What is the pathophysiology of allergy-related asthma?

Updated: Oct 07, 2019
  • Author: John J Oppenheimer, MD; Chief Editor: Michael A Kaliner, MD  more...
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Answer

Answer

The allergic response in the airway is the result of a complex interaction of mast cells, eosinophils, T lymphocytes, macrophages, dendritic cells, and neutrophils. More recently discovered is the type 2 innate lymphoid cell (ILC2), which is a type of innate lymphoid cell implicated in inflammatory pathways in asthma. Inhalation-challenge studies with allergens reveal an early allergic response (EAR), which occurs within minutes and peaks at 20 minutes, following inhalation of the allergen.

Clinically, the manifestations of the EAR in the airway include bronchial constriction, airway edema, and mucus plugging. These effects are the result of mast cell–derived mediators. Four to 10 hours later, a late allergic response may occur, which is characterized by infiltration of inflammatory cells into the airway and is most likely caused by cytokine-mediated recruitment and activation of lymphocytes and eosinophils.

Antigen-presenting cells (ie, macrophages, dendritic cells) in the airway capture, process, and present antigen to helper T cells, which, in turn, become activated and secrete cytokines. Helper T cells can be induced by cytokines to develop into TH 1 (ie, by interferon-gamma, interleukin [IL]–2) or TH 2 (ie, by IL-4, IL-5, IL-9, IL-13) cells. Regulatory T cells (Treg) appear to play an important role in TH 2-cell response to allergens. Allergens drive the cytokine pattern toward TH 2, which promotes B-cell IgE production and eosinophil recruitment.

Subsequently, IgE binds to the high-affinity receptor for IgE, Fc-epsilon-RI, on the surface of mast cells and basophils. Upon subsequent exposure to the allergen, the IgE is cross-linked. This leads to degranulation of the mast cell and basophil. Preformed mast-cell mediators, such as histamine and proteases, are released, leading to the EAR.

Newly formed mediators, such as leukotriene C4 and prostaglandin D2, also contribute to the EAR.

Proinflammatory cytokines (IL-3, IL-4, IL-5, tumor necrosis factor-alpha [TNF-α]) are released from mast cells and are generated de novo after mast-cell activation. These cytokines contribute to the late allergic response by attracting neutrophils and eosinophils. The eosinophils release major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase into the airway, causing epithelial denudation and exposure of nerve endings.

The lymphocytes that are attracted to the airway continue to promote the inflammatory response by secreting cytokines and chemokines, which further potentiate the cellular infiltration into the airway.

The ongoing inflammatory process eventually results in hypertrophy of smooth muscles, hyperplasia of mucous glands, thickening of basement membranes, and continuing cellular infiltration. These long-term changes of the airway, referred to as airway remodeling, can ultimately lead to fibrosis and irreversible airway obstruction in some, but not most, patients.


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