The pathophysiology of anaphylaxis

Anaphylaxis is a severe systemic hypersensitivity reaction that is rapid in onset; characterized by life-threatening airway, breathing, and/or circulatory problems; and usually associated with skin and mucosal changes. Because it can be triggered in some persons by minute amounts of antigen (eg, certain foods or single insect stings), anaphylaxis can be considered the most aberrant example of an imbalance between the cost and benefit of an immune response. This review will describe current understanding of the immunopathogenesis and pathophysiology of anaphylaxis, focusing on the roles of IgE and IgG antibodies, immune effector cells, and mediators thought to contribute to examples of the disorder. Evidence from studies of anaphylaxis in human subjects will be discussed, as well as insights gained from analyses of animal models, including mice genetically deficient in the antibodies, antibody receptors, effector cells, or mediators implicated in anaphylaxis and mice that have been “humanized” for some of these elements. We also review possible host factors that might influence the occurrence or severity of anaphylaxis. Finally, we will speculate about anaphylaxis from an evolutionary perspective and argue that, in the context of severe envenomation by arthropods or reptiles, anaphylaxis might even provide a survival advantage. Anaphylaxis is a severe systemic hypersensitivity reaction that is rapid in onset; characterized by life-threatening airway, breathing, and/or circulatory problems; and usually associated with skin and mucosal changes. Because it can be triggered in some persons by minute amounts of antigen (eg, certain foods or single insect stings), anaphylaxis can be considered the most aberrant example of an imbalance between the cost and benefit of an immune response. This review will describe current understanding of the immunopathogenesis and pathophysiology of anaphylaxis, focusing on the roles of IgE and IgG antibodies, immune effector cells, and mediators thought to contribute to examples of the disorder. Evidence from studies of anaphylaxis in human subjects will be discussed, as well as insights gained from analyses of animal models, including mice genetically deficient in the antibodies, antibody receptors, effector cells, or mediators implicated in anaphylaxis and mice that have been “humanized” for some of these elements. We also review possible host factors that might influence the occurrence or severity of anaphylaxis. Finally, we will speculate about anaphylaxis from an evolutionary perspective and argue that, in the context of severe envenomation by arthropods or reptiles, anaphylaxis might even provide a survival advantage. GlossaryACTIVE SYSTEMIC ANAPHYLAXIS (ASA)Anaphylaxis induced by means of active immunization (induction of antibodies involved in anaphylaxis through antigen sensitization of naive hosts).ANGIOTENSINOGENPrimarily synthesized in the liver, angiotensinogen is an α2-globulin that is converted into angiotensin I by renin. Angiotensin I is converted into angiotensin II by angiotensin-converting enzyme. Angiotensin II, in addition to promoting vasoconstriction, also mediates thirst, sodium retention, and aldosterone secretion.c-KIT D816V MUTATIONc-KIT is the gene for KIT, a transmembrane tyrosine kinase receptor whose ligand is stem cell factor. The D816V mutation is the most commonly detected mutation in mastocytosis and occurs in codon 816. It consists of the substitution of valine for aspartate (Asp816Val). This activating mutation results in ligand-independent autophosphorylation of KIT.DISSEMINATED INTRAVASCULAR COAGULATION (DIC)A coagulopathy that occurs as a secondary complication to many different disorders. Key features are microthrombi leading to tissue hypoxia and infarction, as well as hemorrhages caused by depletion of coagulation factors and platelets and activation of fibrinolysis. Trauma, sepsis, and malignancy