The role of IgG subclasses and platelets in experimental anaphylaxis

• Published in: Journal of allergy and clinical immunology Vol. 147; no. 4; pp. 1209 - 1211
• Main Authors: Godon, Ophélie, Hechler, Béatrice, Jönsson, Friederike
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021; Elsevier Limited; Elsevier
• Subjects: Allergens; Allergology; Anaphylaxis; Antibodies; Antigens; Blood platelets; CD11b antigen; CD18 antigen; Cell activation; Elastase; Experimental anaphylaxis; FcγRs; Histamine; Hydrolase; Hypersensitivity; IgG subclasses; Immunoglobulin E; Immunoglobulin G; Immunology; Leukocytes (basophilic); Leukocytes (neutrophilic); Life Sciences; Mast cells; mouse models; Neutrophils; Pathophysiology; Peroxidase; Platelet-activating factor; Platelets; Serotonin; Thrombocytopenia; Transgenic animals; Transgenic mice; mouse models; FcγRs; Experimental anaphylaxis; platelets; IgG subclasses; FcgRs; Mouse model
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2021.01.009

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. 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.6,7 Activated platelets released serotonin, which determined the severity of anaphylaxis.6,7 Platelets also contributed to IgG-PSA in a more complex mouse model of cognate hFcγR expression.6 Recently, platelet-released PAF was similarly proposed to trigger a transient disruption of endothelial integrity and mast cell activation resulting in shock.8 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).Relevance for human anaphylaxis and conclusions 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 mice6 is a strong indicator for the relevance of IgG anaphylaxis in humans. Cases of anaphylaxis were reported after administration of different therapeutic IgG antibodies,1 and serum PAF concentrations correlate with anaphylaxis severity in humans.9 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.10 Notably, neutrophil activation could be observed in patients lacking evidence of classical IgE-anaphylaxis.10 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.6 These findings open new perspectives for the understanding and management of IgE-independent anaphylaxis in humans.