LOCALIZATION OF AN FC-BINDING REACTIVITY TO THE CONSTANT-REGION OF HUMAN IGG4 - IMPLICATIONS FOR THE PATHOGENESIS OF RHEUMATOID-ARTHRITIS

The majority of plasma cells in rheumatoid arthritis (RA) synovium pro duce rheumatoid factors (RF). IgG RF predominate in the immune complex es found in RA synovial fluid and have been implicated in the pathogen esis of RA. IgC4 RF are a major component of IgG RF produced in serum and synovium of RA patients, even though this subclass comprises only 4% of the serum IgG, We produced an IgG4 mAb, hRF-1, with RF reactivit y from the synovial tissue of a patient with RA. mAb hRF-1 had binding specificity for mammalian IgG similar to Staphylococcus aureus protei n A, which is characteristic of RF from patients with RA. To determine the molecular basis of this particular RF reactivity, the heavy and l ight chain genes of mAb hRF-1 were amplified by PCR, cloned, and ligat ed into the pSC5 plasmid for expression in COS-7 cells. Chain recombin ation experiments localized the Fc-binding reactivity to the hRF-1 hea vy chain. Using a series of chimeric Ab sequences, the Fc-binding reac tivity was mapped to the constant region of IgG4 rather than the varia ble region involved in classic RF reactivity. Multiple domains, includ ing Hinge, CH2, and CH3 of the IgG4 constant region were required for Fc binding. Our studies demonstrate an example of RF-like Fc-binding r eactivity that is conferred by the gamma-4 constant region rather than the classic Ag binding site and suggest that increased production of IgG4 may contribute to the pathogenesis of RA.