are common triggers.MASS SPECTROMETRYA laboratory tool that can be used to detect and quantify the protein composition of a biological sample. Proteins are ionized, followed by separation of the ions by mass/charge ratio. Ions then pass through a tuned field and generate an electric current that can be analyzed.MYELOPEROXIDASE (MPO)An enzyme that mediates the conversion of H2O2 to HOCl, which can contribute to the killing of phagocytosed bacteria, fungi, and viruses, as well as to oxidative damage to host tissues.PASSIVE SYSTEMIC ANAPHYLAXIS (PSA)A model in which the adoptive transfer of IgE or IgG antibodies to normal mice permits them to exhibit anaphylaxis on subsequent challenge with antigens recognized by such antibodies.TRYPTASEA serine esterase with both mature and immature forms and the most abundant serine protease of mast cells. Basophils have about 500-fold lower levels of tryptase than mast cells. The immature form is released constitutively by unstimulated mast cells, whereas the mature form is released on mast cell activation, such as in anaphylaxis. In human subjects there are 4 different tryptases (α, β, γ, and δ), of which the α and β tryptases are thought to be medically important. Tryptases can act locally, as well as remotely, on release. Tryptase's biological functions are not entirely understood, but it is thought to have proinflammatory effects, including promotion of tissue edema and remodeling, chemokine secretion, and neutrophil recruitment. Anti-inflammatory effects include degradation of proteins, such as allergens and neuropeptides.The Editors wish to acknowledge Daniel Searing, MS, for preparing this glossary. Anaphylaxis induced by means of active immunization (induction of antibodies involved in anaphylaxis through antigen sensitization of naive hosts). Primarily synthesized in the liver, angiotensinogen is an α2-globulin that is converted into angiotensin I by renin. Angiotensin I is converted into angiotensin II by angiotensin-converting enzyme. Angiotensin II, in addition to promoting vasoconstriction, also mediates thirst, sodium retention, and aldosterone secretion. c-KIT is the gene for KIT, a transmembrane tyrosine kinase receptor whose ligand is stem cell factor. The D816V mutation is the most commonly detected mutation in mastocytosis and occurs in codon 816. It consists of the substitution of valine for aspartate (Asp816Val). This activating mutation results in ligand-independent autophosphorylation of KIT. A coagulopathy that occurs as a secondary complication to many different disorders. Key features are microthrombi leading to tissue hypoxia and infarction, as well as hemorrhages caused by depletion of coagulation factors and platelets and activation of fibrinolysis. Trauma, sepsis, and malignancy are common triggers. A laboratory tool that can be used to detect and quantify the protein composition of a biological sample. Proteins are ionized, followed by separation of the ions by mass/charge ratio. Ions then pass through a tuned field and generate an electric current that can be analyzed. An enzyme that mediates the conversion of H2O2 to HOCl, which can contribute to the killing of phagocytosed bacteria, fungi, and viruses, as well as to oxidative damage to host tissues. A model in which the adoptive transfer of IgE or IgG antibodies to normal mice permits them to exhibit anaphylaxis on subsequent challenge with antigens recognized by such antibodies. A serine esterase with both mature and immature forms and the most abundant serine protease of mast cells. Basophils have about 500-fold lower levels of tryptase than mast cells. The immature form is released constitutively by unstimulated mast cells, whereas the mature form is released on mast cell activation, such as in anaphylaxis. In human subjects there are 4 different tryptases (α, β, γ, and δ), of which the α and β tryptases are thought to be medically important. Tryptases can act locally, as