Mechanisms
The immunological processes underlying IgE-mediated AR are not dissimilar in children and adults, involving activation of the adaptive immunity and class switching towards production of IgE antibodies. Nevertheless, the vast amount of evidence derives from adult studies with extrapolation on younger ages, while data from mechanistic studies in children are limited. Of importance, despite innate immunity being present from infancy, quantitative differences and qualitative maturation, potentially affecting downstream responses have been observed from early life though preschool and teenage years [4]. AR, which constitutes the most studied phenotype of Pediatric rhinitis, is predominantly defined by type 2 inflammation, mediated by type 2 innate lymphoid cells (ILC2) and Th2 lymphocyte-driven responses locally and systematically[5]. In addition, infiltration of multiple inflammatory cells in the nasal mucosa including T cells, eosinophils, neutrophils, and mast cells has been confirmed [6]. Activated/damaged by aeroallergens nasal epithelial cells secrete matrix metalloproteinase, IL-25, IL-31, IL-33 and thymic stromal lymphopoietin (TSLP), which augment Th2 inflammation either via ILC2s or through antigen presenting cells located underneath the nasal epithelium [7]. ILC2s express receptors such as CRTh2, CD127 (the interleukin 7 receptor) and ST-2, the receptor for IL-33 and release particularly IL-9, IL-5 and IL-13, further activating type 2 inflammation. ILC2s also express high levels of GATA3, contributing to CD4+ Th2 activation and subsequent release of IL-4, IL-5, IL-9 and IL-13, which maintain the Th2-cell lineage and furthermore interact with B lymphocytes to induce class-switching and synthesis of allergen-specific IgE (IgE sensitization) [8]. On re-exposure cross—linking of sIgE on effector cells induce the early, within 2-4 hours and subsequently the late phase response characterized predominant by a sustained nasal congestion [9]. In an ex-vivo model, the presence of ILC2s, myeloid and plasmacytoid dendritic cells (mDCs and pDCs respectively) was documented in the nasal mucosa of AR patients. Of importance, mDCs promoted ILC2 function and proliferation by the IL-33/ST2 pathway, while activation of pDCs suppressed ILC2 function through IL-6 in AR patients, suggesting a differential role for distinct dendritic cell subtypes [10].
T regulatory cells (Tregs) are key mediators in immune regulation thus prevent airway allergic inflammation. Inflammation in AR appears to be a functional defect of Tregs which results in decreased production of IL-10 and transforming growth factor (TGF)-β [11]. Certain microRNAs (miRNAs) mediate Treg function [12]. In children with AR, miR‐155 promoted Treg differentiation in CD4+ T cells, while other miRNA mediate response to respiratory infections, providing new potential treatment targets [13]. Moreover, other less studied T cell populations, such as the gammadelta (γ δ) T cells, that facilitate eosinophil migration, were significantly more abundant in the nasal mucosa of AR patients compared to controls, while their number and distribution were positively associated with eosinophils, macrophages and mast cells locally, suggesting an essential role in mucosal inflammation [14]. Earlier studies showed a dysregulated pattern of Th1 transcription factors such as STAT6+ and GATA3+ potentially contributing to the enhance Th2 responses in AR patients compared to controls [15]. More recently the Notch signaling pathway which downregulates FOXp3 expression and differentiation of T-reg was significantly elevated in AR patients [16].
Studies on the role of B-cells in the pathogenesis of AR, indicate a significant skewing of circulating B-cell population towards memory B cells with markedly increased expression of CD23, which facilitate antigen presentation and IgE synthesis in AR patients [17]; nevertheless, other studies were not confirmatory of differences in B-regulatory cell populations or Il-10 production [18].
Recently, AR patients were shown to exhibit increased number of specific sets of activated neutrophils_CD16(high)-CD62L(dim)_either locally or systematically, resulting in T cell priming and enhancing eosinophil migration [19]. Recently, activated neutrophils were shown to serve as functional antigen presenting cells (APC) in late phase reactions and activate allergen-specific effector CD4+ T-cells to synthesize cytokines, thus they potentially contribute to magnified nasal allergic inflammation [20].
There is evidence that autophagy, a catabolic intracellular process playing a substantial role in maintaining tissue and cellular homeostasis, is implicated in immune response regulation and asthma pathogenesis [21]. More recently, highly expressed autophagic markers were observed in the upper airways of AR patients, strongly associated with indices of nasal remodeling [22].