title: Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation.
abstract: OBJECTIVE
  Immunological events in the lungs might trigger production of anti-citrullinated protein antibodies during early rheumatoid arthritis (RA). We investigated the presence of shared immunological citrullinated targets in joints and lungs of patients with RA.
  
  
  METHODS
  Proteins extracted from bronchial (n=6) and synovial (n=7) biopsy specimens from patients with RA were investigated by mass spectrometry-based proteomics. One candidate peptide was synthesised and used to investigate by ELISA the presence of antibodies in patients with RA (n=393), healthy controls (n=152) and disease controls (n=236). HLA-DRB1 shared epitope (SE) alleles were detected in patients with RA.
  
  
  RESULTS
  Ten citrullinated peptides belonging to seven proteins were identified, with two peptides shared between the synovial and bronchial biopsy samples. Further analysis, using accurate mass and retention time, enabled detection of eight citrullinated peptides in synovial and seven in bronchial biopsy specimens, with five peptides shared between the synovial and bronchial biopsy specimens. Two citrullinated vimentin (cit-vim) peptides were detected in the majority of synovial and lung tissues. Antibodies to a synthesised cit-vim peptide candidate (covering both cit-vim peptides identified in vivo) were present in 1.8% of healthy controls, 15% of patients with RA, and 3.4% of disease controls. Antibodies to cit-vim peptide were associated with the presence of the SE alleles in RA.
  
  
  CONCLUSIONS
  Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A Jimmy
authors.initials: AJ
authors.lastname: Ytterberg
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vijay
authors.initials: V
authors.lastname: Joshua
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Reynisdottir
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nataliya K
authors.initials: NK
authors.lastname: Tarasova
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Rutishauser
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Elena
authors.initials: E
authors.lastname: Ossipova
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aase
authors.initials: A
authors.lastname: Haj Hensvold
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Karolinska Institutet, and Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Eklund
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Karolinska Institutet, and Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: C Magnus
authors.initials: CM
authors.lastname: Sköld
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Karolinska Institutet, and Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Grunewald
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.affiliation: Clinical Immunology Unit, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Rönnelid
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zubarev
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anca I
authors.initials: AI
authors.lastname: Catrina
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001980:Bronchi / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002956:Citrulline / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007596:Joints / Q000276:immunology; D008168:Lung / Q000276:immunology; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D010456:Peptides, Cyclic / Q000276:immunology; D040901:Proteomics; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism; D014746:Vimentin / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D059811:HLA-DRB1 Chains; D010455:Peptides; D010456:Peptides, Cyclic; D014746:Vimentin; C487763:cyclic citrullinated peptide; D002956:Citrulline
keywords: Ant-CCP; Early Rheumatoid Arthritis; Rheumatoid Arthritis