A1 Refereed original research article in a scientific journal
Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
Authors: Ge CR, Tong DM, Liang BB, Lonnblom E, Schneider N, Hagert C, Viljanen J, Ayoglu B, Stawikowska R, Nilsson P, Fields GB, Skogh T, Kastbom A, Kihlberg J, Burkhardt H, Dobritzsch D, Holmdahl R, Holmdahl R
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Publication year: 2017
Journal: JCI Insight
Journal name in source: JCI INSIGHT
Journal acronym: JCI INSIGHT
Article number: ARTN e93688
Volume: 2
Issue: 13
Number of pages: 19
ISSN: 2379-3708
DOI: https://doi.org/10.1172/jci.insight.93688
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/26036558
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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