IgE is synthesized and secreted by B cells that have undergone heavy-chain class switching from IgM to IgE. The IgE binds to FcRI on mast cells and antigen-presenting cells (APCs) (a) and sensitizes these cells to allergens. Omalizumab inhibits the binding of IgE to FcRI on mast cells and APCs (b). Allergen binding to IgE triggers mast-cell degranulation to cause an allergic response (c). Allergen binding to the APC leads to the presentation of allergenic peptides to T helper 2 (TH2) cells (d). The allergen-activated TH2 cells secrete interleukin-4 (IL-4) (e) to maintain the TH2-cell lineage and recruit more TH cells into this lineage (e). The TH2 cells also secrete IL-13 and express CD40 ligand (CD40L), which together with IL-4 stimulates heavy-chain class switching to IgE (f). The allergen-activated mast cells contribute to the production of IL-4 and IL-13 (and express CD40L), which may also stimulate heavy-chain class switching to IgE (g). IL-4, IL-13 and CD40L also stimulate the expression of CD23 and the release of soluble CD23 (h). In humans, soluble trimeric CD23 upregulates IgE synthesis and secretion through interaction with CD21 (i). Thus, allergen acts in pump priming of the allergic response.
The mechanism of adrenergic receptors. β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis. Image source: Wikipedia, GNU Free Documentation License.
In this Argentinean study, beta 2-Adrenergic receptor polymorphisms and total serum IgE levels were analyzed in 124 white asthmatic children using polymerase chain reaction during a 3-year period.
In pre-disposed individuals, initial exposure(s) to allergen leads to the activation of allergen-specific T helper 2 (TH2) cells and IgE synthesis, which is known as allergic sensitization. Subsequent exposures to allergen cause inflammatory-cell recruitment and activation and mediator release, which are responsible for early (acute) allergic responses (EARs) and late allergic responses (LARs). In the EAR, within minutes of contact with allergen, IgE-sensitized mast cells degranulate, releasing both pre-formed and newly synthesized mediators in sensitized individuals. These include histamine, leukotrienes and cytokines, which promote vascular permeability, smooth-muscle contraction and mucus production. Chemokines released by mast cells and other cell types direct recruitment of inflammatory cells that contribute to the LAR, which is characterized by an influx of eosinophils and TH2 cells. Eosinophils release an array of pro-inflammatory mediators, including leukotrienes and basic proteins (cationic proteins, eosinophil peroxidase, major basic protein and eosinophil-derived neurotoxin), and they might be an important source of interleukin-3 (IL-3), IL-5, IL-13 and granulocyte/macrophage colony-stimulating factor. Neuropeptides are also proposed to contribute to the pathophysiology of allergic symptoms. TCR, T-cell receptor.
Asthma is a complex and interactive process involving many cell types, mediators and target-organ responses. Furthermore, the process can involve a progression from acute events (a) such as allergen-induced activation of mast cells to release pro-inflammatory cytokines and mediators, leading to acute bronchoconstriction and airway obstruction, to chronic inflammation (b) characterized by activation of T helper (TH) 2 cells and macrophages, and recruitment and degranulation of eosinophils. The changes in the airway cause not only airflow obstruction but also an increase in airway responsiveness. Finally, in some subjects, there is a further progression of the inflammatory changes towards airway remodelling (c). The remodelling changes can lead to permanent alterations in the airway architecture such that obstructive events are irreversible. IgE, immunoglobulin E; IL-4, interleukin 4; TH1, T helper 1 cells; TNF-, tumour necrosis factor .
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