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IgG-mediated activation of leukocytes is independent of Fc-γ receptor polymorphism
Arthritis Research & Therapy volume 4, Article number: 37 (2002)
Ligation of Fc-γ receptors for IgG (FcγR) can trigger potent effector cell responses. Genetic polymorphisms of these receptors modify IgG binding, and influence internalization of immune complexes. In patients with infectious or autoimmune diseases, skewing towards low-binding FcγR alleles has been demonstrated. The objective of this study was to investigate the influence of FcγR polymorphism on leukocyte activation.
We analyzed activation of neutrophils and monocytes stimulated by aggregated or solid phase-coated IgG1, IgG2, and total IgG. Neutrophil donors were selected based on their FcγR genotype and homozygous for either FcγRIIa-H131/FcγRIIIb-NA1/1(HH-NA1/1) or FcγRIIa-R131/FcγRIIIb-NA2 (RR-NA2/2). Monocyte donors were homozygous for either FcγRIIa-H131/FcγRI-IIa-V158 (HH-VV) or FcγRIIa-R131/FcγRIIIa-F158 (RR-FF). Binding of immunoglobulins to lymphocytes was determined by flow cytometry. Activation of neutrophils was measured as the production of reactive oxygen intermediates (ferricytochrome c reduction), degranulation (lactoferrin release), and cytokine production (IL-8). TNF-α secretion was used as a measure of monocyte activation.
IgG1 aggregates firmly bound to neutrophils of both types of donors, albeit more avidly to donors expressing HH-NA1/1 alleles. In contrast, IgG2 aggregates firmly bound to HH-NA1/1 FcγR neutrophils only. This binding could be blocked by preincubation of neutrophils with FcγRIIa and FcγRIIIb blocking antibodies. Despite the differences in binding of IgG subclasses to HH-NA1/1 and RR-NA2/2 neutrophils, we observed no differences in their activation. Activation of both types of neutrophils with IgG1 or IgG2 aggregates could be at least partially blocked by the addition of FcγR blocking antibodies. Similar to neutrophils, HH-VV and RR-FF monocytes were not distinguishable in their response to IgG, IgG1, and IgG2 as measured by TNF-α release, although RR-FF monocytes did not bind IgG2 complexes.
Although IgG-mediated activation of leukocytes is dependent on FcγR, it does not appear to be influenced by FcγR polymorphisms. These results are in favour of a new mechanism for IgG-mediated leukocyte activation, in which a short interaction between IgG and FcγR is sufficient to generate an appropriate inflammatory response. This may have important implications for inflammatory responses in infectious and autoimmune diseases.
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Dijstelbloem, H., Rarok, A., Huitema, M. et al. IgG-mediated activation of leukocytes is independent of Fc-γ receptor polymorphism. Arthritis Res Ther 4, 37 (2002) doi:10.1186/ar478
- Reactive Oxygen Intermediate
- Leukocyte Activation
- Blocking Antibody
- Monocyte Activation
- IgG2 Aggregate