Setting Of Allergic Rhinitis Research Articles

Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis

Cystatin SN (CST1) and cystatin SA (CST2) are cysteine protease inhibitors that protect against allergen, viral, and bacterial proteases. Cystatins are overexpressed in the setting of allergic rhinitis and chronic rhinosinusitis with nasal polyps (CRSwNP); however, their role in promoting type 2 inflammation remains poorly characterized. The purpose of this study was to use integrated poly-omics and a murine exposure model to explore the link between cystatin overexpression in CRSwNP and type 2 inflammation. In this institutional review board- and institutional animal care and use committee-approved study, we compared tissue, exosome, and mucus CST1 and CST2 between CRSwNP and controls (n= 10 per group) by using matched whole exome sequencing, transcriptomic, proteomic, posttranslational modification, histologic, functional, and bioinformatic analyses. C57/BL6 mice were dosed with 3.9 μg/mL of CST1 or PBS intranasally for 5 to 18 days in the presence or absence of epithelial ABCB1a knockdown. Inflammatory cytokines were quantified by using Quansys multiplex assays or ELISAs. Of the 1305 proteins quantified, CST1 and CST2 were among the most overexpressed protease inhibitors in tissue, exosome, and mucus samples; they were localized to the epithelial layer. Multiple posttranslational modifications were identified in the polyp tissue. Exosomal CST1 and CST2 were strongly and significantly correlated with eosinophils and Lund-Mackay scores. Murine type 2 cytokine secretion and TH2 cell infiltration increased in a time-dependent manner following CST1 exposure and was abrogated by epithelial knockdown of ABCB1a, a regulator of epithelial cytokine secretion. CST1 is a potent upstream initiator of epithelial-derived type 2 inflammation in CRSwNP. Therapeutic strategies targeting CST activity and its associated posttranslational modifications deserve further interrogation.

Clara cell 10-kDa protein inhibits TH17 responses through modulating dendritic cells in the setting of allergic rhinitis

T(H)17 responses have recently been implicated to play a role in allergic airway diseases, but their local expression in the setting of allergic rhinitis (AR) and their regulation in allergic airway diseases remain unclear. We sought to investigate the regulatory role of Clara cell 10-kDa protein (CC10), an endogenous regulator of airway inflammation, on T(H)17 responses in the setting of AR. Wild-type and homozygous CC10-null mice were used to establish an ovalbumin (OVA)-induced AR model. Human recombinant CC10 was given during sensitization or challenge. T(H)17 responses in human subjects and mice were examined by using flow cytometry, quantitative RT-PCR assay, immunohistochemistry, and ELISA. The direct effect of CC10 on T(H)17 cells and CD11c(+) dendritic cells (DCs) was studied by means of cell culture. Adoptive transfer was used to examine the influence of CC10-conditioned DCs on airway inflammation. The regulatory effect of CC10 on the expression of the CCL20 gene was tested by using the BEAS-2B cell line. Compared with those of control subjects, T(H)17 responses were enhanced in the nasal mucosa of patients with AR. CC10-null mice with AR showed enhanced T(H)17 responses, and CC10 treatment significantly decreased T(H)17 responses. CC10 had no direct effect on invitro T(H)17 cell differentiation. CC10 could significantly decrease the expression of OX40 ligand, IL-23, and IL-6 but enhance CD86 and TGF-β expression in DCs. Importantly, CC10 was able to inhibit T(H)17 cell polarization in the presence of OVA-pulsed DCs. CC10 pretreatment inhibited T(H)17 responses elicited by adoptive transfer of OVA-pulsed DCs. Furthermore, CC10 decreased the expression of CCL20 in BEAS-2B cells induced by inflammatory cytokines. T(H)17 responses are enhanced in patients with AR, and CC10 inhibits T(H)17 responses through modulation of the function of DCs.

Morphological and functional changes of epithelial cells in allergic rhinitis

Summary The functions of epithelial cells in the nose can be summarized as follows: (1) building a physical barrier to prevent allergens and foreign bodies from penetrating into the subepithelial layers; (2) secreting airway fluid by transepithelial ion transport and mucin production; and (3) responding to various stimuli by producing mediators that recruit lymphocytes, eosinophils, and mast cells to the nasal mucosa. However, in the setting of allergic rhinitis (AR) various morphological and functional changes occur in these cells, and the physical barrier of epithelial cells becomes vulnerable, which enables allergens to penetrate into the subepithelial layers. Histamine and thrombin are factors that influence the physical barrier. Although it is believed that epithelial damage in AR is less extensive than that in bronchial asthma, continued allergen exposure does damage epithelial cells in allergic animal models. Changes in ion transport during acute allergic reactions in vivo can be studied by nasal transepithelial potential difference. Comparison of nasal potential differences during pollen season has revealed lower values in allergic patients than in normal control subjects; the lowest value was reached 15 min after nasal allergen challenge. In vitro studies revealed that various factors including leukotrienes increase mucin gene transcription. These changes may lead to abnormalities of nasal secretion during allergic reactions.

Upregulation of Oncostatin M in Allergic Rhinitis

Oncostatin M is a multifunctional cytokine belonging to the interleukin-6 family of cytokines. It has been implicated as an important modulator of lower airway remodeling in the setting of asthma. However, there have been few studies regarding a similar role for the upper airway epithelium in the setting of allergic rhinitis. This study was undertaken to investigate the expression of oncostatin M mRNA and protein in normal and allergic rhinitis nasal mucosa and to localize the expression of the oncostatin M protein in allergic rhinitis. Inferior turbinate mucosa samples from 20 patients with perennial allergic rhinitis and 20 matched normal control subjects were obtained. Oncostatin M mRNA was extracted from the inferior turbinate mucosae, then reverse transcriptase-polymerase chain reaction was performed and analyzed semiquantitatively. Differences in expression levels of oncostatin M protein between samples from allergic rhinitis patients and normal control subjects were analyzed through Western blot, and oncostatin M protein was localized immunohistochemically. The expression levels of oncostatin M mRNA and protein were significantly upregulated in patients with allergic rhinitis mucosa. Oncostatin M protein was predominantly localized in the surface epithelium, infiltrating inflammatory cells, vascular endothelium, and submucosal glands and was more strongly expressed in the nasal mucosa of patients with allergic rhinitis than in normal control subjects. Oncostatin M is expressed in the human nasal mucosa and is upregulated in the setting of allergic nasal inflammation. These results suggest a possible contribution of oncostatin M in the remodeling of the nasal mucosa in allergic rhinitis.