Journal Article

Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis

Lundberg, Karin, Payne, Jeffrey B, Venables, Patrick J, Kessler, Benedikt M, Schwenzer, Anja, Fischer, Roman, Sayles, Harlan R, Midwood, Kim S, Jiang, Xia, Mikuls, Ted R, Quirke, Anne-Marie

2016

Overview

ObjectivesWe 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.MethodsCitrullinated 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.ResultsNine 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.ConclusionsThere 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.

• Publisher: Elsevier Limited,BMJ Publishing Group
• Subject: Adult / Antibodies / Antigens / Arginine / Arthritis, Rheumatoid - blood / Arthritis, Rheumatoid - immunology / Autoantibodies / Autoantibodies - blood / Basic and Translational Research / Case-Control Studies / Citrulline / Cross-reactivity / Cytokines / Disease Progression / Enzyme-Linked Immunosorbent Assay / Epitopes / Epitopes - immunology / Extracellular matrix / Female / Fibrinogen / Fibrinogen - immunology / Fibrinogen - metabolism / Homology / Humans / Inflammation / Joint diseases / Joints - immunology / Joints - metabolism / Male / Mass spectroscopy / Matrix protein / Middle Aged / North America / Osteoarthritis / Pathogenesis / Peptides / Peptides, Cyclic - blood / Peptides, Cyclic - immunology / Phosphopyruvate hydratase / Proteins / Rheumatoid arthritis / Rheumatology / Scientific imaging / Sweden / Tenascin / Tenascin - blood / Tenascin - immunology / Tenascin C / United Kingdom / Vimentin