Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis

Abstract

Objective. Modification of antigens represents a trigger for the generation of autoantibodies. In the pathogenesis of rheumatoid arthritis (RA), citrullination of proteins has been shown to be a critical process, and the determination of antibodies against citrullinated antigens has been a diagnostic milestone. We undertook this study to determine whether antibodies to mutated and citrullinated vimentin (MCV) could serve as a diagnostic and prognostic marker for RA.Methods. We identified novel isoforms of human MCV in the synovial fluid of RA patients. The significance of these disease-related modifications was investigated by the analysis of autoantibody reactivities. In a group of 1,151 RA patients, the diagnostic significance and the prognostic value of an anti-MCV enzyme-linked immunosorbent assay (ELISA) were compared with that of an anti-cyclic citrullinated peptide (anti-CCP) ELISA.Results. In RA, sensitivities of 82% and 72% were calculated for the anti-MCV and anti-CCP assays, respectively. The specificity of both assays was comparable (98% and 96%, respectively). In followup analyses of 16 RA patients with moderate disease activity (mean Disease Activity Score in 28 joints [DAS28] of 2.72) and 26 RA patients with active disease (mean DAS28 of 5.07), disease stratification of RA was possible using the anti-MCV assay (P ‫؍‬ 0.0084). A significant correlation of anti-MCV antibodies with the DAS28 was documented (r ‫؍‬ 0.5334, P ‫؍‬ 0.0003), in 42 RA patients (n ‫؍‬ 427 antibody determinations at different time points).

Unique Correlation Between Mutated Citrullinated Vimentine IgG Autoantibodies and Markers of Systemic Inflammation in Rheumatoid Arthritis Patients

“…Keskin et al [21] found that the measurement of serum anti-MCV levels is useful for diagnosis of RA and combined use of anti-MCV and RF antibodies may be more useful prognostic factor than RF and anti-CCP. The discrepancy between various studies can be explained by the difference in: (i) patient populations [22], (ii) early RA [23,24] or established RA [12,25], or (iii) number of cases studied [15].…”

“…It is secreted and citrullinated by macrophages undergoing apoptosis, largely present in the RA synovial microenvironment due to impaired clearance [12,13]. Citrullinated vimentin had been identified as potential auto antigen in the pathophysiology of RA and an enzyme-linked immunosorbent assay (ELISA) was developed for the detection of autoantibodies directed against a mutated citrullinated vimentin [2].…”

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

“…A mutated isoform of vimentin was identified by mass spectroscopy analysis of purified vimentin in synovial fluid samples from patients with RA. Subsequently, a human recombinant mutated isoform of vimentin, citrullinated in vitro, was used in a new commercial enzyme-linked immunosorbent assay (ELISA) for detection of the respective antibodies against mutated citrullinated vimentin (anti-MCV) (12). Studies that compared the diagnostic accuracy of anti-MCV and anti-CCP antibodies in RA found comparable sensitivities, while the specificities were higher for anti-CCP in most cases (13)(14)(15)(16)(17)(18)(19).…”

Serum levels of anti-CCP antibodies, anti-MCV antibodies and RF IgA in the follow-up of patients with rheumatoid arthritis treated with rituximab

“…Among the proteins that are targeted by APCA, citrullinated vimentin soon became a very promising target because it is present specifically in the pannus and in the synovial fluid of RA patients [22,23]. Therefore, the industry has recently proposed a specific test for antihuman modified citrullinated vimentin (a-MCV) [24].…”