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].