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JCI Insight. 2017 Jul 6;2(13). pii: 93688. doi: 10.1172/jci.insight.93688. [Epub ahead of print]

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

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Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, China.
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology, and Division of Rheumatology, University Hospital Frankfurt Goethe University, Frankfurt, Germany.
Medicity Research Laboratory, University of Turku, Turku, Finland; National Doctoral Programme in Informational and Structural Biology, Turku, Finland.
Section of Organic Chemistry, Department of Chemistry - Biomedicinskt centrum, Uppsala University, Uppsala, Sweden.
Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
Department of Chemistry & Biochemistry, Florida Atlantic University, Jupiter, Florida, USA.
Department of Rheumatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Section of Biochemistry, Department of Chemistry - Biomedicinskt centrum, Uppsala University, Uppsala, Sweden.
Center for Medical Immunopharmacology Research, Southern Medical University, Guangzhou, China.


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.

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