska (Florida Atlantic University) , Peter Nilsson (KTH Royal Institute of Technology) , Gregg B. Fields (Florida Atlantic University) , Thomas Skogh (Linköping University) , Alf Kastbom (Linköping University) , Jan Kihlberg (Uppsala University) , Harald Burkhardt (University Hospital Frankfurt Goethe University) , Doreen Dobritzsch (Uppsala University) , Rikard Holmdahl (Karolinska Institutet; University of Turku; Southern Medical University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Jci Insight , VOL 2

State: Published (Approved)
Published: July 2017
Diamond Proposal Number(s): 11265 , 8492

Open Access Open Access

Abstract: Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif “RG-TG” within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.

Diamond Keywords: Rheumatoid Arthritis

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 19/07/2017 10:22


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)