well as remotely, on release. Tryptase's biological functions are not entirely understood, but it is thought to have proinflammatory effects, including promotion of tissue edema and remodeling, chemokine secretion, and neutrophil recruitment. Anti-inflammatory effects include degradation of proteins, such as allergens and neuropeptides. The Editors wish to acknowledge Daniel Searing, MS, for preparing this glossary. The recent International Consensus on Anaphylaxis described anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life-threatening or fatal.”1Simons F.E. Ardusso L.R. Bilo M.B. Cardona V. Ebisawa M. El-Gamal Y.M. et al.International consensus on (ICON) anaphylaxis.World Allergy Organ J. 2014; 7: 9Crossref PubMed Scopus (97) Google Scholar This definition is intentionally “generic” in that it does not mention any of the specific immune elements that might be involved in particular instances of the disorder because these can vary depending on individual circumstances. In this review we will describe the key immune elements, such as antibody isotypes, effector cells, and biological mediators, that can contribute to the development and pathophysiologic manifestations of anaphylaxis. In particular, we will note the extent of evidence implicating these immune components in anaphylaxis in human subjects versus that induced in mouse models of the disorder, focusing especially on forms of anaphylaxis induced by reactions of allergens with antigen-specific antibodies. We will not extensively review forms of anaphylaxis induced by the antibody-independent activation of effector cells, such as mast cells and basophils, topics that have been reviewed elsewhere.2Finkelman F.D. Khodoun M.V. Strait R. Human IgE-independent systemic anaphylaxis.J Allergy Clin Immunol. 2016; 137: 1674-1680Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Subramanian H. Gupta K. Ali H. Roles of Mas-related G protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases.J Allergy Clin Immunol. 2016; 138: 700-710Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The clinical definition, classification, nomenclature, and treatment of anaphylaxis have been points of controversy, varying among different medical subspecialties and in different countries, and it became clear that an important goal for the field would be to achieve a true international consensus on these important points.4Bock G. Goode J. Final discussion, in anaphylaxis: Novartis Foundation Symposium 257. John Wiley & Sons, Ltd, Chichester (UK)2004https://doi.org/10.1002/0470861193.ch22Crossref Google Scholar Subsequently, multinational multidisciplinary symposia were convened to agree on the definition of anaphylaxis, the clinical criteria for its diagnosis, and its management.5Sampson H.A. Munoz-Furlong A. Campbell R.L. Adkinson Jr., N.F. Bock S.A. Branum A. et al.Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol. 2006; 117: 391-397Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar Participants agreed on a description of anaphylaxis as “a serious allergic reaction that is rapid in onset and may cause death,” as well as on 3 sets of clinical criteria to diagnose anaphylaxis.5Sampson H.A. Munoz-Furlong A. Campbell R.L. Adkinson Jr., N.F. Bock S.A. Branum A. et al.Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol. 2006; 117: 391-397Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar These criteria were reaffirmed in the recent International Consensus on Anaphylaxis article1Simons F.E. Ardusso L.R. Bilo M.B. Cardona V. Ebisawa M. El-Gamal Y.M. et al.International consensus on (ICON) anaphylaxis.World Allergy Organ J. 2014; 7: 9Crossref PubMed Scopus (97) Google Scholar and are more extensively reviewed elsewhere in this issue of the Journal.6Castells M. The diagnosis and management of anaphylaxis in precision medicine.J Allergy Clin Immunol. 