Dual inhibition of airway inflammation and fibrosis by common ß cytokine receptor blockade.

BACKGROUND: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common ß (ßc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation. OBJECTIVE: To determine the pathogenesis of ßc receptor-mediated inflammation and remodeling in severe asthma and to investigate ßc antagonism as a therapeutic strategy for mixed granulocytic airway disease. METHODS: ßc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human ßc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of ßc was used to block ßc signaling. RESULTS: ßc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. CONCLUSIONS: ßc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-ßc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.

IgE receptor of mast cells signals mediator release and inflammation via adaptor protein 14-3-3ζ.

BACKGROUND: Mast cells (MCs) are tissue-resident immune cells that mediate IgE-dependent allergic responses. Downstream of FcεRI, an intricate network of receptor-specific signaling pathways and adaptor proteins govern MC function. The 14-3-3 family of serine-threonine phosphorylation-dependent adapter proteins are known to organize intracellular signaling. However, the role of 14-3-3 in IgE-dependent activation remains poorly defined. OBJECTIVE: We sought to determine whether 14-3-3 proteins are required for IgE-dependent MC activation and whether 14-3-3 is a viable target for the treatment of MC-mediated inflammatory diseases. METHODS: Genetic manipulation of 14-3-3ζ expression in human and mouse MCs was performed and IgE-dependent mediator release assessed. Pharmacologic inhibitors of 14-3-3 and 14-3-3ζ knockout mice were used to assess 14-3-3ζ function in a MC-dependent in vivo passive cutaneous anaphylaxis (PCA) model of allergic inflammation. Expression and function of 14-3-3ζ were assessed in human nasal polyp tissue MCs. RESULTS: IgE-dependent mediator release from human MCs was decreased by 14-3-3ζ knockdown and increased by 14-3-3ζ overexpression. Deletion of the 14-3-3ζ gene decreased IgE-dependent activation of mouse MCs in vitro and PCA responses in vivo. Furthermore, the 14-3-3 inhibitor, RB-11, which impairs dimerization of 14-3-3, inhibited cultured MC and polyp tissue MC activation and signaling downstream of the FcεRI receptor and dose-dependently attenuated PCA responses. CONCLUSION: IgE/FcεRI-mediated MC activation is positively regulated by 14-3-3ζ. We identify a critical role for this p-Ser/Thr-binding protein in the regulation of MC FcεRI signaling and IgE-dependent immune responses and show that this pathway may be amenable to pharmacologic targeting.

Translating the biology of ß common receptor-engaging cytokines into clinical medicine.

The family of cytokines that comprises IL-3, IL-5, and GM-CSF was discovered over 30 years ago, and their biological activities and resulting impact in clinical medicine has continued to expand ever since. Originally identified as bone marrow growth factors capable of acting on hemopoietic progenitor cells to induce their proliferation and differentiation into mature blood cells, these cytokines are also recognized as key mediators of inflammation and the pathobiology of diverse immunologic diseases. This increased understanding of the functional repertoire of IL-3, IL-5, and GM-CSF has led to an explosion of interest in modulating their functions for clinical management. Key to the successful clinical translation of this knowledge is the recognition that these cytokines act by engaging distinct dimeric receptors and that they share a common signaling subunit called ß-common or ßc. The structural determination of how IL-3, IL-5, and GM-CSF interact with their receptors and linking this to their differential biological functions on effector cells has unveiled new paradigms of cell signaling. This knowledge has paved the way for novel mAbs and other molecules as selective or pan inhibitors for use in different clinical settings.

Morphometric Analysis of the Cervical Canal Using Computed Tomography Scan Among Patients With Neck Pain in North India.

