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Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden..
Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden.;Southern Med Univ, Dept Pathophysiol, Key Lab Shock & Microcirculat Res Guangdong, Guangzhou, Guangdong, Peoples R China..
Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden.;Southern Med Univ, Dept Pathophysiol, Key Lab Shock & Microcirculat Res Guangdong, Guangzhou, Guangdong, Peoples R China..
Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden..
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2017 (English)In: JCI INSIGHT, ISSN 2379-3708, Vol. 2, no 13, e93688Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC , 2017. Vol. 2, no 13, e93688
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-331243DOI: 10.1172/jci.insight.93688ISI: 000405181200012OAI: oai:DiVA.org:uu-331243DiVA: diva2:1150534
Funder
Swedish Foundation for Strategic Research , RB13-015Knut and Alice Wallenberg Foundation, KAW 2010.0148Swedish Research Council, 2015-02662EU, FP7, Seventh Framework Programme, 283570
Available from: 2017-10-19 Created: 2017-10-19 Last updated: 2017-10-19Bibliographically approved

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Viljanen, Johan V.Kihlberg, JanDobritzsch, Doreen

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