Asthma is a heterogeneous, complex chronic disease. Children with severe asthma often experience acute exacerbations, leading to impaired lung function and poor quality of life. In the past, asthma was simply classified as either atopic or non-atopic. With deeper research into the mechanisms of asthma, asthma subtypes based on different inflammatory pathways have emerged, namely type 2 (T2-high) and non-type 2 (T2-low) asthma. Inflammation is crucial to the pathophysiology of T2 asthma, and T2 asthma can be accompanied by multiple T2 inflammatory comorbidities, such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Most asthma patients' symptoms can be effectively controlled with standardized treatment, but a small number of patients still have uncontrolled or even worsening symptoms, developing into refractory asthma. The application of biologics offers a new method for precise treatment of refractory asthma patients while also addressing their T2 inflammatory comorbidities. Currently, biologics used in the treatment of asthma mainly target T2 asthma.
Mechanisms of Type 2 Inflammation in Asthma
Type 2 inflammation is the pathological basis of chronic inflammation in asthma. Type 2 asthma is characterized by airway inflammation mediated primarily by T-bet+CD+4 1-type helper T cells (Th2), type 2 innate lymphoid cells (ILC2), and related cytokines. The type 2 immune response in the airways is mainly mediated by eosinophils, mast cells, basophils, Th2 cells, ILC2, and B cells that produce IgE. When external environmental factors such as bacteria, viruses, fungi, pollutants, and allergens disrupt the airway epithelial barrier, damaged epithelial cells undergo metaplasia into goblet cells, releasing cytokines such as interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) as warning-like cell factors. These factors recruit dendritic cells (DCs) to present antigens and act together to activate and induce the differentiation of T lymphocytes into Th2 cells. At the same time, warning-like cell factors can also activate ILC2, thereby secreting type 2 inflammation-related cytokines IL-4, IL-5, and IL-13, leading to the vulnerability of the epithelial barrier. Furthermore, warning-like cell factors are also chemoattractants for eosinophils and neutrophils. Secretion of TSLP, IL-25, and IL-33 can further stimulate the secretion of key type 2 cytokines.
IL-4 and IL-13 stimulate B cells to produce allergen-specific IgE, which binds to the FcεRI receptors on mast cells and basophils. When external environmental factors re-enter the body, allergen-IgE-cell crosslinking occurs, activating mast cells and basophils to degranulate and release mediators such as prostaglandin D2 (PGD2), leukotrienes, and histamine, promoting local vasodilation and increased vascular permeability. This causes contraction of the bronchial smooth muscle and triggers airway hyperresponsiveness. IL-13 can act on epithelial cells, disrupting the epithelial barrier and increasing epithelial permeability. It induces the secretion of IL-33 and metaplasia of goblet cells. IL-13 can also directly act on airway smooth muscle cells, causing their contraction and proliferation. Additionally, IL-13 induces fibroblast proliferation and promotes collagen synthesis, contributing to airway remodeling. IL-5 is a key cytokine that regulates the maturation of eosinophils in the bone marrow. It mobilizes and promotes the production, proliferation, and survival of eosinophils in the bone marrow and peripheral tissues, leading to infiltration in the airways and involvement in airway remodeling.
In type 2 asthma, the expression of cytokines such as IL-4, IL-5, IL-13, IL-25, IL-33, and TSLP is increased. Biomarkers of type 2 cytokines include fractional exhaled nitric oxide (FeNO), serum total IgE, allergen-specific IgE, and elevated levels of eosinophils in blood and sputum. Biologic agents specifically target key components of the immune mechanisms underlying type 2 inflammation in asthma.
Research Application of Biological Agents in Pediatric Asthma
1. Anti-IgE Antibodies
In 2003 and 2005, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved omalizumab for the treatment of moderate to severe persistent allergic asthma in individuals aged 12 years and older. In 2009 and 2016, it was also approved for ...
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