2017; 140: 321-333Abstract Full Text Full Text PDF Google Scholar A minority of patients exhibit biphasic allergic reactions, in which signs and symptoms of anaphylaxis recur hours after the early phase of the reaction has waned, and in some patients late-phase reactions occur without initial hypotension or airway obstruction.7Golden D.B. Patterns of anaphylaxis: acute and late phase features of allergic reactions.Novartis Found Symp. 2004; 257 (157-60, 276-85): 101-115Crossref PubMed Google Scholar, 8Lee S. Sadosty A.T. Campbell R.L. Update on biphasic anaphylaxis.Curr Opin Allergy Clin Immunol. 2016; 16: 346-351Crossref PubMed Scopus (0) Google Scholar In addition to the biphasic reactions observed in some patients with anaphylaxis induced by a variety of causes, patients who have IgE reactive with the oligosaccharide galactose-alpha-1,3-galactose, which is present in mammalian meat and in some therapeutic antibodies, can exhibit anaphylaxis after a delay of several hours during which no signs or symptoms are apparent.9Commins S.P. Jerath M.R. Cox K. Erickson L.D. Platts-Mills T. Delayed anaphylaxis to alpha-gal, an oligosaccharide in mammalian meat.Allergol Int. 2016; 65: 16-20Abstract Full Text Full Text PDF PubMed Google Scholar Although there is broad consensus on many aspects of the treatment of anaphylaxis,6Castells M. The diagnosis and management of anaphylaxis in precision medicine.J Allergy Clin Immunol. 2017; 140: 321-333Abstract Full Text Full Text PDF Google Scholar, 10Lieberman P. Nicklas R.A. Randolph C. Oppenheimer J. Bernstein D. Bernstein J. et al.Anaphylaxis—a practice parameter update 2015.Ann Allergy Asthma Immunol. 2015; 115: 341-384Abstract Full Text Full Text PDF PubMed Google Scholar, 11Simons F.E. Ebisawa M. Sanchez-Borges M. Thong B.Y. Worm M. Tanno L.K. et al.2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.World Allergy Organ J. 2015; 8: 32Crossref PubMed Scopus (45) Google Scholar, 12Muraro A. Roberts G. Worm M. Bilo M.B. Brockow K. Fernandez Rivas M. et al.Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.Allergy. 2014; 69: 1026-1045Crossref PubMed Scopus (166) Google Scholar such recommendations are based largely on observational studies, extrapolation from retrospective case reviews, and a few clinical trials.10Lieberman P. Nicklas R.A. Randolph C. Oppenheimer J. Bernstein D. Bernstein J. et al.Anaphylaxis—a practice parameter update 2015.Ann Allergy Asthma Immunol. 2015; 115: 341-384Abstract Full Text Full Text PDF PubMed Google Scholar, 11Simons F.E. Ebisawa M. Sanchez-Borges M. Thong B.Y. Worm M. Tanno L.K. et al.2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.World Allergy Organ J. 2015; 8: 32Crossref PubMed Scopus (45) Google Scholar Injectable epinephrine is universally agreed upon as the first-line therapy for anaphylaxis10Lieberman P. Nicklas R.A. Randolph C. Oppenheimer J. Bernstein D. Bernstein J. et al.Anaphylaxis—a practice parameter update 2015.Ann Allergy Asthma Immunol. 2015; 115: 341-384Abstract Full Text Full Text PDF PubMed Google Scholar, 11Simons F.E. Ebisawa M. Sanchez-Borges M. Thong B.Y. Worm M. Tanno L.K. et al.2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.World Allergy Organ J. 2015; 8: 32Crossref PubMed Scopus (45) Google Scholar, 12Muraro A. Roberts G. Worm M. Bilo M.B. Brockow K. Fernandez Rivas M. et al.Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.Allergy. 2014; 69: 1026-1045Crossref PubMed Scopus (166) Google Scholar and can counteract many pathophysiologic changes in patients with anaphylaxis by acting through α1-adrenergic receptors to induce vasoconstriction, which prevents or diminishes tissue/airway edema, hypotension, and distributive shock; β1-adrenergic receptors to increase heart rate and cardiac contractility; and β2-adrenergic receptors to dilate the airways.11Simons F.E. Ebisawa M. Sanchez-Borges M. Thong B.Y. Worm M. Tanno L.K. et al.2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.World Allergy Organ J. 2015; 8: 32Crossref PubMed Scopus (45) Google Scholar In addition, epinephrine's action on β2-adrenergic receptors might potentially block further release of mediators (histamine and eicosanoids) by mast cells and perhaps other effector cells.13Broder I. Baumal R. Studies of reversed anaphylaxis in the perfused guinea-pig lung.Immunology. 