Rheumatoid peripheral blood phagocytes are primed for activation but have impaired Fc-mediated generation of reactive oxygen species

Anna-Marie Fairhurst,Paul K Wallace,Nicolas J Goulding,Ali Sm Jawad

doi:10.1186/ar2144

Abstract

Significant levels of circulating immune complexes (ICs) containing rheumatoid factors and immunoglobulin G in peripheral blood are a characteristic feature of rheumatoid arthritis (RA). ICs interact through Fcγ receptors (FcγR) to activate phagocytes in numerous inflammatory processes. The high concentration of neutrophils in synovial fluid during active phases of the disease, together with their destructive capacity, pose important questions as to their role in the pathogenesis of RA. Functional defects in RA or control peripheral blood neutrophil FcγRs were examined with a specific FcγR-mediated reactive oxygen species (ROS) assay. Heterologous cross-linking of FcγRIIa and FcγRIIIb on neutrophils resulted in a significantly decreased production of ROS by RA cells compared with controls matched for age and sex. However, expression and homologous ligation of receptors did not differ between these groups. These data suggest that neutrophil priming does occur before emigration into the joint and that blood neutrophils from patients with RA have a functional impairment in cooperative FcγR-mediated ROS generation. This may account for the increased susceptibility to bacterial infection that arises in patients with severe disease.

Highlights

Immune complex (IC) formation is a characteristic feature of rheumatoid arthritis (RA)
Expression of FcγRIII Analysis of receptor expression of basal peripheral leucocytes determined no significant difference between neutrophil FcγRIIIb expression in RA and control subjects (p > 0.05; Figure 1a)
The distributions of FcγRIIIb allotypes were similar in RA cases and controls

Summary

Introduction

Immune complex (IC) formation is a characteristic feature of rheumatoid arthritis (RA). Neutrophils express FcγRIIa (CD32a), which is a single-transmembrane receptor with its own immunoreceptor tyrosinebased activation motif (ITAM) in the intracellular domain, and FcγRIIIb (CD16b), which does not have a cytoplasmic tail but is inserted into the membrane by means of a BSA = bovine serum albumin; CR3 = complement receptor type 3; CRP = C-reactive protein; DHR = dihydrorhodamine; ESR = erythrocyte sedimentation rate; FBS = fetal bovine serum; FcγR = Fcγ receptor; fMLP = fMet-Leu-Phe; GAM = goat anti-mouse IgG; HAIgG = heat-aggregated IgG; PBS = phosphate-buffered saline; ROS = reactive oxygen species; TNF = tumour necrosis factor. This FcγRIII isotype is expressed exclusively on granulocytes It is the most abundant FcγR present on neutrophils and it believed to be the primary binding molecule for ICs, working in tandem with FcγRIIa or complement receptor type 3(CR3; referred to as CD11b/CD18 or Mac-1) to mediate a full inflammatory response. The basal and stimulated expression of FcγRIIa was similar to that of FcγRIIIb, heterologous ligation of both receptors resulted in a decrease in FcγR-mediated ROS generation in patients with RA. Several studies have demonstrated that individual homologous or heterologous ligation of FcγRIIa and FcγRIIIb may induce ROS generation, this is the first report to demonstrate a deficiency in the co-ligation of these receptors in RA [17,37,38]

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10. Ravetch JV