Introduction Cervical spinal stenosis is a common disease that results in considerable morbidity and disability. To avoid long-term disability caused by irreversible spinal cord damage, quick diagnosis and treatment are required. To our knowledge, until recently, there has been no report or study evaluating the cervical canal stenosis and associated facet joint arthrosis as the major cause of neck pain, so the current study used computed tomography (CT) scans to determine the prevalence of cervical canal stenosis and facet joint osteoarthrosis in patients who presented with neck pain, including its relationship with age, sex, and cervical spinal levels (C3-C7). Methods The current clinical descriptive cross-sectional study was conducted in the Department of Anatomy and Radiodiagnosis at Santosh Medical College, Ghaziabad, for a period of 24 months among newly diagnosed outpatient department (OPD) cases of neck pain (18 years or older) with suspected cervical canal stenosis and facet joint arthrosis. Clinical history, patient-specific clinical examination, and relevant information were obtained in a structured data collection schedule through interviews during OPD hours. All of the participants underwent a CT scan of the cervical region. The independent factors (age, gender, height, and weight) were used in a multiple linear regression analysis of neck pain grading, Torg ratio (TR), and right and left facet joint degeneration, which were expressed as R-squared (R2) and adjusted R-squared (aR2). Statistical tests were executed at a 5% level of significance; an association was considered significant if the p-value was <0.05. Results A total of 83 subjects were enrolled in this study with equal representation from both sexes, i.e., males (49.4%) and females (50.6%). The transverse vertebral canal (T-VC) diameter was narrowest at the level of C3 (25.00 ± 1.13) and gradually increased at the level of C6 (25.18 ± 1.14) in this study. The mean TR of cervical vertebrae C3-C4 dropped gradually from C3 (0.78 ± 0.05) to C7 (0.76 ± 0.05) in this study. Severe left and right facet joint degeneration were observed in 13.3% and 10.5% of study subjects, respectively. In almost every subject, neck pain was a neurological symptom, so multiple linear regression analysis of neck pain grading was carried out with the independent variables (age, gender, height, and weight) and it was found to be not significant (R2 = 0.0617, aR2 = 0.0136, p = 0.2842). Conclusion The articulations of the posterior arch of the vertebrae are known as facet joints. They are a vital component of the vertebral column's structural stability. The superior and inner articular facets of the vertebrae are joined by these joints, which are encased in a fibrous capsule.

Targeting the Human ßc Receptor Inhibits Contact Dermatitis in a Transgenic Mouse Model.

Allergic contact dermatitis (ACD) is a prevalent and poorly controlled inflammatory disease caused by skin infiltration of T cells and granulocytes. The beta common (ßc) cytokines GM-CSF, IL-3, and IL-5 are powerful regulators of granulocyte function that signal through their common receptor subunit ßc, a property that has made ßc an attractive target to simultaneously inhibit these cytokines. However, the species specificity of ßc has precluded testing of inhibitors of human ßc in mouse models. To overcome this problem, we developed a human ßc receptor transgenic mouse strain with a hematopoietic cell‒specific expression of human ßc instead of mouse ßc. Human ßc receptor transgenic cells responded to mouse GM-CSF and IL-5 but not to IL-3 in vitro and developed tissue pathology and cellular inflammation comparable with those in wild-type mice in a model of ACD. Similarly, Il3-/- mice developed ACD pathology comparable with that of wild-type mice. Importantly, the blocking anti-human ßc antibody CSL311 strongly suppressed ear pinna thickening and histopathological changes typical of ACD and reduced accumulation of neutrophils, mast cells, and eosinophils in the skin. These results show that GM-CSF and IL-5 but not IL-3 are major mediators of ACD and define the human ßc receptor transgenic mouse as a unique platform to test the inhibitors of ßc in vivo.

Understanding mast cell heterogeneity at single cell resolution.

Mast cells (MC)s are evolutionarily conserved, tissue-resident immune cells with diverse roles in allergy, cancer, and protection from infection by helminths and microorganisms. The significant diversity in MC development and tissue-specific functional characteristics has recently begun to be understood. Exciting developments in single-cell-based RNA, protein, and chromatin profiling technologies offer new opportunities to characterize MC heterogeneity and to uncover novel MC functions and subtypes; these developments might lead to new and clinically effective therapies for certain pathologies. In this review, we provide an overview of the current understanding of MC development and heterogeneity and discuss new insights gained from single-cell-based studies that may lead to future research directions and therapeutic opportunities.

AIM2 nuclear exit and inflammasome activation in chronic obstructive pulmonary disease and response to cigarette smoke.

