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

Abstract

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.

Deiminated Epstein‐Barr virus nuclear antigen 1 is a target of anti–citrullinated protein antibodies in rheumatoid arthritis

“…T cell epitopes have been identified on 2 deiminated self proteins that are targets of ACPAs: a deiminated vimentin peptide has been shown to induce a strong T cell proliferative response in mice transgenic for HLA-DRB1 (34), and T cells specific for the glycosylated epitopes on type II collagen may help in the production of antibodies directed to deiminated type II collagen sequences (35).…”

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

“…It is not clear which proteins harbor the epitopes targeted by ACPAs, although several candidates, including citrullinated fibrinogen (29), vimentin (30), and type II collagen (31), have been suggested, and we recently identified citrullinated ␣-enolase as another potential autoantigen (32). Alpha-enolase is abundantly expressed in the rheumatoid joint, antibodies targeting only the citrullinated form of the protein are specific for the disease, and our group recently demonstrated the presence in vivo of citrullinated ␣-enolase in synovial fluid from patients with RA (33).…”

Abatacept: a T-cell co-stimulation modulator for the treatment of rheumatoid arthritis

“…Activated T cells play a central role in this pathway by initiating this cascade with subsequent stimulation of macrophages and synovial fibroblasts to produce inflammatory cytokines, including TNF-α, interleukin-2, and interferon-γ [22]. T cells are also involved in activating B cells, which then produce autoantibodies, such as rheumatoid factor and anti-cyclic citrullinated peptides [23,24]. In addition, activated T cells produce the receptor activator of nuclear factor-κB (RANK) ligand that, in turn, binds to RANK on osteoclasts.…”

“…Patients who received placebo plus DMARDs during the initial doubleblind period were reallocated to abatacept plus DMARDs at the start of the LTE. Both double-blind (day 1 to month 6) and LTE (month 6 to month 24) (108.8 and 5.3/100 patients-years, respectively). For the cumulative period, discontinuations due to infections occurred in five patients, three of which had serious infections (pneumonia, streptococcal sepsis, and subacute endocarditis).…”