Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis

• Published in: European journal of immunology Vol. 35; no. 5; pp. 1643 - 1652
• Main Authors: Burkhardt, Harald, Sehnert, Bettina, Bockermann, Robert, Engström, Åke, Kalden, Jochen R., Holmdahl, Rikard
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag 01.05.2005
• Subjects: Amino Acid Sequence; Animals; Antibody Formation; Arginine - metabolism; Arthritis, Rheumatoid - immunology; Autoantibodies; Autoantibodies - blood; Basic Medicine; Blotting, Western; Citrullination; Citrulline - immunology; Citrulline - metabolism; Citrulline/immunology/metabolism; Collagen; Collagen Type II - chemistry; Collagen Type II - immunology; Collagen Type II - metabolism; Collagen Type II/chemistry/immunology/metabolism; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Epitopes, B-Lymphocyte - immunology; Female; Humans; Hydrolases - metabolism; Immunoglobulin G - blood; Immunologi inom det medicinska området; Immunology in the medical area; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Middle Aged; Molecular Sequence Data; Protein-Arginine Deiminases; Rheumatoid arthritis; T-Lymphocytes - immunology; Western; Rheumatoid/immunology; Research Support; Arthritis; B-Lymphocyte/immunology; Epitopes; Blotting; Non-U.S. Gov't
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.200526000

Collagen type II (CII) is a relevant joint‐specific autoantigen in the pathogenesis of rheumatoid arthritis (RA). Whereas the reasons for the breakage of self tolerance to this major cartilage component are still enigmatic, T cell responses to glycosylated CII determinants in RA patients indicate that post‐translational modifications play a role. Since the conversion of arginine into citrulline by peptidylarginine deiminases (PAD) in some non‐joint‐specific antigens such as filaggrin or fibrin has been shown to give rise to RA‐specific humoral immune responses, we investigated whether PAD modification of cartilage‐specific CII might affect its recognition by circulating autoantibodies in early RA. In vitro treatment with purified PAD led to arginine deimination of native CII or of synthetic CII peptides as evidenced by amino acid analysis. The citrullination resulted in modified recognition of the immunodominant CII epitope C1III (amino acid residues 359–369) by murine and human antibodies. In a cohort of early RA patients (n=286), IgG antibodies directed toward a synthetic citrullinated C1III peptide (citC1III‐P) were detectable with a prevalence of 40.4%. The partial autoantibody cross‐reactivity between citC1III‐P and citrullinated peptides mimicking epitopes of the cytoskeletal autoantigen filaggrin suggests that autoimmunity to cartilage‐specific modified self might be a critical intermediate bridging recognition of PAD‐modified extra‐articular autoantigens with the disruption of tolerance to native cartilage constituents.