INTRODUCTION: The role inflammasomes play in chronic obstructive pulmonary disease (COPD) is unclear. We hypothesised that the AIM2 inflammasome is activated in the airways of COPD patients, and in response to cigarette smoke. METHODS: Lung tissue, bronchoscopy-derived alveolar macrophages and bronchial epithelial cells from COPD patients and healthy donors; lungs from cigarette smoke-exposed mice; and cigarette smoke extract-stimulated alveolar macrophages from healthy controls and HBEC30KT cell line were investigated. AIM2 inflammasome activation was assessed by multi-fluorescence quantitative confocal microscopy of speck foci positive for AIM2, inflammasome component ASC and cleaved IL-1ß. Subcellular AIM2 localization was assessed by confocal microscopy, and immunoblot of fractionated cell lysates. Nuclear localization was supported by in-silico analysis of nuclear localization predicted scores of peptide sequences. Nuclear and cytoplasmic AIM2 was demonstrated by immunoblot in both cellular fractions from HBEC30KT cells. RESULTS: Increased cytoplasmic AIM2 speck foci, colocalized with cleaved IL-1ß, were demonstrated in COPD lungs (n = 9) vs. control (n = 5), showing significant positive correlations with GOLD stages. AIM2 nuclear-to-cytoplasmic redistribution was demonstrated in bronchiolar epithelium in cigarette-exposed mice and in HBEC30KT cells post 24 h stimulation with 5% cigarette smoke extract. Alveolar macrophages from 8 healthy non-smokers responded to cigarette smoke extract with an > 8-fold increase (p < 0.05) of cytoplasmic AIM2 and > 6-fold increase (p < 0.01) of colocalized cleaved IL-1ß speck foci, which were also localized with ASC. CONCLUSION: The AIM2 inflammasome is activated in the airway of COPD patients, and in response to cigarette smoke exposure, associated with a nuclear to cytoplasmic shift in the distribution of AIM2.

Short-term Oral Steroids Significantly Improves Chronic Rhinosinusitis Without Nasal Polyps.

OBJECTIVES/HYPOTHESIS: The efficacy of short-term oral corticosteroids in chronic rhinosinusitis without nasal polyps (CRSsNP) is unknown. The aim of this controlled study was to assess the immediate and long-term outcomes from a short course of a commonly used oral corticosteroid, prednisolone, in well-defined CRSsNP patients. STUDY DESIGN: Prospective, observational controlled study. METHODS: A prospective-controlled study of CRSsNP patients treated with prednisolone at 0.5 mg/kg tapered over 10 days and non-prednisolone treated CRSsNP patients (controls) and follow-up at 2, 6, and 12 months. Baseline and follow-up SinoNasal Outcome Test (SNOT)-22, nasal endoscopy (Lund-Kennedy), and sinus CT scan scores (Lund-Mackay) were compared. RESULTS: At 2 months, there was a significant improvement in the SNOT-22, nasal endoscopy, and sinus CT scan scores in the prednisolone group (P < .0001) compared with controls (p = ns, Mann-Whitney U test). 52.5% of prednisolone-treated CRSsNP patients had improved symptoms and did not require sinus surgery at 12 months compared with 14.3% of controls (P < .001). Side-effects were reported in 8.9% of prednisolone-treated patients. Patients who benefited from prednisolone had a median symptom duration of 7.25 (99% confidence, upper limit of 11) months compared with 18 months in those requiring surgery. CONCLUSIONS: Short-term oral prednisolone significantly improved all three clinical measures of disease in CRSsNP patients and avoided surgical intervention in 52.5% patients in the first 12 months. Patients with symptoms for less than 11 months were most likely to benefit. The side-effects of oral steroids require careful consideration and further studies are needed to ascertain appropriate dosage and treatment duration. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2618-E2626, 2021.

Genome-wide Analyses of Chromatin State in Human Mast Cells Reveal Molecular Drivers and Mediators of Allergic and Inflammatory Diseases.

Mast cells (MCs) are versatile immune cells capable of rapidly responding to a diverse range of extracellular cues. Here, we mapped the genomic and transcriptomic changes in human MCs upon diverse stimuli. Our analyses revealed broad H3K4me3 domains and enhancers associated with activation. Notably, the rise of intracellular calcium concentration upon immunoglobulin E (IgE)-mediated crosslinking of the high-affinity IgE receptor (FcεRI) resulted in genome-wide reorganization of the chromatin landscape and was associated with a specific chromatin signature, which we term Ca2+-dependent open chromatin (COC) domains. Examination of differentially expressed genes revealed potential effectors of MC function, and we provide evidence for fibrinogen-like protein 2 (FGL2) as an MC mediator with potential relevance in chronic spontaneous urticaria. Disease-associated single-nucleotide polymorphisms mapped onto cis-regulatory regions of human MCs suggest that MC function may impact a broad range of pathologies. The datasets presented here constitute a resource for the further study of MC function.

