The presence of citrullinated proteins is not specific for rheumatoid synovial tissue

Abstract

Objective. Antibodies directed toward citrullinated proteins (e.g., anti-cyclic citrullinated peptide antibodies) are highly specific for rheumatoid arthritis (RA) and are produced locally at the site of inflammation. Although the presence of citrullinated proteins in rheumatoid synovium has been described in the literature, it is uncertain whether their presence is specific for RA. The present study was undertaken to investigate this.Methods. The local production of the anticitrullinated protein antibodies was investigated by comparing the concentration of the antibodies (corrected for the total amount of IgG present) in paired samples of serum and synovial fluid from RA patients. The presence of citrullinated proteins in the synovial tissue was investigated by immunohistochemical analysis of synovial tissue from RA patients and from patients with other arthropathies, using a variety of specific antibodies to citrullinated proteins.Results. In RA patients, anti-citrullinated protein antibodies constituted a 1.4-fold higher proportion of IgG in synovial fluid compared with serum, which is indicative of a local production of the antibodies. Immunohistochemical staining of citrullinated proteins was observed in the lining layer, the sublining layer, and in extravascular fibrin deposits in inflamed synovial tissue from RA as well as non-RA patients.Conclusion. The presence of citrullinated proteins in the inflamed synovium is not specific for RA, but rather, it may be an inflammation-associated phenomenon. The high specificity of the anti-citrullinated protein antibodies is, therefore, most likely the result of an abnormal humoral response to these proteins.

Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis–specific humoral autoimmunity

“…Finally, the relationship between intracellular citrullinated proteins and ACPAs was stronger locally in SF than systemically in serum, with higher SF than serum ACPA levels in intracellular citrullinated protein-positive but not intracellular citrullinated protein-negative joints. Since this cannot be fully explained by immobilization of ACPAs by complex formation with citrullinated targets in the joints, these data are consistent with the previous demonstration of local ACPA production (14,49) and also suggest that this could be driven by specific synovial deiminated proteins.…”

“…The relevance of this finding is emphasized by several facts. First, previous studies failed to demonstrate a link between ACPAs and non-RA-specific citrullinated proteins, including fibrin (20,49). Second, our findings indicated that the presence of intracellular citrullinated proteins is independent of the degree of synovial inflammation and that the demonstrated link with ACPAs is thus not merely a secondary phenomenon due to higher ACPA levels leading to enhanced inflammation.…”

Antibodies to mutated citrullinated vimentin and antibodies to cyclic citrullinated peptides in juvenile idiopathic arthritis

“…It appears that the presence of citrullinated proteins in inflamed synovium is not specific for RA, but rather may be an inflammation-associated phenomenon (40). Independent of disease duration, synovitis in patients with anti-CCP-positive RA differs from that in patients with anti-CCP-negative RA, notably with respect to increased infiltrating lymphocytes and higher rate of local joint destruction (41).…”

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

“…In addition, the accumulation of citrullinated proteins has been described at sites of inflammation, including the joints of patients with all forms of arthritis (17), the brains of patients with multiple sclerosis (18) or Alzheimer's disease (19), and in the muscle fibers of patients with myositis (20). Hence, citrullinated proteins are present in the setting of both health and disease, while tolerance to citrullinated proteins appears to be selectively lost in patients with RA.…”