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: 1) RSC‐RF had at least twice as much reactivity with human IgG as with rabbit IgG; 2) serum RF had approximately equal reactivity with human and rabbit IgG; 3) RSC‐RF had greater reactivity and avidity for IgG3 and IgG3 pFc' than for IgG1; and 4) 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.

Rheumatoid factors in immune complexes of patients with rheumatoid arthritis

“…Furthermore, the data indicated that the avidity between IgG3 and IgM RF produced locally was higher than between these antibodies and other IgG subclasses. These findings were corroborated by a solidphase enzyme immunoassay, in which the synovial cell IgM RFs bound better to IgG3 than to IgG1 [48]. These IgM RFs also bound to the pFc' fragment of IgG3, indicating reaction with antigenic determinants on the C3,3 domain.…”

“…Antibodies to type II collagen were recovered from cartilage of patients with RA in larger amounts than from patients with osteoarthritis, but RFs were recovered only from cartilage of patients with RA [19]. Furthermore, the circulating antibodies to type II collagen were predominantly IgG3 subclass [64] and IgM RFs produced by synovial cells were directed more often to IgG3 than IgM RFs in circulation [47,48]. Therefore, the possibility exists that in RA the development of IgG3 antibodies to type II collagen leads to their deposition in articular cartilage and this stimulates in genetically programmed individuals local RF synthesis with specificity to IgG3 subclass.…”

Importance of the IgG isotype, not the state of glycosylation, in determining human rheumatoid factor binding

“…It is clear that we do not know which, if any, of the RF are most associated with an active disease process. Studies of the isotype specificity of polyclonal RF have found that, in contrast to serum RF, which bind primarily to the IgGl isotype, polyclonal RF produced by synovial cells bind preferentially to the IgG3 subclass (28). Our study suggests that representatives of this synovial B cell population can also be found in peripheral blood, since our hybridoma fusions were done with peripheral blood lymphocytes of patients with RA.…”

Rheumatoid Factors Induce Signaling from B Cells, Leading to Epstein-Barr Virus and B-Cell Activation

“…Since RFs in sera are bound by serum IgG, they must have lower IgG-binding capabilities. Moreover, several reports demonstrated that RFs produced by rheumatoid synovial cells had greater reactivity to the IgG3 subclass, in contrast to serum RF, which had greater reactivity to the human IgG1 subclass (29). Further observations indicated that synovium-derived RFs had greater affinity than PBMC-derived RFs (3).…”

“…It is known that crosslinking of BCR is followed by phosphorylation of tyrosine kinases and elevation of the intracellular calcium concentration (10,29), and both are required for EBV activation (9). We therefore studied whether RFs could stimulate these pathways.…”