Article

The high-affinity human IgG receptor Fc RI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy

Institut Pasteur, Departement d'Immunologie, Laboratoire Anticorps en Therapie et Pathologie, Paris, France
Blood (Impact Factor: 10.43). 01/2013; DOI: 10.1182/blood-2012-07-442541
Source: PubMed

ABSTRACT IgG receptors (FcγRs) are mandatory for the induction of various IgG-dependent models of autoimmunity, inflammation, anaphylaxis and cancer immunotherapy. A few FcγRs have the ability to bind monomeric IgG, i.e. high-affinity mouse mFcγRI, mFcγRIV and human hFcγRI, whereas all others bind IgG only when aggregated, in complexes or bound to cells or surfaces, i.e. low-affinity mouse mFcγRIIB, mFcγRIII and human hFcγRIIA/B/C and hFcγRIIIA/B. Although it was proposed that high-affinity FcγRs are occupied by circulating IgG, multiple roles for mFcγRI and mFcγRIV have been reported in vivo. The potential roles of hFcγRI that is expressed on monocytes, macrophages and neutrophils, have however not been reported. We therefore investigated the role of hFcγRI in antibody-mediated models of disease and therapy by generating hFcγRI-transgenic mice deficient for multiple endogenous FcRs. hFcγRI was sufficient to trigger autoimmune arthritis and thrombocytopenia, immune complex-induced airway inflammation, active and passive systemic anaphylaxis. We identified monocyte/macrophages to be responsible for thrombocytopenia, neutrophils to be responsible for systemic anaphylaxis, and both cell types to be responsible for arthritis induction. Finally, hFcγRI was capable of mediating antibody-induced immunotherapy of metastatic melanoma. Altogether, our results unravel novel capabilities of human FcγRI that confirm the role of high-affinity IgG receptors in vivo.

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