Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage

Abstract

Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.

Cross‐reactivity of a human IgG1 anticitrullinated fibrinogen monoclonal antibody to a citrullinated profilaggrin peptide

“…39 These findings are in accordance to the literature, describing that antibodies to homocitrulline are noncross-reactive. 40 To our knowledge, this study is the first to illustrate cross-reactivity of the Cit mAb to a glycine backbone containing a single citrulline, confirming that this mAb (and probably related antibodies) indeed is cross-reactive. Hence, these findings will be used for comparison in future studies of RA patient sera as results achieved are in accordance to earlier studies 9,29 describing ACPA reactivity to LCPa/CCPa, indicating that our results may relate to ACPA responses of RA patient sera.…”

Review: Preclinical Rheumatoid Arthritis: Progress Toward Prevention

“…New serum biomarkers in pre-RA Autoantibodies against carbamylated proteins (anti-CarP) have recently been described in RA patients (51). Although homocitrulline, the product of carbamylation, shares structural similarities with citrulline, the role of anti-CarP antibodies in RA pathogenesis is unclear.…”

How Do We Classify Rheumatoid Arthritis in Established Disease — Can We Apply the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria?

“…It could be postulated that patients with so-called "seronegative disease", eventually differentiate into non-RA phenotypes. Other autoantibodies (such as antimutated citrullinated vimentin antibodies, an ACPA that is not detected by second-generation anti-CCP2, the most widely used test; and anticarbamylated protein antibodies) have been identified in anti-CCP-negative patients and associated with poor prognosis 20,21 . It is possible, therefore, that inclusion of other antibodies in the criteria could account for all those patients with poor outcomes.…”