Distinct genes encode 6 human receptors for IgG (hFc␥Rs), 3 of which have 2 or 3 polymorphic variants. The specificity and affinity of individual hFc␥Rs for the 4 human IgG subclasses is unknown. This information is critical for antibodybased immunotherapy which has been increasingly used in the clinics. We investigated the binding of polyclonal and monoclonal IgG1, IgG2, IgG3, and IgG4 to Fc␥RI; Fc␥RIIA, IIB, and IIC; Fc␥RIIIA and IIIB; and all known polymorphic variants. Wild-type and low-fucosylated IgG1 anti-CD20 and anti-RhD mAbs were also examined. We found that (1) IgG1 and IgG3 bind to all hFc␥Rs; (2) IgG2 bind not only to Fc␥RIIA H131 , but also, with a lower affinity, to Fc␥RIIA R131 4 Other FcRs are inserted in the outer layer of the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and contain no signaling motif. 5 FcRs have been associated with many antibodydependent diseases 6 and are key molecules in antibody-based immunotherapy. These include the treatment, for instance, of non-Hodgkin lymphomas by mouse/human chimeric IgG1 anti-CD20 antibodies 7 and the prevention of hemolytic disease of the newborn by a mixture of polyclonal IgG1 and IgG3 anti-RhD antibodies (eg, Rophylac). Therapeutic antibodies are, however, potentially harmful, as exemplified by a recent clinical trial using IgG4 anti-CD28 antibodies.Four human subclasses of IgG are produced in different amounts in response to various antigens. T-dependent protein antigens elicit primarily IgG1 and IgG3 antibodies, whereas T-independent carbohydrate antigens elicit primarily IgG2 antibodies. Chronic antigen stimulation, as in allergic desensitization, elicits IgG4 antibodies. The biological activities of each subclass of IgG are poorly known. IgG receptors (Fc␥Rs) are strikingly numerous in humans. They comprise high-affinity and low-affinity receptors. 8 Both high-affinity and low-affinity Fc␥Rs bind IgGimmune complexes with a high avidity, but only high-affinity Fc␥Rs bind monomeric IgG. There is one high-affinity IgG receptor in humans, hFc␥RI (CD64), and 2 families of low-affinity IgG receptors, hFc␥RIIA, IIB, and IIC (CD32), and hFc␥RIIIA and IIIB (CD16). hFc␥RI and hFc␥RIIIA are FcR␥-associated activating receptors, hFc␥RIIA and hFc␥RIIC are single-chain activating receptors, hFc␥RIIB are single-chain inhibitory receptors, and hFc␥RIIIB are GPI-anchored receptors whose function is uncertain. 1 The multiplicity of hFc␥Rs is further increased by a series of polymorphisms in their extracellular domains (reviewed in van Sorge et al 9 ). Two alleles of the gene encoding hFc␥RIIA generate 2 variants differing at position 131, named low-responder (H 131 ) and high-responder (R 131 ). 10 The H 131 and R 131 alleles are differentially distributed in whites, Japanese, and Chinese. 11 Two alleles of the gene-encoding hFc␥RIIIA generate 2 variants differing at 23 and hFc␥RIIIB NA2 to SLE in Japanese people. 24 The subclass specificity of hFc␥Rs has been investigated since the 1980s, that is, at a time when the complexity of hFc␥R...

Anaphylaxis is a life-threatening hyperacute immediate hypersensitivity reaction. Classically, it depends on IgE, FcεRI, mast cells, and histamine. However, anaphylaxis can also be induced by IgG antibodies, and an IgG1-induced passive type of systemic anaphylaxis has been reported to depend on basophils. In addition, it was found that neither mast cells nor basophils were required in mouse models of active systemic anaphylaxis. Therefore, we investigated what antibodies, receptors, and cells are involved in active systemic anaphylaxis in mice. We found that IgG antibodies, FcγRIIIA and FcγRIV, platelet-activating factor, neutrophils, and, to a lesser extent, basophils were involved. Neutrophil activation could be monitored in vivo during anaphylaxis. Neutrophil depletion inhibited active, and also passive, systemic anaphylaxis. Importantly, mouse and human neutrophils each restored anaphylaxis in anaphylaxis-resistant mice, demonstrating that neutrophils are sufficient to induce anaphylaxis in mice and suggesting that neutrophils can contribute to anaphylaxis in humans. Our results therefore reveal an unexpected role for IgG, IgG receptors, and neutrophils in anaphylaxis in mice. These molecules and cells could be potential new targets for the development of anaphylaxis therapeutics if the same mechanism is responsible for anaphylaxis in humans.

FcγRIV is a recently identified mouse activating receptor for IgG2a and IgG2b that is expressed on monocytes, macrophages, and neutrophils; herein it is referred to as mFcγRIV. Although little is known about mFcγRIV, it has been proposed to be the mouse homolog of human FcγRIIIA (hFcγRIIIA) because of high sequence homology. Our work, however, has revealed what we believe to be new properties of mFcγRIV that endow this receptor with a previously unsuspected biological significance; we have shown that it is a low-affinity IgE receptor for all IgE allotypes. Although mFcγRIV functioned as a high-affinity IgG receptor, mFcγRIV-bound monomeric IgGs were readily displaced by IgE immune complexes. Engagement of mFcγRIV by IgE immune complexes induced bronchoalveolar and peritoneal macrophages to secrete cytokines, suggesting that mFcγRIV may be an equivalent of human FcεRI(αγ), which is expressed by macrophages and neutrophils and especially in atopic individuals, rather than an equivalent of hFcγRIIIA, which has no affinity for IgE. Using mice lacking 3 FcγRs and 2 FcεRs and expressing mFcγRIV only, we further demonstrated that mFcγRIV promotes IgE-induced lung inflammation. These data lead us to propose a mouse model of IgE-induced lung inflammation in which cooperation exists between mast cells and mFcγRIV-expressing lung cells. We therefore suggest that a similar cooperation may occur between mast cells and hFcεRI-expressing lung cells in human allergic asthma.

IgE and IgE receptors (FcϵRI) are well-known inducers of allergy. We recently found in mice that active systemic anaphylaxis depends on IgG and IgG receptors (FcγRIIIA and FcγRIV) expressed by neutrophils, rather than on IgE and FcϵRI expressed by mast cells and basophils. In humans, neutrophils, mast cells, basophils, and eosinophils do not express FcγRIIIA or FcγRIV, but FcγRIIA. We therefore investigated the possible role of FcγRIIA in allergy by generating novel FcγRIIA-transgenic mice, in which various models of allergic reactions induced by IgG could be studied. In mice, FcγRIIA was sufficient to trigger active and passive anaphylaxis, and airway inflammation in vivo. Blocking FcγRIIA in vivo abolished these reactions. We identified mast cells to be responsible for FcγRIIA-dependent passive cutaneous anaphylaxis, and monocytes/macrophages and neutrophils to be responsible for FcγRIIA-dependent passive systemic anaphylaxis. Supporting these findings, human mast cells, monocytes and neutrophils produced anaphylactogenic mediators after FcγRIIA engagement. IgG and FcγRIIA may therefore contribute to allergic and anaphylactic reactions in humans.