IgG-dependent activation of human mast cells following up-regulation of FcγRI by IFN-γ

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Abstract
It has been reported that FcγRI is up-regulated on human mast cells (huMC) by IFN-γ and aggregation of this receptor using mouse F(ab′)2 specific for receptor-bound, mouse anti-CD64 F(ab′)2 results in activation. To determine whether huMC can similarly be stimulated by aggregation of FcγRI-bound human IgG, IFN-γ-treated, CD34+-derived, cultured uMC were sensitized with human immunoglobulins and activation was evaluated following addition of antibodies specific for each IgG isotype. Degranulation was also examined following simultaneous IgG- and IgE-dependent aggregation of FcγRI and FcϵRI. Activation of IFN-γ-treated huMC sensitized with 100 ng/ml IgG1 resulted in 40% β-hexosaminidase (β-hex) release; minimal degranulation was observed using IgG2, IgG3 or IgG4. IgG1-dependent activation led to PGD2 and LTC4 generation as well as elevated cytokine production, most notably TNF–α. Preincubation of cells with F(ab′)2 from CD64-specific clones 10.1 and 32.2 reduced IgG1-mediated β-hex release by 46% and 74%, respectively. While IgG-dependent cell stimulation induced half-maximal degranulation by 11 min, IgE-dependent activation resulted in half maximal responses within 1 min. Simultaneous activation of huMC via FcγRI and FcϵRI led to additive degranulation using suboptimal concentrations of IgG1 and IgE. Activation of huMC thus may occur via monomeric IgG and FcγRI thereby providing a novel paradigm for huMC recruitment into inflammation.