Type 2 immunity in the skin and lungs

Abstract

There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 activate B cells to class-switch to IgE and also play a role in T-cell and eosinophil migration to allergic inflammatory tissues. IL-13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL-4 and IL-13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL-5 acts on activation, recruitment, and survival of eosinophils. IL-9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL-5 and | 1583 AKDIS et Al. 1 | INTRODUC TI ON Allergic diseases cause significant morbidity and mortality with almost one billion cases, accounting for a significant portion of overall healthcare costs. The dysregulated immune response, chronic inflammation, and remodeling in the affected tissues define a dynamic and heterogeneous spectrum of anaphylaxis, food allergy, asthma, allergic rhinitis, chronic rhinosinusitis with nasal polyposis (CRSwNP), and atopic dermatitis (AD). Two main subtypes of immune responses driving asthma and AD have been defined, namely type 2-high and type 2-low. 1-4 Precision medicine and biomarker discovery is important for the management of asthma and AD in the context of a better selection of good responders to treatment, prediction of outcomes, and design of disease-modifying strategies. Progress has been made in profiling the type 2 immune response-driven diseases. In contrast, the non-type 2 immune response in asthma and AD is insufficiently understood. The majority of patients with AD, CRS and asthma involve, or result from, an overexpression of type 2 inflammatory pathways (Figure 1). 5-7 A specific type 2 set of cytokines are produced during the induction and maintenance of allergic immune response with the contribution of epithelial cells, dendritic cells (DC), T cells, innate lymphoid cells (ILC), eosinophils, mast cells (MC), and basophils. Activation of Th2 and ILC2 pathways is at the core of type 2 inflammation. Th2 cytokines include interleukin (IL)-4, IL-5, IL-9, IL-13, and IL-31, and main type 2 cytokines of ILC2 are IL-5, IL-9, and IL-13. 8,9 IL-4 induces Th2 cell di...

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“…Late-phase reactions are initiated by the accumulation of mediators and by the activation of allergen-specific memory Th2 via mechanisms depending on IgE-facilitated presentation by DCs and B cells. Th2 cells in cooperation with ILC2s activated by ep-ithelial cell-derived alarmins (TSLP, IL-33, or IL-25) produce large amounts of IL-4, IL-5, IL-9, and IL-13 that contribute to maintain allergen-specific IgE levels, eosinophilia, mucus production, inflammatory cell recruitment, and tissue inflammation, leading to chronicity and the most severe clinical manifestation of allergy [8,9,96].…”

“…It is defined by chronic inflammation of the nasal mucosa that promotes the appearance of its main clinical symptoms: sneezing, itch, nasal congestion, and rhinorrhoea [101,102]. The pathophysiology of allergic rhinitis is mediated by a type 2 immune response where Th2 cells, ILC2s, B cells, mast cells, basophils, and eosinophils together with structural cells from the nasal mucosa interact and release a range of mediators that end up in the development of classical features of rhinitis [8,9]. Several pathophysiological mechanisms of allergic rhinitis are also present in the lower respiratory tract of asthmatic patients.…”

“…Allergic asthma represents one of the most common and well-studied asthma phenotypes [108]. It is associated with an early age onset, increased levels of total and allergen-specific serum IgE, and type 2 immune responses [8,108]. Corticosteroids and bronchodilators are the mainstay treatment for asthma and many patients are properly controlled with them.…”

“…Despite their low mortality rates, allergic skin disorders such as AD and allergic contact dermatitis (ACD) have a great impact on patients' quality of life. Skin allergies are complex diseases initiated by allergens and multiple environmental factors on genetically susceptible individuals that rely on the communication be- tween immune cells and other cell types such as keratinocytes and fibroblasts [8]. Regardless of the triggering factor, allergic skin disorders involve increased interleukins and chemokines, leading to the expansion of different T-helper subsets and activation of effector cells that may cause the chronicity of the disease [131].…”

“…The main clinical manifestations of allergy include allergic rhinitis, allergic asthma, atopic dermatitis (AD) and other skin diseases, food allergy, and anaphy-laxis. Allergic diseases can be generally considered as type 2-mediated diseases characterized by the production of high levels of IgE against innocuous substances called allergens [8,9]. Allergic disorders significantly affect patients' quality of life, decrease productivity at work, and enhance sanitary costs of health care systems, thus representing a significant health problem with high socio-economic impact [10,11].…”