T-helper-2 cells and atopic disease: lessons learnt from inborn errors of immunity

In the Western world, allergic and atopic diseases such as atopic dermatitis, food and environmental allergies, allergic rhinitis, and asthma are among the fastest-growing chronic conditions affecting the general population. It is estimated that 1 in 3 individuals are affected by allergic disease and 1 in 10 infants experience some form of food allergy 1, 2. Furthermore, the incidence of severe allergies and number of allergy-related hospitalizations has increased 2–4-fold in most countries in the last 20 years 3, 4. These conditions represent major health issues and impose significant medical and financial burdens on health services and society. The cellular basis of most atopic diseases includes dysregulated development and/or function of CD4+ T-helper-2 (Th2) lymphocytes tha aberrantly produce excessive amounts of the cytokines interleukin (IL) -4, IL-5, and IL-13. Th2 cells develop in the presence of IL-4 with lineage commitment dependent on the transcription factors signal transducer and activator of transcription (STAT)6 and GATA binding protein 3 (GATA3) [5]. While Th2 cells have a protective function in host defense against parasites and helminths, Th2 cells can also be pathogenic. Thus, in the setting of atopic disease, aberrant generation and/or function of Th2 cells underpin clinical sequelae such as eosinophilia, increased production of allergen-specific immunoglobulin (Ig)E by B cells, and subsequent degranulation of mast cells and basophils. Consequently, numerous biologics that target either Th2 cytokines IL-4, IL-5, and IL-13 (i.e. Mepolizum, Reslizumab, Benralizumab, Lebrikzumab, Tralokinumab, Anrukinzumab, GSK679586, IMA-026, Dupilumab, Pitrakinra, and AMG-317) or IgE (Omalizumab, Ligelizumab) have revolutionized the treatment of atopic diseases 6, 7. However, these therapeutics often only treat disease after collateral damage inflicted by aberrant Th2-driven immunity has been established. Many of the pathways that disrupt lymphocyte dysregulation and subsequently lead to atopic disease are largely unknown. In addition, attempts to track pathogenic immune cells, and other biomarkers, as surrogates for quantifying disease burden and the effects of allergen-specific immunotherapy have been underwhelming 8, 9. Thus, novel approaches at dissecting the complexities of immune dysregulation resulting in atopic diseases are needed.

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