The role of invariant T cells in inflammation of the skin and airways.

Invariant and semi-invariant T cells are emerging as important regulators of host environment interactions at barrier tissues such as the airway and skin. In contrast to conventional T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells express T cell receptors of very limited diversity. iNKT and MAIT cells recognise antigens presented by the MHC class 1-like monomorphic molecules CD1d and MR1, respectively. Both iNKT cells and MAIT cells have been identified in the skin and airways and can rapidly produce cytokines after activation. Numerous studies have implicated iNKT cells in the pathology of both skin and airway disease, but conflicting evidence in human disease means that more studies are necessary to resolve the exact roles of iNKT in inflammation. The functions of MAIT cells in skin and lung inflammation are even less well defined. We herein describe the current literature on iNKT and MAIT cells in allergic and non-allergic skin diseases (dermatitis and psoriasis) and airway diseases (asthma, chronic obstructive pulmonary disease, rhinitis, and chronic rhinosinusitis).

Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology.

BACKGROUND: Natural killer T (NKT) cells express a T-cell receptor that recognizes endogenous and environmental glycolipid antigens. Several subsets of NKT cells have been identified, including IFN-γ-producing NKT1 cells, IL-4-producing NKT2 cells, and IL-17-producing NKT17 cells. However, little is known about the factors that regulate their differentiation and respective functions within the immune system. OBJECTIVE: We sought to determine whether the polycomb repressive complex 2 protein enhancer of zeste homolog 2 (Ezh2) restrains pathogenicity of NKT cells in the context of asthma-like lung disease. METHODS: Numbers of invariant natural killer T (iNKT) 1, iNKT2, and iNKT17 cells and tissue distribution, cytokine production, lymphoid tissue localization, and transcriptional profiles of iNKT cells from wild-type and Ezh2 knockout (KO) iNKT mice were determined. The contribution of NKT cells to development of spontaneous and house dust mite-induced airways pathology, including airways hyperreactivity (AHR) to methacholine, was also assessed in wild-type, Ezh2 KO, and Ezh2 KO mice lacking NKT cells. RESULTS: Ezh2 restrains development of pathogenic NKT cells, which induce spontaneous asthma-like disease in mice. Deletion of Ezh2 increased production of IL-4 and IL-13 and induced spontaneous AHR, lung inflammation, mucus production, and IgE. Increased IL-4 and IL-13 levels, AHR, lung inflammation, and IgE levels were all dependent on iNKT cells. In house dust mite-exposed animals Ezh2 KO resulted in enhanced AHR that was also dependent on iNKT cells. CONCLUSION: Ezh2 is a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology.

The transcriptional program, functional heterogeneity, and clinical targeting of mast cells.

Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen-immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions. We bring to light recent discoveries and developments in mast cell research, including regulation of mast cell functions, differentiation, survival, and novel mouse models. Finally, we highlight the current and future opportunities for therapeutic intervention of mast cell functions in inflammatory diseases.

Hemostasis in Endoscopic Sinus Surgery.

Intraoperative bleeding during endoscopic sinus surgery poses an additional dimension to an already technically challenging surgical approach because of the narrow sinonasal surgical field, single working hand, and the use of endoscopic instruments. Poor visualization is one of the most important factors that increase the risk of intraoperative complications such as inadvertent injury to major vessels and nerves, and incomplete surgery. This article provide a logical approach to improving the surgical field, minimizing risk of inadvertent vascular injury, and managing intraoperative bleeding.

Endoscopic Management of Vascular Sinonasal Tumors, Including Angiofibroma.

The greatest challenge in the surgical treatment of angiofibromas is dealing with the hypervascularity of these tumors. Staging systems that take into account the vascularity of the tumor may be more prognostic. A variety of treatment strategies are used to deal with the vascularity of angiofibromas, including preoperative embolization, segmentation of the tumor into vascular territories, use of hemostatic tools, and staging of surgery. Even large angiofibromas with intracranial extension and residual vascularity can be successfully managed by a skull base team using endoscopic techniques.

CD4(+) and CD8(+) regulatory T cells in chronic rhinosinusitis mucosa.

