Differential reactivity of rheumatoid synovial cells and serum rheumatoid factors to human immunoglobulin G subclasses 1 and 3 and their CH3 domains in rheumatoid arthritis

Abstract

19S IgM rheumatoid factors (RF) are polyclonal autoantibodies that may play an important pathogenic role in sustaining inflammatory synovitis in rheumatoid arthritis (RA). RF in RA have reactivity for as-yet-uncharacterized antigenic determinants in IgG Fc. We hypothesized that qualitative differences might exist between some of these RF molecules, and that differences such as reactivity and affinity might characterize more pathogenic RF molecules. Previous observations in our laboratory indicate that RF produced by rheumatoid synovial cells (RSC) have greater reactivity with human IgG and IgG3 subclass, in contrast to serum RF, which has greater reactivity with rabbit IgG and human IgG1. These observations were made using a complement-dependent RF plaque-forming cell assay. The purpose of this study was to validate and extend those observations. Therefore, we examined the reactivity of RSC and serum RF with human and rabbit IgG and the reactivity and avidity of RSC-RF for IgG1 and IgG3 molecules and Fab, F(ab')2, and pFc' fragments thereof in a solid-phase enzyme immunoassay. In particular, we found: RSC-RF had at least twice as much reactivity with human IgG as with rabbit IgG; serum RF had approximately equal reactivity with human and rabbit IgG; RSC-RF had greater reactivity and avidity for IgG3 and IgG3 pFc' than for IgG1; and RSC-RF was nonreactive with Fab or F(ab')2 from either IgG1 or IgG3. These results suggest that the major antigenic determinant for RSC-RF resides in the CH3 domain of the IgG3 molecule. Precise characterization of this epitope may provide further insight into the etiology and pathogenesis of RA.