title: Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis.
abstract: We investigated whether citrullinated tenascin-C (cTNC), an extracellular matrix protein expressed at high levels in the joints of patients with rheumatoid arthritis (RA), is a target for the autoantibodies in RA.
  
  
  
  Citrullinated sites were mapped by mass spectrometry in the fibrinogen-like globe (FBG) domain of tenascin-C treated with peptidylarginine deiminases (PAD) 2 and 4. Antibodies to cyclic peptides containing citrullinated sites were screened in sera from patients with RA by ELISA. Potential cross-reactivity with well-established anticitrullinated protein antibody (ACPA) epitopes was tested by inhibition assays. The autoantibody response to one immunodominant cTNC peptide was then analysed in 101 pre-RA sera (median 7 years before onset) and two large independent RA cohorts.
  
  
  
  Nine arginine residues within FBG were citrullinated by PAD2 and PAD4. Two immunodominant peptides cTNC1 (VFLRRKNG-cit-ENFYQNW) and cTNC5 (EHSIQFAEMKL-cit-PSNF-cit-NLEG-cit-cit-KR) were identified. Antibodies to both showed limited cross-reactivity with ACPA epitopes from α-enolase, vimentin and fibrinogen, and no reactivity with citrullinated fibrinogen peptides sharing sequence homology with FBG. cTNC5 antibodies were detected in 18% of pre-RA sera, and in 47% of 1985 Swedish patients with RA and 51% of 287 North American patients with RA. The specificity was 98% compared with 160 healthy controls and 330 patients with osteoarthritis.
  
  
  
  There are multiple citrullination sites in the FBG domain of tenascin-C. Among these, one epitope is recognised by autoantibodies that are detected years before disease onset, and which may serve as a useful biomarker to identify ACPA-positive patients with high sensitivity and specificity in established disease.
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Anja
authors.initials: A
authors.lastname: Schwenzer
authors.affiliation: Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Stockholm, Sweden.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Medicine, University of Nebraska, Medical Center, Omaha, Nebraska, USA.
authors.forename: Ted R
authors.initials: TR
authors.lastname: Mikuls
authors.affiliation: Department of Medicine, University of Nebraska, Medical Center, Omaha, Nebraska, USA Department of Surgical Specialties, University of Nebraska, Medical Center, College of Dentistry, Lincoln, Nebraska, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Payne
authors.affiliation: Department of Biostatistics, University of Nebraska, Medical Center, Omaha, Nebraska, USA.
authors.forename: Harlan R
authors.initials: HR
authors.lastname: Sayles
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Quirke
authors.affiliation: Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Venables
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Lundberg
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
authors.forename: Kim S
authors.initials: KS
authors.lastname: Midwood
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005260:Female; D005340:Fibrinogen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007596:Joints / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009656:North America; D010456:Peptides, Cyclic / Q000097:blood* / Q000276:immunology; D013548:Sweden; D019063:Tenascin / Q000097:blood* / Q000276:immunology; D006113:United Kingdom
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D010456:Peptides, Cyclic; D019063:Tenascin; C487763:cyclic citrullinated peptide; D005340:Fibrinogen
keywords: Ant-CCP; Autoantibodies; Rheumatoid Arthritis