1972; 22: 651-661PubMed Google Scholar, 14Peachell P. Regulation of mast cells by beta-agonists.Clin Rev Allergy Immunol. 2006; 31: 131-142Crossref PubMed Scopus (0) Google Scholar Other therapies should be considered second-line therapies and not a substitute for epinephrine. Guidelines generally agree that patients should be placed in a supine position and given crystalloid to maintain perfusion, and oxygen.10Lieberman P. Nicklas R.A. Randolph C. Oppenheimer J. Bernstein D. Bernstein J. et al.Anaphylaxis—a practice parameter update 2015.Ann Allergy Asthma Immunol. 2015; 115: 341-384Abstract Full Text Full Text PDF PubMed Google Scholar, 12Muraro A. Roberts G. Worm M. Bilo M.B. Brockow K. Fernandez Rivas M. et al.Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.Allergy. 2014; 69: 1026-1045Crossref PubMed Scopus (166) Google Scholar H1- and H2-antihistamines might be helpful in treating cutaneous and upper respiratory signs and symptoms, and corticosteroids might help prevent biphasic reactions but neither prevent nor treat airway obstruction or circulatory collapse and therefore cannot be considered alternatives to epinephrine.10Lieberman P. Nicklas R.A. Randolph C. Oppenheimer J. Bernstein D. Bernstein J. et al.Anaphylaxis—a practice parameter update 2015.Ann Allergy Asthma Immunol. 2015; 115: 341-384Abstract Full Text Full Text PDF PubMed Google Scholar, 11Simons F.E. Ebisawa M. Sanchez-Borges M. Thong B.Y. Worm M. Tanno L.K. et al.2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.World Allergy Organ J. 2015; 8: 32Crossref PubMed Scopus (45) Google Scholar, 12Muraro A. Roberts G. Worm M. Bilo M.B. Brockow K. Fernandez Rivas M. et al.Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.Allergy. 2014; 69: 1026-1045Crossref PubMed Scopus (166) Google Scholar Development of novel therapies for anaphylaxis is likely to be guided mainly by limited data from human subjects and by observations made using animal models. Only limited data on immunologic mechanisms of anaphylaxis from human subjects are available because of the life-threatening nature of anaphylaxis and obvious ethical concerns. Human studies of anaphylaxis have included inducing anaphylaxis in volunteers (most often through Hymenoptera sting challenge) and collecting samples from patients presenting for emergency management of anaphylaxis. Data obtained in such studies, as well as key findings obtained by using mouse models of anaphylaxis, are summarized in Fig 1 and Table I.15Galli S.J. Tsai M. IgE and mast cells in allergic disease.Nat Med. 2012; 18: 693-704Crossref PubMed Scopus (352) Google Scholar, 16Platts-Mills T.A. Schuyler A.J. Erwin E.A. Commins S.P. Woodfolk J.A. IgE in the diagnosis and treatment of allergic disease.J Allergy Clin Immunol. 2016; 137: 1662-1670Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 17Kraft S. Kinet J.P. New developments in FcepsilonRI regulation, function and inhibition.Nat Rev Immunol. 2007; 7: 365-378Crossref PubMed Scopus (318) Google Scholar, 18Stanworth D.R. Humphrey J.H. Bennich H. Johansson S.G. Specific inhibition of the Prausnitz-Kustner reaction by an atypical human myeloma protein.Lancet. 1967; 2: 330-332Abstract PubMed Google Scholar, 19Ishizaka K. Ishizaka T. Richter M. Effect of reduction and alkylation on allergen-combining properties of reaginic antibody.J Allergy. 1966; 37: 135-144Abstract Full Text PDF PubMed Google Scholar, 20Ribatti D. The discovery of immunoglobulin E.Immunol Lett. 2016; 171: 1-4Crossref PubMed Scopus (1) Google Scholar, 21Wershil B.K. Mekori Y.A. Murakami T. Galli S.J. 125I-fibrin deposition in IgE-dependent immediate hypersensitivity reactions in mouse skin. Demonstration of the role of mast cells using genetically mast cell-deficient mice locally reconstituted with cultured mast cells.J Immunol. 