Product information and disease description Place of product in therapy Disease description

Pathophysiology

9 evidence topics · 5 sources

Sensitization and IgE binding to high-affinity receptors on mast cells and basophils

“The initial pathogenic step in the development of IgE-dependent type I allergy is sensitization, a process mediated by the uptake of allergens by antigen-presenting cells (APCs). APCs capture and process allergens, presenting fragments on their surface via MHC class II molecules, undergo maturation, and migrate to regional lymph nodes, where they present these antigens to naïve T cells.” (opens the source at this quote in a new tab)
“During the effector phase, re-exposure to the same allergen cross-links the IgE molecules bound to FcεRI receptors on mast cells and basophils” (opens the source at this quote in a new tab)

IgE cross-linking on effector cells as the classic mechanism

“IgE-mediated anaphylaxis is considered the classic and most frequent mechanism. In this type, anaphylaxis is triggered by the interaction of an allergen (usually a protein) interacting with the allergen-specific IgE/high-affinity receptor (FcεRI) complex expressed on effector cells, predominantly mast cells and basophils.” (opens the source at this quote in a new tab)

Preformed and newly synthesized mediators released on 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).” (opens the source at this quote in a new tab)

Histamine actions at H1 and H2 receptors

“Experimental intravenous infusion of histamine in healthy volunteers can reproduce many of the symptoms and signs of anaphylaxis: flushing, headache, wheezing and transient hemodynamic changes such as systemic hypotension and tachycardia” (opens the source at this quote in a new tab)
“Histamine binding to H1 receptor causes increased vascular permeability, bronchospasm, and GI contraction. Histamine binding to H2 receptor leads to flushing, glandular secretion, and cardiac contraction.” (opens the source at this quote in a new tab)

Mechanism of vasodilation, capillary leak, hypotension, and airway edema

“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.” (opens the source at this quote in a new tab)

Platelet-activating factor and reaction severity

“The platelet activating factor is the most potent mast cell mediator identified to date and is associated with decreased cardiac output, vascular hyperpermeability, smooth muscle contraction, hypovolemia, and cardiac collapse” (opens the source at this quote in a new tab)

Tryptase as a mast cell mediator and biomarker

“tryptase is a serine protease released by mast cells and basophils that possesses pro-inflammatory effects triggering tissue edema, chemokine secretion, and subsequent neutrophil recruitment.” (opens the source at this quote in a new tab)

Non-IgE-mediated and non-immunologic pathways

“The most relevant non-IgE-mediated immunologic mechanisms may involve the activation of pathways such as the complement system (anaphylatoxins, C3a, and C5a),35 the contact and coagulation system activation,36, 37, 38 or immunoglobulin G (IgG)-mediated anaphylaxis.” (opens the source at this quote in a new tab)
“Mast cells may be activated through receptors such as Mas-related G-protein coupled receptor member X2 (MRGPRX2) by certain drugs such as neuromuscular blocking agents and fluoroquinolones.” (opens the source at this quote in a new tab)

How epinephrine reverses the physiology of anaphylaxis

“In anaphylaxis, effector cell mediators drive vasodilation, capillary leak and bronchospasm, which are responsible for the main clinical features” (opens the source at this quote in a new tab)
“Adrenaline's alpha‐adrenergic stimulation of vascular smooth muscle and endothelial cells mediates potent vasoconstriction, mitigating against vasodilation, further capillary leak and hypotension. Beta‐1‐adrenergic stimulation has inotropic and chronotropic effects on the heart, increasing myocardial contractility and heart rate. Beta‐2‐adrenergic stimulation produces bronchodilation, counteracting the bronchospasm and wheeze seen in anaphylaxis.” (opens the source at this quote in a new tab)