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The role of IgG subclasses and platelets in experimental anaphylaxis

2021; Elsevier BV; Volume: 147; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2021.01.009

1097-6825

Ophélie Godon, Béatrice Hechler, Friederike Jönsson,

Drug-Induced Adverse Reactions

In 1902, Charles Richet coined the term “anaphylaxis” to describe a “state of heightened sensitivity of a subject to a substance induced by a first injection, that instead of protecting the organism, renders it more fragile and more susceptible.” Since this first description, experimental work led to identification of antibodies, receptors, cells, and mediators in this severe allergic reaction, leading to the paradigm that anaphylaxis is an IgE-dependent affliction that is triggered when allergens aggregate cognate IgE antibodies bound to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils. Their activation leads to the release of diverse bioactive mediators, including histamine, which are responsible for the associated clinical signs.1Reber L.L. Hernandez J.D. Galli S.J. The pathophysiology of anaphylaxis.J Allergy Clin Immunol. 2017; 140: 335-348Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Seminal works from the Galli, Kinet, and Finkelman labs revealed, however, that anaphylaxis can also occur in mice deficient for IgE, FcεRI, or mast cells, and suggested that it could be driven by IgG antibodies engaging FcRγ-chain–containing receptors (reviewed in Reber et al1Reber L.L. Hernandez J.D. Galli S.J. The pathophysiology of anaphylaxis.J Allergy Clin Immunol. 2017; 140: 335-348Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). Nowadays, the international consensus on anaphylaxis defines anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life-threatening or fatal.” This deliberately generic definition excludes any precision on the pathophysiological mechanism involved. In this article, we will discuss recent findings on IgG-dependent anaphylaxis with a focus on the role of IgG subclasses and platelets in these reactions. IgG-dependent passive systemic anaphylaxis (IgG-PSA) can be elicited in mice by the transfer of specific IgG antibodies (of either IgG1, IgG2a/c, or IgG2b subclass, but not IgG3) followed by injection of their cognate antigen, or by transfer of precomplexed IgG (ie, immune complexes [IgG-ICs] or heat-aggregated IgG). IgG-PSA depends on IgG receptor (FcγR)-transduced activation of myeloid cells, leading to mediator release, which notably include platelet-activating factor (PAF).1Reber L.L. Hernandez J.D. Galli S.J. The pathophysiology of anaphylaxis.J Allergy Clin Immunol. 2017; 140: 335-348Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar,2Beutier H. Gillis C.M. Iannascoli B. Godon O. England P. Sibilano R. et al.IgG subclasses determine pathways of anaphylaxis in mice.J Allergy Clin Immunol. 2017; 139: 269-280.e7Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Mice express 3 activating FcγRs (FcγRI, FcγRIII, and FcγRIV) and 1 inhibitory FcγR (FcγRIIB), each having a specific expression profile and distinct affinities for the different IgG subclasses. IgG-PSA in mice is associated with vasodilation, augmented vascular permeability, and a reduction in core temperature, motility, and awareness (Fig 1). Animals usually return to normal activity and behavior within 1 to 2 hours, but in rare cases cardiopulmonary failure results in death. (IgG)-anaphylaxis can also be triggered by antigen exposure of previously immunized mice that lack key players of the IgE-dependent pathway. IgG-independent immune players may however contribute to the reaction, rendering the interpretation of results more complex. To efficiently engage activating IgG receptors, IgG generally need to be present as multivalent complexes. There is a large consensus that IgG-PSA relies mainly on the engagement of FcγRIII and, to a lesser extent, on FcγRIV and possibly on FcγRI.2Beutier H. Gillis C.M. Iannascoli B. Godon O. England P. Sibilano R. et al.IgG subclasses determine pathways of anaphylaxis in mice.J Allergy Clin Immunol. 