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Mechanisms Governing Anaphylaxis: Inflammatory Cells, Mediators

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International Journal of Molecular Sciences Review Mechanisms Governing Anaphylaxis: Inflammatory Cells, Mediators, Endothelial Gap Junctions and Beyond Samantha Minh Thy Nguyen 1, Chase Preston Rupprecht 2, Aaisha Haque 3, Debendra Pattanaik 4, Joseph Yusin 5 and Guha Krishnaswamy 1,3,* 1 Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27106, USA; [email protected] 2 The Rowan School of Osteopathic Medicine, Stratford, NJ 08084, USA; [email protected] 3 The Bill Hefner VA Medical Center, Salisbury, NC 27106, USA; [email protected] 4 Division of Allergy and Immunology, UT Memphis College of Medicine, Memphis, TN 38103, USA; [email protected] 5 The Division of Allergy and Immunology, Greater Los Angeles VA Medical Center, Los Angeles, CA 90011, USA; [email protected] * Correspondence: [email protected] Abstract: Anaphylaxis is a severe, acute, life-threatening multisystem allergic reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal. Medications, foods, latex, exercise, hormones (progesterone), and clonal mast cell disorders may be responsible. More recently, novel syndromes such as delayed reactions to red meat and hereditary alpha tryptasemia have been described. Anaphylaxis manifests as sudden onset urticaria, pruritus, flushing, erythema, Citation: Nguyen, S.M.T.; Rupprecht, angioedema (lips, tongue, airways, periphery), myocardial dysfunction (hypovolemia, distributive C.P.; Haque, A.; Pattanaik, D.; Yusin, or mixed shock and arrhythmias), rhinitis, wheezing and stridor. Vomiting, diarrhea, scrotal edema, J.; Krishnaswamy, G. Mechanisms uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope Governing Anaphylaxis: may occur. The traditional (or classical) pathway is mediated via T cells, Th2 cytokines (such as Inflammatory Cells, Mediators, IL-4 and 5), B cell production of IgE and subsequent crosslinking of the high affinity IgE receptor Endothelial Gap Junctions and (Fc"RI) on mast cells and basophils by IgE-antigen complexes, culminating in mast cell and basophil Beyond. Int. J. Mol. Sci. 2021, 22, 7785. degranulation. Degranulation results in the release of preformed mediators (histamine, heparin, https://doi.org/10.3390/ α ijms22157785 tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF- ), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor Academic Editor: Kurt A. Jellinger (PAF), cytokines and growth factors such as vascular endothelial growth factor (VEGF). Of these, histamine, tryptase, cathepsin G, TNF-α, LTC4, PAF and VEGF can increase vascular permeability. Received: 1 June 2021 Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production Accepted: 13 July 2021 from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels Published: 21 July 2021 and dysfunction of the endothelial barrier. The latter, characterized by the opening of adherens junctions, leads to increased capillary permeability and fluid extravasation. These changes contribute Publisher’s Note: MDPI stays neutral to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences. In this with regard to jurisdictional claims in review, besides mechanisms (endotypes) underlying IgE-mediated anaphylaxis, we also provide a published maps and institutional affil- brief overview of IgG-, complement-, contact system-, cytokine- and mast cell-mediated reactions iations. that can result in phenotypes resembling IgE-mediated anaphylaxis. Such classifications can lead the way to precision medicine approaches to the management of this complex disease. Keywords: anaphylaxis; anaphylactic shock; hypotension; allergic reaction; angioedema; epinephrine; Copyright: © 2021 by the authors. food allergy; mast cell; tryptase; histamine; coagulation; complement; cytokines; allergy Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons 1. Introduction Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Anaphylaxis is a severe acute life-threatening multi-system reaction resulting from 4.0/). the release of a plethora of mediators from mast cells culminating in serious respiratory, Int. J. Mol. Sci. 2021, 22, 7785. https://doi.org/10.3390/ijms22157785 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 23 1. Introduction Int. J. Mol. Sci. 2021, 22, 7785 2 of 23 Anaphylaxis is a severe acute life-threatening multi-system reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal [1,2]. This manifests cardiovascularas urticaria, pruritus, and mucocutaneous