Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis: As Good as it Gets?

Abstract

Anti-citrullinated protein antibodies (ACPAs) have recently emerged as sensitive and specific serological markers of rheumatoid arthritis (RA), providing superior alternative of the rheumatoid factor (RF) test in the laboratory diagnostics of RA. The first members of this autoantibody family were anti-perinuclear factor (APF) and anti-keratin antibodies (AKA). It became evident that both APF and AKA recognize citrullinated epitopes of filaggrin. Citrullination is a post-translational modification of arginine by deimination, physiologically occurring during apoptosis, inflammation or keratinization. The presence of several citrullinated proteins has been demonstrated in the RA synovium. The identification of citrullinated epitopes as targets for anti-filaggrin antibodies led to the development of the first and later second generation anti-cyclic citrullinated peptide (anti-CCP) antibody assays. The widely used anti-CCP2 assays have high diagnostic sensitivity and specificity, and they also show important predictive and prognostic value in RA. The anti-Sa antibody has been identified a decade ago; however, recent studies confirmed that anti-Sa is directed against citrullinated vimentin, hence it is a new member of the family of ACPAs. The newly developed anti-mutated citrullinated vimentin (anti-MCV) assay has similar diagnostic performance than the anti-CCP2 ELISA; however, the diagnostic spectrum of the anti-MCV test is somewhat different from that of anti-CCP2. It's especially useful in the diagnosis of RA in RF and anti-CCP2 seronegative patients. The combined application of anti-CCP2 and anti-MCV assays can improve the laboratory diagnostics of RA. The family of ACPAs is expected to expand; there is an increasing need for developing new diagnostic strategies after careful evaluation of the characteristics of the available assays.

Anti-mutated citrullinated vimentin (anti-MCV) and anti-65kDa heat shock protein (anti-hsp65): New biomarkers in ankylosing spondylitis

“…ACPAs are considered to be specific and sensitive diagnostic markers of RA [5][6][7]38]. The anti-MCV test had a higher sensitivity than two anti-CCP tests.…”

“…In early stages, spinal and sacroiliac MRI may be a useful radiological tool for the diagnosis and follow-up of AS [3,4], however, there is a need for laboratory biomarkers. While anti-citrullinated protein/peptide antibodies (ACPA) have become rather specific and sensitive diagnostic tools in rheumatoid arthritis (RA) [5][6][7][8][9][10], such autoantibodies have not yet been identified in AS.…”

“…ACPAs including anti-cyclic citrullinated peptide (CCP), anti-citrullinated vimentin (CF), anti-citrullinated fibrinogen (CF), anti-citrullinated α enolase and some others have been implicated in the pathogenesis and outcome of RA [6][7][8][11][12][13][14][15][16][17][18][19]. ACPA production has been associated with interactions of HLA-DRB1 alleles and lifestyle-related factors, such as smoking in RA, as well as more destructive joint damage [8,11,[19][20][21].…”

Contribution of Myelin Autoantigen Citrullination to T Cell Autoaggression in the Central Nervous System

“…The de novo recognition of self-Ags that have been modified as a result of pathophysiological disturbance (3,4) is an appealing basis for breakdown in immunologic self tolerance; namely, the immune system would target the modified self-Ag as if it were pathogen derived. The literature provides various examples of Ab-and/or T cell-reactivity against antigenic epitopes that contain PTM such as glycosylation, deamidation, and citrullination (5)(6)(7)(8). Citrullination, the deimination of Arg to citrulline (Cit) (9), has received particular interest as an autoantigen modification.…”

A Contra Capture Protein Array Platform for Studying Post-translationally Modified (PTM) Auto-antigenomes

“…Furthermore, reported diagnostic sensitivities for anti-CCP assay in RA patients range from 68 -79% at 86 -95% specificity (37,38). The identification of additional citrullinated antigens and elucidation of their immunodominant epitopes will help develop more sensitive diagnostic assays, and by comparing citrullinated antigens in different diseases, the assays will achieve higher disease specificity (39,40). We have also developed a complementary enzyme-linked immunosorbent assay (ELISA) validation platform that allows the assessment of antibody reactivity of a large number of patients to full-length citrullinated antigens of interest.…”