2017; 139: 269-280.e7Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar,3Khodoun M.V. Kucuk Z.Y. Strait R.T. Krishnamurthy D. Janek K. Clay C.D. et al.Rapid desensitization of mice with anti-FcgammaRIIb/FcgammaRIII mAb safely prevents IgG-mediated anaphylaxis.J Allergy Clin Immunol. 2013; 132: 1375-1387Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar The relative importance of FcγR-bearing effector cells to IgG-PSA remains more debated and is likely to depend on the experimental conditions.1Reber L.L. Hernandez J.D. Galli S.J. The pathophysiology of anaphylaxis.J Allergy Clin Immunol. 2017; 140: 335-348Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 2Beutier H. Gillis C.M. Iannascoli B. Godon O. England P. Sibilano R. et al.IgG subclasses determine pathways of anaphylaxis in mice.J Allergy Clin Immunol. 2017; 139: 269-280.e7Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 3Khodoun M.V. Kucuk Z.Y. Strait R.T. Krishnamurthy D. Janek K. Clay C.D. et al.Rapid desensitization of mice with anti-FcgammaRIIb/FcgammaRIII mAb safely prevents IgG-mediated anaphylaxis.J Allergy Clin Immunol. 2013; 132: 1375-1387Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Indeed, all cells of hematopoietic origin express at least 1 activating FcγR with the exception of T cells, B cells, and platelets, and could hence contribute to the reaction. Their involvement in anaphylaxis is often assessed either using depleting antibodies, which is problematic in the context of an antibody-dependent reaction, or using inhibitors, which may not be specific. In a comparative study using mouse IgG1, IgG2a, and IgG2b with the same specificity to induce IgG subclass–specific anaphylaxis, we found that IgG1 and IgG2b-PSA shared a common mechanism that involved all tested myeloid cells and in which histamine H1 receptor blockade showed a stronger beneficial effect on PSA-associated temperature drop than PAF receptor blockade.2Beutier H. Gillis C.M. Iannascoli B. Godon O. England P. Sibilano R. et al.IgG subclasses determine pathways of anaphylaxis in mice.J Allergy Clin Immunol. 2017; 139: 269-280.e7Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar IgG1- and IgG2b-PSA were regulated by the inhibitory IgG receptor FcγRIIB present on all myeloid cells and B cells. In contrast, in IgG2a-PSA, FcγRIIB-driven inhibition was negligible. IgG2a-PSA was significantly reduced through depletion of neutrophils or monocytes/macrophages and attentuated by both PAF-receptor and histamine H1 receptor antagonists.2Beutier H. Gillis C.M. Iannascoli B. Godon O. England P. Sibilano R. et al.IgG subclasses determine pathways of anaphylaxis in mice.J Allergy Clin Immunol. 2017; 139: 269-280.e7Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar This particularity of IgG2a-PSA may be due to the overall higher affinity of IgG2a to FcγRs,2Beutier H. Gillis C.M. Iannascoli B. Godon O. England P. Sibilano R. et al.IgG subclasses determine pathways of anaphylaxis in mice.J Allergy Clin Immunol. 2017; 139: 269-280.e7Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar which also may explain the relative resistance of IgG2a-PSA to changes in IgG/FcγR affinity induced by modification of IgG-glycosylation (ie, terminal sialylation) compared with IgG1/IgG2b-PSA.4Epp A. Hobusch J. Bartsch Y.C. Petry J. Lilienthal G.M. Koeleman C.A.M. et al.Sialylation of IgG antibodies inhibits IgG-mediated allergic reactions.J Allergy Clin Immunol. 2018; 141: 399-402.e8Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar To approach human pathophysiology, anaphylaxis has been studied in mice carrying human FcγRs, either as a single transgene, as in the case of hFcγRIIA,5Jonsson F. Mancardi D.A. Zhao W. Kita Y. Iannascoli B. Khun H. et al.Human FcgammaRIIA induces anaphylactic and allergic reactions.Blood. 2012; 119: 2533-2544Crossref PubMed Scopus (88) Google Scholar, 6Beutier H. Hechler B. Godon O. Wang Y. Gillis C.M. de Chaisemartin L. et al.Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis.Sci Immunol. 