OBJECTIVE: To investigate type II collagen (CII) as a joint-specific target of the anti-citrullinated protein antibody (ACPA) response in rheumatoid arthritis (RA). METHODS: Potential citrullinated neoepitopes were identified by high-resolution tandem mass spectrometry (MS/MS) of in vitro peptidylarginine deiminase 2 (PAD-2)-treated CII, and the relationship between citrullination and CII conformation was investigated by circular dichroism and conformation-dependent antibodies. Based on the MS analyses, synthetic peptides were designed and analyzed for serum IgG reactivity in the Epidemiological Investigation of RA (EIRA) case-control cohort of 1,949 RA patients and 278 healthy controls. Peptide-specific antibodies were purified from RA patient serum and used to stain RA cartilage specimens. RESULTS: We described the conformation-dependent citrullination pattern of CII after PAD-2 treatment at room temperature and 37°C and showed that CII could be citrullinated in its native triple-helical conformation. Screening of Arg and Cit pairs of synthetic peptides revealed new citrullinated B cell epitopes on CII. Antibodies directed to 2 proximal epitopes close to the C-terminus of the CII triple helix were recognized by autoantibodies in 21% and 17% of RA patients, respectively. Affinity-purified antibodies from RA sera directed to these 2 epitopes, but not antibodies directed to citrullinated α-enolase peptide 1, bound to RA cartilage. CONCLUSION: These findings suggest that cartilage-directed anticitrulline immunity contributes to the induction of joint inflammation in RA.
OBJECTIVE: To investigate type II collagen (CII) as a joint-specific target of the anti-citrullinated protein antibody (ACPA) response in rheumatoid arthritis (RA). METHODS: Potential citrullinated neoepitopes were identified by high-resolution tandem mass spectrometry (MS/MS) of in vitro peptidylarginine deiminase 2 (PAD-2)-treated CII, and the relationship between citrullination and CII conformation was investigated by circular dichroism and conformation-dependent antibodies. Based on the MS analyses, synthetic peptides were designed and analyzed for serum IgG reactivity in the Epidemiological Investigation of RA (EIRA) case-control cohort of 1,949 RA patients and 278 healthy controls. Peptide-specific antibodies were purified from RA patient serum and used to stain RA cartilage specimens. RESULTS: We described the conformation-dependent citrullination pattern of CII after PAD-2 treatment at room temperature and 37°C and showed that CII could be citrullinated in its native triple-helical conformation. Screening of Arg and Cit pairs of synthetic peptides revealed new citrullinated B cell epitopes on CII. Antibodies directed to 2 proximal epitopes close to the C-terminus of the CII triple helix were recognized by autoantibodies in 21% and 17% of RA patients, respectively. Affinity-purified antibodies from RA sera directed to these 2 epitopes, but not antibodies directed to citrullinated α-enolase peptide 1, bound to RA cartilage. CONCLUSION: These findings suggest that cartilage-directed anticitrulline immunity contributes to the induction of joint inflammation in RA.
Authors: Anca I Catrina; Camilla I Svensson; Vivianne Malmström; Georg Schett; Lars Klareskog Journal: Nat Rev Rheumatol Date: 2016-12-15 Impact factor: 20.543
Authors: Daniel Nyberg Larsen; Christian Engelbrecht Mikkelsen; Mads Kierkegaard; Grzegorz P Bereta; Zuzanna Nowakowska; Jakub Z Kaczmarek; Jan Potempa; Peter Højrup Journal: Mol Cell Proteomics Date: 2019-11-21 Impact factor: 5.911
Authors: A O Guerreiro-Cacais; U Norin; A Gyllenberg; R Berglund; A D Beyeen; E Petit-Teixeira; F Cornélis; A Saoudi; G J Fournié; R Holmdahl; L Alfredsson; L Klareskog; M Jagodic; T Olsson; I Kockum; L Padyukov Journal: Genes Immun Date: 2017-01-05 Impact factor: 2.676