1987; 139: 2605-2614PubMed Google Scholar, 22Dombrowicz D. Flamand V. Brigman K.K. Koller B.H. Kinet J.P. Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor alpha chain gene.Cell. 1993; 75: 969-976Abstract Full Text PDF PubMed Scopus (280) Google Scholar, 23Feyerabend T.B. Weiser A. Tietz A. Stassen M. Harris N. Kopf M. et al.Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity.Immunity. 2011; 35: 832-844Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 24Oka T. Kalesnikoff J. Starkl P. Tsai M. Galli S.J. Evidence questioning cromolyn's effectiveness and selectivity as a ‘mast cell stabilizer’ in mice.Lab Invest. 2012; 92: 1472-1482Crossref PubMed Scopus (0) Google Scholar, 25Lilla J.N. Chen C.C. Mukai K. BenBarak M.J. Franco C.B. Kalesnikoff J. et al.Reduced mast cell and basophil numbers and function in Cpa3-Cre; Mcl-1fl/fl mice.Blood. 2011; 118: 6930-6938Crossref PubMed Scopus (80) Google Scholar, 26Nadeau K.C. Kohli A. Iyengar S. DeKruyff R.H. Umetsu D.T. Oral immunotherapy and anti-IgE antibody-adjunctive treatment for food allergy.Immunol Allergy Clin North Am. 2012; 32: 111-133Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 27MacGinnitie A.J. Rachid R. Gragg H. Little S.V. Lakin P. Cianferoni A. et al.Omalizumab facilitates rapid oral desensitization for peanut allergy.J Allergy Clin Immunol. 2017; 139: 873-881.e8Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 28Wood R.A. Kim J.S. Lindblad R. Nadeau K. Henning A.K. Dawson P. et al.A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy.J Allergy Clin Immunol. 2016; 137 (e1-11): 1103-1110Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 29Boni E. Incorvaia C. Mauro M. Dose-dependence of protection from systemic reactions to venom immunotherapy by omalizumab.Clin Mol Allergy. 2016; 14: 14Crossref PubMed Scopus (0) Google Scholar, 30Ricciardi L. Omalizumab: a useful tool for inducing tolerance to bee venom immunotherapy.Int J Immunopathol Pharmacol. 2016; 29: 726-728Crossref PubMed Google Scholar, 31Carter M.C. Robyn J.A. Bressler P.B. Walker J.C. Shapiro G.G. Metcalfe D.D. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis.J Allergy Clin Immunol. 2007; 119: 1550-1551Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 32Harada M. Nagata M. Takeuchi M. Ohara T. Makino S. Watanabe A. Age-dependent difference in susceptibility to IgE antibody- and IgG1 antibody-mediated passive anaphylactic shock in the mouse.Immunol Invest. 1991; 20: 515-523Crossref PubMed Scopus (7) Google Scholar, 33Miyajima I. Dombrowicz D. Martin T.R. Ravetch J.V. Kinet J.P. Galli S.J. Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc gammaRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis.J Clin Invest. 1997; 99: 901-914Crossref PubMed Google Scholar, 34Beutier 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 (3) Google Scholar, 35Jonsson F. Mancardi D.A. Kita Y. Karasuyama H. Iannascoli B. Van Rooijen N. et al.Mouse and human neutrophils induce anaphylaxis.J Clin Invest. 2011; 121: 1484-1496Crossref PubMed Scopus (134) Google Scholar, 36Tsujimura Y. Obata K. Mukai K. Shindou H. Yoshida M. Nishikado H. et al.Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis.Immunity. 2008; 28: 581-589Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 37Khodoun M.V. Strait R. Armstrong L. Yanase N. Finkelman F.D. Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis.Proc Natl Acad Sci U S A. 2011; 108: 12413-12418Crossref PubMed Scopus (46) Google Scholar, 38Khodoun 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 Google Scholar, 39Finkelman F.D. Rothenberg M.E. Brandt E.B. Morris S.C. Strait R.T. Molecular mechanisms of anaphylaxis: lessons from studies with murine models.J Allergy Clin Immunol. 2005; 115: 449-458Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 40Finkelman F.D. Anaphylaxis: lessons from mouse models.J Allergy Clin Immunol. 