Mechanisms Governing Anaphylaxis: Inflammatory Cells, Mediators, Endothelial Gap Junctions and Beyond

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, angioedema (lips, tongue, airways, periphery), myocardial dysfunction (hypovolemia, distributive or mixed shock and arrhythmias), rhinitis, wheezing and stridor. Vomiting, diarrhea, scrotal edema, uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope may occur. The traditional (or classical) pathway is mediated via T cells, Th2 cytokines (such as IL-4 and 5), B cell production of IgE and subsequent crosslinking of the high affinity IgE receptor (FcεRI) on mast cells and basophils by IgE-antigen complexes, culminating in mast cell and basophil degranulation. Degranulation results in the release of preformed mediators (histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF-α), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor (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. Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels 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 to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences. In this review, besides mechanisms (endotypes) underlying IgE-mediated anaphylaxis, we also provide a brief overview of IgG-, complement-, contact system-, cytokine- and mast cell-mediated reactions 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.

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air

“…Human mast cells, first described by Paul Ehrlich, are multifunctional immune cells of myeloid lineage, intimately involved in allergic reactions [ 1 , 2 , 3 , 5 , 32 , 33 ]. Mast cells originate from CD34 + /CD117 + /CD13 + multipotent, hematopoietic progenitors [ 4 , 5 ].…”

“…Human mast cells, first described by Paul Ehrlich, are multifunctional immune cells of myeloid lineage, intimately involved in allergic reactions [ 1 , 2 , 3 , 5 , 32 , 33 ]. Mast cells originate from CD34 + /CD117 + /CD13 + multipotent, hematopoietic progenitors [ 4 , 5 ]. They migrate to peripheral tissues and undergo differentiation and maturation under the influence of growth factors, including stem cell factor (SCF), where interactions with other cell types, including eosinophils and T cells, occur [ 2 , 3 , 4 , 5 , 34 , 35 ].…”

“…Mast cells originate from CD34 + /CD117 + /CD13 + multipotent, hematopoietic progenitors [ 4 , 5 ]. They migrate to peripheral tissues and undergo differentiation and maturation under the influence of growth factors, including stem cell factor (SCF), where interactions with other cell types, including eosinophils and T cells, occur [ 2 , 3 , 4 , 5 , 34 , 35 ]. SCF is a mast cell chemoattractant that also influences the proliferation, differentiation, maturation, adhesion, and survival of mast cells.…”

“…Under the influence of local tissue-derived maturation factors, mast cell differentiation results in the development of well-recognized phenotypes: mucosal mast cells (mainly tryptase-expressing or MCT cells, located predominantly in the mucosa) and alveoli and connective tissue mast cells (expressing tryptase, chymase, and carboxypeptidase A3 or MC-TC, located in submucosal and connective tissue sites such as skin) [ 2 , 3 , 4 , 5 ]. Atiakshin and co-workers have demonstrated the colocalization of tryptase and chymase in the same mast cell granules using sophisticated immunohistochemical techniques [ 41 ].…”

“…Since the discovery of mast cells (MCs) in the nineteenth century, our knowledge about these fascinating and multifunctional cells has grown exponentially [ 1 , 2 , 3 , 4 , 5 ]. Over the last few decades, disease associated with mast cell function and biology has been described.…”