For the following discussion of mechanisms of asthma, we will focus on the most common endotype, common allergic asthma. In patients with allergic asthma, allergen challenge can cause activation of mast cells in an antigen-specific, IgE-dependent fashion, leading to mast-cell mediator release. Allergens can also stimulate the airway epithelium directly, through TLRs and other damage receptors, to release IL-25 and IL-33. These cytokines can lead to the activation of submucosal type 2 innate lymphoid cells (ILC2s), inducing them to release IL-4, IL-5, IL-9, and IL-13. At the same time, bronchial epithelial cells can produce at least two of the chemokine ligands—CCL5 and CCL11—that bind to the receptor CCR3 expressed on TH2 cells, macrophages, eosinophils, and basophils. Thus, these chemokines, together with the products of activated ILC2s, enhance the type 2 response by attracting more TH2 cells and eosinophils to the damaged lungs. The direct effects of ILC2and TH2 cell-derived cytokines and chemokines on airway smooth muscle cells and fibroblasts lead to the apoptosis of epithelial cells and airway remodeling. The remodeling is induced in part by the production of TGF-β, which has numerous effects on the epithelium, ranging from inducing apoptosis to stimulating cell proliferation. The direct action of additional TH2-type cytokines such as IL-9 and IL-13 on airway epithelial cells may also have a dominant role in another major feature of chronic allergic asthma, the induction of goblet-cell metaplasia, which is the increased differentiation of epithelial cells into goblet cells, and a consequent increase in mucus secretion. CD1d-restricted invariant NKT cells (iNKTs, a type of innate-like lymphocyte; see Sections 3-27, 6-18, and 8-26) also seem to have an important role in the development of airway hyperreactivity, whether allergen-induced or nonspecific, and this function can be enhanced by the cooperation of ILC2s. Animal models of asthma have shown that airway hyperreactivity is exacerbated by the presence of iNKT cells. Additionally, in mouse models, superoxide-producing myeloid lineage regulatory cells also appear to play pathological roles in the establishment of airway hyperreactivity.
Mice do not naturally develop asthma, but a disease resembling human asthma develops in mice that lack the transcription factor T-bet. This transcription factor is required for TH1 differentiation (see Section 9-21). When T-bet is absent, T-cell responses are skewed toward the TH2 phenotype. T-bet-deficient mice have increased levels of the TH2 cytokines IL-4, IL-5, and IL-13, and develop airway inflammation involving lymphocytes and eosinophils (Fig. 14.14).
T-bet+/+ T-bet–/– Normal lung biopsy Airway in˜ammation with lymphocytes and eosinophils Normal airway Airway remodeling with increased collagen deposited around airway
Fig. 14.14 Mice lacking the transcription factor T-bet develop allergic airway inflammation and T-cell responses polarized toward TH2.