flushing, erythema, manifestations angioedema that (lips, can betongue, fatal [airways,1,2]. This periphery), manifests asmyocardial urticaria, dysfunction pruritus, flushing, (hypovolemia, erythema, distributive angioedema or mixed (lips, tongue,shock and airways, arrhythmias), periphery), rhi- myocardialnitis, wheezing, dysfunction and stridor. (hypovolemia, Nausea, vomiting, distributive diarrhea, or mixed scrotal shock edema, and uterine arrhythmias), cramps, rhinitis,vaginal wheezing,bleeding, urinary and stridor. incontinence, Nausea, vomiting, dizziness, diarrhea, seizures, scrotal confusion, edema, and uterine syncope cramps, may vaginalalso be bleeding,seen (Figure urinary 1) [2,3] incontinence,. Despite many dizziness, advances seizures, in understanding confusion, and etiology, syncope mecha- may alsonisms be and seen management, (Figure1)[ 2,3 ].anaphylaxis Despite many remains advances underdiagnosed in understanding and etiology,undertreated mechanisms [4]. An- andaphylaxis management, is highly anaphylaxis likely when remains any one underdiagnosed of the following and two undertreated criteria are [satisfied4]. Anaphylaxis [1,2,5]: is highly likely when any one of the following two criteria are satisfied [1,2,5]: Figure 1. Anaphylaxis-triggers (including endotypes), genetic predisposition, selected cofactors and role of mast cells and Figure 1. Anaphylaxis-triggers (including endotypes), genetic predisposition, selected cofactors and role of mast cells and mediators in manifestations and culminating potentially in cardiorespiratory arrest. CNS = central nervous system, NSAIDs mediators in manifestations and culminating potentially in cardiorespiratory arrest. CNS = central nervous system, =NSAIDs nonsteroidal = nonsteroidal anti-inflammatory anti-inflammatory drugs, ACE drugs, = angiotensin ACE = angiotensin converting converting enzyme, enzyme, HATS = HATS hereditary = hereditary alpha tryptasemia alpha tryp- syndrome,tasemia syndrome, PAF = platelet PAF = activating platelet activating factor, IgE factor, = immunoglobulin IgE = immunoglobulin E, IgG = immunoglobulinE, IgG = immunoglobulin G. G. 1.1. Acute onset of an illness (minutes to hours) with involvement of thethe skinskin (urticaria,(urticaria, pruritus, flushing) flushing) and/or mucosa mucosa (angioedema/swelling (angioedema/swelling of of lips, lips, tongue, tongue, larynx) larynx) Plus at Least One of the Following: a. RespiRespiratoryratory involvement involvement (dyspnea,(dyspnea, wheezing, wheezing, stridor, stridor, reduced reduced peak flowsflows oror hypoxemia)hypoxemia);; b. ReducedReduced blood blood pressure pressure andand associated associated symptoms of end-organend-organ dysfunctiondysfunction (syncope,(syncope, fecal fecal or or urinary urinary incontinence, incontinence, hypotonia/collapse) hypotonia/collapse);; c. SevereSevere gastrointestinal gastrointestinal symptoms symptoms (severe(severe crampy crampy abdominal abdominal pain, pain, severe severe di- arrhea,diarrhea, repetitive repetitive vomiting) vomiting).. 2.2. Acute onset of hypotension * or bronchospasm or laryngeal involvementinvolvement (stridor, voice change, odynophagia) after exposure to a knownknown oror highlyhighly probableprobable allergenallergen for the patient even in the absence of skin involvement. for the patient even in the absence of skin involvement. ** HypotensionHypotension in in adults adults is regardedis regarded as systolicas systolic blood blood pressure pressure of <90 of mm <90 Hg mm or greaterHg or thangreater a 30% than decrease a 30% decrease in systolic in bloodsystolic pressure blood pressure from the from patient’s the baseline.patient’s Hypotensionbaseline. Hypo- in infantstension and in infants children: and systolic children: blood systolic pressure blood <70 pressure mm Hg <70 (1–12 mm months); Hg (1– <(7012 months); mm Hg < + (7 [20 × age]) (1–10 years); <90 mm Hg (11–17 years); or >30% decrease in systolic blood pressure from baseline for the patient. Globally, the true rate of anaphylaxis is difficult to measure due to both under- diagnosis and misdiagnosis. It is generally agreed that the incidence of anaphylaxis Int. J. Mol. Sci. 2021, 22, 7785 3 of 23 is increasing worldwide with estimates for case fatality rates at 0.5–1% of patients hospital- ized for the condition [6]. Anaphylaxis accounts for approximately 0.26% of all hospital admissions worldwide, with medications and food contributing to most cases [6]. Novel allergens have also contributed to the rise in anaphylaxis
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