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


CONCLUSIONS
Antigenic properties of vimentin were determined by mutation and citrullination. Anti-MCV antibodies are a novel diagnostic marker for RA. Furthermore, they may allow monitoring and-if confirmed in even larger series of patients-stratification of disease.
Bang
Holger
H
Orgentec Diagnostika, Mainz, Germany.
Egerer
Karl
K
Gauliard
Anke
A
Lüthke
Kirsten
K
Rudolph
Paul E
PE
Fredenhagen
Gert
G
Berg
Wigbert
W
Feist
Eugen
E
Burmester
Gerd-R
GR
D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002956:Citrulline / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects; D020033:Protein Isoforms; D011994:Recombinant Proteins; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013582:Synovial Fluid / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D014746:Vimentin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D020033:Protein Isoforms; D011994:Recombinant Proteins; D014746:Vimentin; D002956:Citrulline; D006861:Hydrogen Peroxide