2007; 120: 506-517Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 41Hirayama N. Hirano T. Kohler G. Kurata A. Okumura K. Ovary Z. Biological activities of antitrinitrophenyl and antidinitrophenyl mouse monoclonal antibodies.Proc Natl Acad Sci U S A. 1982; 79: 613-615Crossref PubMed Scopus (46) Google Scholar, 42Grey H.M. Hirst J.W. Cohn M. A new mouse immunoglobulin: IgG3.J Exp Med. 1971; 133: 289-304Crossref PubMed Google Scholar, 43Brown S.G. Stone S.F. Fatovich D.M. Burrows S.A. Holdgate A. Celenza A. et al.Anaphylaxis: clinical patterns, mediator release, and severity.J Allergy Clin Immunol. 2013; 132: 1141-1149.e5Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 44Lepow I.H. Willms-Kretschmer K. Patrick R.A. Rosen F.S. Gross and ultrastructural observations on lesions produced by intradermal injection of human C3a in man.Am J Pathol. 1970; 61: 13-23PubMed Google Scholar, 45Wuepper K.D. Bokisch V.A. Muller-Eberhard H.J. Stoughton R.B. Cutaneous responses to human C 3 anaphylatoxin in man.Clin Exp Immunol. 1972; 11: 13-20PubMed Google Scholar, 46Yancey K.B. Hammer C.H. Harvath L. Renfer L. Frank M.M. Lawley T.J. Studies of human C5a as a mediator of inflammation in normal human skin.J Clin Invest. 1985; 75: 486-495Crossref PubMed Google Scholar, 47Gorski J.P. Hugli T.E. Muller-Eberhard H.J. C4a: the third anaphylatoxin of the human complement system.Proc Natl Acad Sci U S A. 1979; 76: 5299-5302Crossref PubMed Google Scholar, 48Schwartz L.B. Diagnostic value of tryptase in anaphylaxis and mastocytosis.Immunol Allergy Clin North Am. 2006; 26: 451-463Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 49Schwartz L.B. Metcalfe D.D. Miller J.S. Earl H. Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis.N Engl J Med. 1987; 316: 1622-1626Crossref PubMed Google Scholar, 50Stone S.F. Cotterell C. Isbister G.K. Holdgate A. Brown S.G. Emergency Department Anaphylaxis Investigators. Elevated serum cytokines during human anaphylaxis: identification of potential mediators of acute allergic reactions.J Allergy Clin Immunol. 2009; 124: 786-792.e4Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 51Vadas 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 (72) Google Scholar, 52Schuch A. Brockow K. Mastocytosis and Anaphylaxis.Immunol Allergy Clin North Am. 2017; 37: 153-164Abstract Full Text Full Text PDF PubMed Google Scholar, 53Brockow K. Jofer C. Behrendt H. Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients.Allergy. 2008; 63: 226-232Crossref PubMed Scopus (221) Google Scholar, 54Alvarez-Twose I. Vano-Galvan S. Sanchez-Munoz L. Morgado J.M. Matito A. Torrelo A. et al.Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis.Allergy. 2012; 67: 813-821Crossref PubMed Scopus (51) Google Scholar, 55Sawaguchi M. Tanaka S. Nakatani Y. Harada Y. Mukai K. Matsunaga Y. et al.Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness.J Immunol. 2012; 188: 1809-1818Crossref PubMed Scopus (68) Google Scholar, 56Arias K. Chu D.K. Flader K. Botelho F. Walker T. Arias N. et al.Distinct immune effector pathways contribute to the full expression of peanut-induced anaphylactic reactions in mice.J Allergy Clin Immunol. 2011; 127: 1552-1561.e1Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 57Burton O.T. Noval Rivas M. Zhou J.S. Logsdon S.L. Darling A.R. Koleoglou K.J. et al.Immunoglobulin E signal inhibition during allergen ingestion leads to reversal of established food allergy and induction of regulatory T cells.Immunity. 2014; 41: 141-151Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 58Reber L.L. Marichal T. Mukai K. Kita Y. Tokuoka S.M. Roers A. et al.Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice.J Allergy Clin Immunol. 2013; 132 (e1-11): 881-888Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 59Smit J.J. Willemsen K. Hassing I. Fiechter D. Storm G. van Bloois L. et al.Contribution of classic and alternative effector pathways in pean