Allergic diseases are conditions triggered by localized or systemic dysfunctions of the immune system (IS). These pathologies are an increasing global public health concern, placing a significant and growing burden on healthcare systems worldwide. The rising incidence of conditions such as asthma, allergic rhinitis (AR), food allergies (FA), and atopic dermatitis (AD) highlights the urgent need for a deeper understanding of their underlying mechanisms. This knowledge is crucial for developing new and more effective therapeutic approaches.

Epithelial cells serve as the primary barrier against environmental triggers, including allergens (Salazar & Ghaemmaghami, 2013). Upon allergen exposure, these cells directly release “alarmins,” such as interleukin (IL)-33, IL-25, and thymic stromal lymphopoietin (TSLP) (Gandhi and Vliagoftis, 2015, King et al., 1998), which are key cytokines in initiating the allergic response. However, some allergens do not inherently provoke cytokine release unless external factors, such as air pollutants or microbial components, or internal mediators create an inflammatory environment that irritates epithelial surfaces (Salazar & Ghaemmaghami, 2013). This irritation activates pattern recognition receptor (PRR)-mediated signaling pathways, leading to cytokine production (Molinari et al., 2020). The released cytokines then stimulate the activation of antigen-presenting cells (APCs), particularly dendritic cells (DCs) (Lopez et al., 2009, Lopez et al., 2010, Lopez et al., 2015, Rodriguez-Pena et al., 2006). DCs play a pivotal role in the differentiation and expansion of type 2 helper (Th2) T lymphocytes. Th2 cells drive the allergic response by promoting the switching of B cells to produce immunoglobulin E (IgE) through the actions of IL-4 and IL-13. Additionally, Th2 cells contribute to eosinophil recruitment via IL-5 and enhance smooth muscle contraction and mucus secretion through IL-13, leading to the common symptoms of allergic inflammation. The allergic response reaches its peak when allergen-specific IgE antibodies bind to their receptors on effector cells, i.e mast cells, basophils, eosinophils and neutrophils (Alcaniz et al., 2013, Chacon et al., 2005, Monteseirin et al., 2007, Stone et al., 2010, Vega et al., 2006). This binding triggers a cascade of events culminating in the release of inflammatory mediators such as histamine, leukotrienes, and prostaglandins, which drive the onset of inflammation and subsequent allergic symptoms.

Beyond the Th2-driven pathway, type 2 innate lymphoid cells (ILC2) also play a significant role in amplifying the allergic response by releasing Th2 cytokines (Palomares et al., 2021). Other T lymphocyte subsets also contribute to allergic disease pathogenesis. For instance, type 17 helper (Th17) T cells produce IL-17, a cytokine that recruits neutrophils to the site of inflammation, thereby intensifying the inflammatory response. Conversely, regulatory T cells (Tregs) act as a counterbalance, secreting anti-inflammatory cytokines like IL-10 and transforming growth factor-beta (TGF-β), which help suppress inflammation and maintain IS balance (Komlosi et al., 2022, Wang et al., 2023).

Recent studies have highlighted the dual role of γδ T cells in allergic diseases, showing that they can either exacerbate or mitigate allergic inflammation (Hahn et al., 2004). In asthma, γδ T cells influence airway hyperresponsiveness (AHR) through the production Th2-type cytokines (Belkadi et al., 2019, Hahn et al., 2004) or IL-17 (Belkadi et al., 2019, Murdoch and Lloyd, 2010, Ullah et al., 2015, Zarobkiewicz et al., 2021) or Th1 cytokines that suppress AHR (Huang et al., 2009, Huang et al., 2013). In AR, γδ T cells appear to play both pro-inflammatory and immunoregulatory roles (Wang et al., 2020). In FA, γδ T cells exhibit a protective regulatory function by maintaining immune tolerance, while in AD, they may have protective effects. The function of γδ T cells is further modulated by external factors, such as microbiota from the lungs, gut, and skin, with microbial metabolites influencing their activity.