Infliximab treatment shifts the balance between stimulatory and inhibitory Fcgamma receptor type II isoforms on neutrophils in patients with rheumatoid arthritis.

Abstract

OBJECTIVE:

Human neutrophils express both activating and inhibitory Fcgamma receptors (FcgammaR), and their relative expression determines the inflammatory response to immune complexes. Tumor necrosis factor alpha (TNFalpha) up-regulates the expression of stimulatory FcgammaRIIa on neutrophils in vitro, and amplifies immune complex-induced activation of neutrophils in vivo. This study was undertaken to determine whether TNFalpha blockade in patients with rheumatoid arthritis (RA) alters the balance of activating FcgammaR and inhibitory FcgammaR and thereby decreases inflammation.

METHODS:

We used fluorescence-activated cell sorting and Western blotting to examine FcgammaR expression on neutrophils in 24 patients with RA, preceding their first infusion of infliximab and immediately prior to >or=3 subsequent infusions.

RESULTS:

In 13 of 24 patients (54.2%), there was a decrease in the expression of the predominant activating FcgammaR, FcgammaRIIa, after treatment with infliximab, an effect that persisted over >or=3 months of treatment. Although prior to initiation of infliximab therapy the inhibitory FcgammaR, FcgammaRIIb, was undetectable in neutrophils from 23 of 24 patients with RA, FcgammaRIIb protein was detected by Western blotting in 9 patients (37.5%) at the time of the third infliximab infusion. The induction of inhibitory FcgammaRIIb was always associated with decreased levels of FcgammaRIIa, and improvement following infliximab therapy, measured using the Health Assessment Questionnaire, was significantly associated with down-regulation of FcgammaRIIa.

CONCLUSION:

Our findings indicate that TNFalpha inhibition may reduce inflammation in patients with RA by restoring the balance of activating and inhibitory FcgammaR and thereby raising the threshold for immune complex-mediated activation of neutrophils.

• Authors: Kristina Belostocki, Luminita Pricop, Patricia B Redecha, Ani Aydin, Linda Leff, Melanie J Harrison, Jane E Salmon
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 58 Issue 2 Pg. 384-8 (Feb 2008) ISSN: 0004-3591 [Print] United States
• PMID: 18240208 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigen-Antibody Complex
• Antigens, CD
• Antirheumatic Agents
• FCGR2B protein, human
• Fc gamma receptor IIA
• Receptors, IgG
• Tumor Necrosis Factor-alpha
• Infliximab

Topics

• Adult
• Antibodies, Monoclonal (administration & dosage)
• Antigen-Antibody Complex (immunology, metabolism)
• Antigens, CD (immunology, metabolism)
• Antirheumatic Agents (administration & dosage)
• Arthritis, Rheumatoid (drug therapy, immunology)
• Blotting, Western
• Female
• Flow Cytometry
• Humans
• Infliximab
• Male
• Middle Aged
• Neutrophils (drug effects, immunology, metabolism)
• Receptors, IgG (immunology, metabolism)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)