Thymic stromal lymphopoietin (TSLP), an epithelial cytokine (alarmin), is a central regulator of the immune response to inhaled environmental insults such as allergens, viruses and pollutants, init...

Rationale: Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines, initiate eosinophilic inflammatory responses in murine models of asthma. Objectives: To investigate the role of ILC2 in allergen-induced airway eosinophilic responses in subjects with atopy and asthma. Methods: Using a diluent-controlled allergen challenge crossover study, where all subjects (n = 10) developed allergen-induced early and late responses, airway eosinophilia, and increased methacholine airway responsiveness, bone marrow, blood, and sputum samples were collected before and after inhalation challenge. Measurements and Main Results: ILC2 (lin−FcεRI−CD45+CD127+ST2+) and CD4+T lymphocytes were enumerated by flow cytometry, as well as intracellular IL-5 and IL-13 expression. Steroid sensitivity of ILC2 and CD4+ T cells was investigated in vitro. A significant increase in total, IL-5+, IL-13+, and CRTH2+ ILC2 was found in sputum, 24 hours after allergen, coincident with a significant decrease in blood ILC2. Total, IL-5+, and IL-13+, but not CRTH2+, CD4+ T cells significantly increased at 24 and 48 hours after allergen in sputum. In blood and bone marrow, only CD4+ cells demonstrated increased activation after allergen. Airway eosinophilia correlated with IL-5+ ILC2 at all time points and allergen-induced changes in IL-5+ CD4+ cells at 48 hours after allergen. Dexamethasone significantly attenuated IL-2– and IL-33–stimulated IL-5 and IL-13 production by both cell types. Conclusions: Innate and adaptive immune cells are increased in the airways associated with allergic asthmatic responses. Total and type 2 cytokine–positive ILC2 are increased only within the airways, whereas CD4+ T lymphocytes demonstrated local and systemic increases. Steroid sensitivity of both cells may explain effectiveness of this therapy in those with mild asthma.

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)‐33, and IL‐25 are epithelial cell‐derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen‐induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti‐TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2‐high and with T2‐low asthma. Clinical trials blocking IL‐33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL‐33/ST2 axis in T2‐high versus T2‐low asthma is unclear. To date, there is no evidence that IL‐25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL‐25, IL‐33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.

In recent decades, the worldwide prevalence of allergic disease has increased considerably. The atopic march is a model aimed at explaining the apparent progression of allergic diseases from atopic dermatitis (AD) to allergic asthma (AA) and to allergic rhinitis (AR). It hypothesizes that allergic disease begins, typically in children, with the development of AD, then AA, and finally progresses to AR. This theory has been widely studied in cross-sectional and long-term longitudinal studies and it has been found that as prevalence of AD declines, prevalence of AA increases. A similar relationship is reported between AA and AR. The legitimacy of the atopic march model is, however, currently debated. Epidemiological evidence and criticism of longitudinal studies point to an overstatement of the atopic march’s prevalence and incorrect mechanisms, opening a discussion for alternative models to better explain the pathophysiological and epidemiological processes that promote this progression of allergic diseases. Albeit, risk factors for the development and progression of allergic disease, particularly AD, are critical in identifying disease progression. Investigating the role of age, severity, family history, phenotype, and genetic traits may give a better indication into the progression of allergic diseases. In addition, studies following patients from infancy into adulthood and a general increase in longitudinal studies would help broaden the knowledge of allergic disease progression and the atopic march.