Infliximab treatment shifts the balance between stimulatory and inhibitory Fcγ receptor type II isoforms on Neutrophils in patients with rheumatoid arthritis

Objective. Human neutrophils express both activating and inhibitory Fc gamma receptors (Fc gamma R), and their relative expression determines the inflammatory response to immune complexes. Tumor necrosis factor a (TNF alpha) up-regulates the expression of stimulatory Fc gamma RIIa on neutrophils in vitro, and amplifies immune complex-induced activation of neutrophils in vivo. This study was undertaken to determine whether TNFa blockade in patients with rheumatoid arthritis (RA) alters the balance of activating Fc gamma R and inhibitory Fc gamma R and thereby decreases inflammation. Methods. We used fluorescence-activated cell sorting and Western blotting to examine FcyR expression on neutrophils in 24 patients with RA, preceding their first infusion of infliximab and immediately prior to :3 subsequent infusions. Results. In 13 of 24 patients (54.2%), there was a decrease in the expression of the predominant activating Fc gamma R, Fc gamma RIIa, after treatment with infliximab, an effect that persisted over >= 3 months of treatment. Although prior to initiation of infliximab therapy the inhibitory Fc gamma R, Fc gamma RIIb, was undetectable in neutrophils from 23 of 24 patients with RA, Fc gamma RIIb protein was detected by Western blotting in 9 patients (37.5%) at the time of the third infliximab infusion. The induction of inhibitory Fc gamma RIIb was always associated with decreased levels of Fc gamma RIIa, and improvement following infliximab therapy, measured using the Health Assessment Questionnaire, was significantly associated with down-regulation of Fc gamma RIIa. Conclusion. Our findings indicate that TNF alpha inhibition may reduce inflammation in patients with RA by restoring the balance of activating and inhibitory Fc gamma R and thereby raising the threshold for immune complex-mediated activation of neutrophils.