IgG subclass distribution of the rheumatoid arthritis-specific autoantibodies to citrullinated fibrin

Abstract

SummaryIn the rheumatoid synovium, deiminated ('citrullinated') forms of fibrin are the major targets of IgG autoantibodies to citrullinated proteins (ACPA), the most specific serological markers of rheumatoid arthritis (RA). To further the characterization of ACPA, we determined their subclass distribution. From a previously validated highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) onto in vitro deiminated human fibrinogen ----antihuman fibrin(ogen) autoantibodies (AhFibA)-ELISA ----we derived and calibrated four ELISAs, using monoclonal antibodies to each of the four IgG subclasses, to determine the proportions of AhFibA subclasses in the sera. A series of 186 serum samples from RA patients was analysed. All AhFibA-positive sera contained IgG1-AhFibA, which reached the highest titres and accounted for more than 80% of AhFibA in three-quarters of the sera. One or two other subclasses were associated with IgG1 in 39% of the sera, IgG4-AhFibA being observed much more frequently and at higher titres than IgG3-or IgG2-AhFibA. IgG1 alone or IgG(1 + 4)-AhFibA were the AhFibA subclass profiles found in more than 80% of patients. AhFibA are mainly IgG1 and, to a lesser extent, IgG4. Such IgG subclass profiles may influence the effector phases of the immunological conflict between ACPA and deiminated fibrin that takes place specifically in the rheumatoid synovium and therefore may play a critical role in the self-maintenance of rheumatoid inflammation.

Citrullination-dependent Differential Presentation of a Self-peptide by HLA-B27 Subtypes

“…In addition, an analysis of synovial tissue from a patient with rheumatoid arthritis has demonstrated that 51 (5.2%) of 990 identified synovial proteins exhibited citrullination, and 13 citrullinated autoantigens could unambiguously be assigned by mass spectrometry (54). Apart from fibrinogen, a major citrullinated autoantigen in these patients (55,56), all other proteins identified in this study (54) were polypeptides for which citrullination had not been described previously. Similarly, a comparative proteomic study (see Ref.…”

Immunoglobulin G Subclass Profile of Anticitrullinated Peptide Antibodies Specific for Epstein Barr Virus-derived and Histone-derived Citrullinated Peptides

“…ACPA are polyclonal in the usage of different IgG subclasses, but in this case the pattern is more heterogeneous. So far the studies conducted indicate the dominance of IgG1 and IgG4, while IgG3 have been detected with cyclic citrullinated peptide (CCP) and vimentin, but not with fibrinogen 4,5 .…”

Human IgG4 Binds to IgG4 and Conformationally Altered IgG1 via Fc-Fc Interactions

“…Apart from giving rise to, possibly false, high RF titers, this Fcmediated binding of IgG4 to IgG1 Abs may result in overestimated values for IgG4 in binding assays involving catching Abs, depending on the animal source. Elevated levels of IgG4 are associated with other RA-related autoantibodies as well (7).…”