2018; 3: eaan5997Crossref PubMed Scopus (33) Google Scholar, 7Cloutier N. Allaeys I. Marcoux G. Machlus K.R. Mailhot B. Zufferey A. et al.Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration.Proc Natl Acad Sci U S A. 2018; 115: E1550-E1559Crossref PubMed Scopus (100) Google Scholar or in more complex models expressing several FcγRs.6Beutier H. Hechler B. Godon O. Wang Y. Gillis C.M. de Chaisemartin L. et al.Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis.Sci Immunol. 2018; 3: eaan5997Crossref PubMed Scopus (33) Google Scholar Indeed, extrapolating results from IgG/FcγR-dependent reactions from mouse to human pathophysiology is challenging, because both species express very different sets of FcγRs (4 in mice and 6 in humans) that each shows distinct interaction profile with the different IgG subclasses (IgG1-4 in humans). Among human FcγRs, only FcγRIIB is inhibitory and expressed at much lower levels than in mice, suggesting that the regulation of IgG-driven reactions though coengagment of this inhibitory receptor remains limited in humans. Furthermore, as an example, whereas IgG3 binds to all human FcγRs, its murine counterpart exclusively engages mouse FcγRI. These differences extend through all IgG subclasses, their affinities for FcγRs, and their capacity to trigger Fc-dependent effector functions. Studies in FcγR-humanized mice revealed that engagement of human FcγRs by IgG-ICs is sufficient to trigger anaphylaxis.5Jonsson F. Mancardi D.A. Zhao W. Kita Y. Iannascoli B. Khun H. et al.Human FcgammaRIIA induces anaphylactic and allergic reactions.Blood. 2012; 119: 2533-2544Crossref PubMed Scopus (88) Google Scholar Among hFcγRs, hFcγRIIA appears to be the major contributor in IgG-PSA6Beutier H. Hechler B. Godon O. Wang Y. Gillis C.M. de Chaisemartin L. et al.Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis.Sci Immunol. 2018; 3: eaan5997Crossref PubMed Scopus (33) Google Scholar and despite its expression on all myeloid cells, hFcγRIIA-expressing neutrophils and monocytes/macrophages, through their release of PAF, play a predominant role over mast cells, basophils, and eosinophils.5Jonsson F. Mancardi D.A. Zhao W. Kita Y. Iannascoli B. Khun H. et al.Human FcgammaRIIA induces anaphylactic and allergic reactions.Blood. 2012; 119: 2533-2544Crossref PubMed Scopus (88) Google Scholar Unexpectedly, hFcγRIIA-transgenic mice also revealed the critical contribution of a blood component that was until then overlooked in the context of anaphylaxis. Mouse platelets are devoid of any FcγR. Human platelets on the contrary express FcγRIIA/CD32A and incubation with IgG-ICs can induce their activation, aggregation, and release of granular content. Using hFcγRIIA-transgenic mice that confer IgG receptor expression to platelets, we and others demonstrated that IgG-induced platelet activation is critical for experimental anaphylaxis, and results in a rapid, severe, and prolonged (24-hour) thrombocytopenia.6Beutier H. Hechler B. Godon O. Wang Y. Gillis C.M. de Chaisemartin L. et al.Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis.Sci Immunol. 2018; 3: eaan5997Crossref PubMed Scopus (33) Google Scholar,7Cloutier N. Allaeys I. Marcoux G. Machlus K.R. Mailhot B. Zufferey A. et al.Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration.Proc Natl Acad Sci U S A. 2018; 115: E1550-E1559Crossref PubMed Scopus (100) Google Scholar Activated platelets released serotonin, which determined the severity of anaphylaxis.6Beutier H. Hechler B. Godon O. Wang Y. Gillis C.M. de Chaisemartin L. et al.Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis.Sci Immunol. 2018; 3: eaan5997Crossref PubMed Scopus (33) Google Scholar,7Cloutier N. Allaeys I. Marcoux G. Machlus K.R. Mailhot B. Zufferey A. et al.Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration.Proc Natl Acad Sci U S A. 2018; 115: E1550-E1559Crossref PubMed Scopus (100) Google Scholar Platelets also contributed to IgG-PSA in a more complex mouse model of cognate hFcγR expression.6Beutier H. Hechler B. Godon O. Wang Y. Gillis C.M. de Chaisemartin L. et al.Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis.Sci Immunol. 2018; 3: eaan5997Crossref PubMed Scopus (33) Google Scholar Recently, platelet-released PAF was similarly proposed to trigger a transient disruption of endothelial integrity and mast cell activation resulting in shock.8Karhausen J. Choi H.W. Maddipati K.R. Mathew J.P. Ma Q. Boulaftali Y. et al.Platelets trigger perivascular mast cell degranulation to cause inflammatory responses and tissue injury.Sci Adv. 2020; 6eaay6314Crossref PubMed Scopus (17) Google Scholar Because of their abundance in blood, it is therefore conceivable that platelets are among the first players to become activated by circulating IgG-ICs, triggering a cascade of events that drives the activation and mediator release from various cell types contributing to anaphylaxis (Fig 2). The fact that transgenic expression of a complete set of human FcγRs reproducing mostly the original expression profiles on all hematopoietic cells stimulated with human aggregated IgG is sufficient to induce anaphylaxis in mice6Beutier H. Hechler B. Godon O. Wang Y. Gillis C.M. de Chaisemartin L. et al.Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis.Sci Immunol. 2018; 3: eaan5997Crossref PubMed Scopus (33) Google Scholar is a strong indicator for the relevance of IgG anaphylaxis in humans. Indeed, several lines of evidence support the existence of IgG/FcγR-, neutrophil-, and PAF-dependent human anaphylaxis. Cases of anaphylaxis were reported after administration of different therapeutic IgG antibodies,1Reber L.L. Hernandez J.D. Galli S.J. The pathophysiology of anaphylaxis.J Allergy Clin Immunol. 2017; 140: 335-348Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar and serum PAF concentrations correlate with anaphylaxis severity in humans.9Vadas P. Perelman B. Liss G. Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis.J Allergy Clin Immunol. 2013; 131: 144-149Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar In a clinical study of neuromuscular-blocking agent–induced anaphylaxis, concentrations of anti-drug IgG, markers of FcγR engagement and neutrophil activation (upregulation of CD11b and CD18, elevated levels of elastase and DNA-myeloperoxidase [MPO] complexes in the plasma), as well as reduced activity of PAF-acetyl hydrolase correlated with anaphylaxis severity.10Jonsson F. de Chaisemartin L. Granger V. Gouel-Cheron A. Gillis C.M. Zhu Q. et al.An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis.Sci Transl Med. 2019; 11: eaat1479Crossref PubMed Scopus (43) Google Scholar Notably, neutrophil activation could be observed in patients lacking evidence of classical IgE-anaphylaxis.10Jonsson F. de Chaisemartin L. Granger V. Gouel-Cheron A. Gillis C.M. Zhu Q. et al.An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis.Sci Transl Med. 2019; 11: eaat1479Crossref PubMed Scopus (43) Google Scholar Limited data from these patients further evidenced that platelet activation (upregulation of CD62P) was associated with anaphylaxis severity and that anaphylaxis occurrence was accompanied by a reduction in circulating platelet numbers.6Beutier H. Hechler B. Godon O. Wang Y. Gillis C.M. de Chaisemartin L. et al.Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis.Sci Immunol. 2018; 3: eaan5997Crossref PubMed Scopus (33) Google Scholar These findings open new perspectives for the understanding and management of IgE-independent anaphylaxis in humans. In addition to certain drugs that can directly activate mast cells (notably through the recently described MRGPRX2), IgG-dependent reactions may account for or contribute to anaphylaxis, in particular when large amounts of IgG-ICs can form in the circulation. Further clinical studies will allow to determine whether it could be beneficial for patients at risk of developing IgG-driven anaphylaxis (ie, programmed intravenous administration of certain antibodies or drugs) to transiently receive treatments to block FcγRs (especially FcγRIIA) or limit the biological effects of serotonin and/or PAF.