BACKGROUND: Chronic rhinosinusitis (CRS) mucosal inflammation is characterized by an accumulation of effector-memory T cells, but their immune regulatory potential has not been adequately examined. Coexpression of transcription factor, forkhead box P3 (Foxp3), and interleukin-2 receptor, CD25, in CD4(+) and CD8(+) T cells is linked with regulatory function in humans. The aim of this study was to investigate the regulatory T cell (Treg) phenotype of CD4(+) (CD4Treg) and CD8(+) (CD8Treg) T cells in peripheral blood (PB) and sinus mucosa of CRS patients. METHODS: Prospective study was performed involving 32 CRS with nasal polyp (CRSwNP), 14 CRS without nasal polyp (CRSsNP), and 8 control patients. Sinus and PB T lymphocytes were stained with CD3, CD4, CD8, CD25, and Foxp3 and analyzed using flow cytometry. Relevant clinical characteristics, sinus bacterial culture results, and eosinophilic mucus were examined. RESULTS: Sinus mucosa had a higher percentage of CD4Treg (CD3(+)CD4(+)CD25(+)Foxp3(+)) population compared with PB in all patients. The percentage of PB CD4Treg and CD8Treg (CD3(+)CD8(+)CD25(+)Foxp3(+)) was not significantly different between the study groups. CRS mucosal tissue had a higher percentage of CD4Treg and activated T-helper cells than controls. There was no significant difference in PB and mucosal CD4Treg populations in CRS patients based on the presence of allergy, sinus culture results, or eosinophilic mucus. In controls, increased mucosal CD4Treg correlated with coexisting allergy. Although overall CD4Treg numbers were higher, the regulatory potential of activated CD4(+) T cells (CD4Treg/activated T-helper cell ratio) was significantly lower in CRS mucosa compared with controls. The CD8Treg subset was also significantly reduced in CRSwNP mucosa compared with controls. CONCLUSION: A higher percentage of CD4Treg and activated T-helper cells in CRS mucosa suggests increased inflammation in CRS, independent of the presence of allergy, microbial culture results, or eosinophilic mucus. However, the decreased ratio of CD4Treg versus activated T-helper cells in CRS and reduced CD8Treg population in CRSwNPs indicates an inflammatory bias and the inability to control mucosal disease.

CD8(+) T cells implicated in the pathogenesis of allergic fungal rhinosinusitis.

Fungi in paranasal sinuses are characteristic and considered a major pathogenic factor in a subset of chronic rhinosinusitis (CRS) patients, known as allergic fungal rhinosinusitis (AFRS). CD8(+) T cells are enriched in AFRS sinuses but their role in fungal-specific responses is unknown. Alternaria alternata- and Aspergillus fumigatus-specific T lymphocyte responses were investigated in 6 AFRS patients, 10 eosinophilic mucus CRS (EMCRS) patients, 10 CRS with nasal polyps (CRSwNPs) patients, 6 allergic rhinitis with fungal allergy (ARFA) patients, and five controls. Fungal-specific proliferation of human peripheral blood mononuclear cells (PBMCs) was studied prospectively. Proliferating cells were examined for CD3, CD4, CD8, and CD25 expression. Relevant clinical characteristics, fungal allergy, detection of fungi in sinuses, and CD4(+) and CD8(+) composition of sinus T cells were also examined. CD4(+) T-cell division to fungi occurred in all samples, regardless of fungal allergy or CRS. Fungal-specific CD8(+) T-cell division occurred in all ARFA and control samples and the majority of CRSwNP patients; however, CD8(+) T cells failed to proliferate in AFRS and EMCRS patients. The CD8(+) T cells from AFRS patients also did not up-regulate the activation marker, CD25, with fungal antigen exposure. Presence of A. alternata- and A. fumigatus-specific CD4(+) and CD8(+) T-cell proliferation in healthy individuals, ARFA, and CRSwNP patients suggests that both T-cell subsets may be important in immune responses to these fungi. In AFRS and EMCRS patients, only fungal-specific CD4(+) T-cell proliferation occurred; hence, a lack of CD8(+) T-cell proliferation and activation in the presence of sinus eosinophilic mucus in these patients, regardless of fungal allergy, is a novel finding. This raises the question whether a dysfunctional CD8(+) T-cell response predisposes to ineffective clearance and accumulation of fungi in the sinuses of susceptible patients.

CD4+ and CD8+ regulatory T cells in chronic rhinosinusitis mucosa.

BACKGROUND: Chronic rhinosinusitis (CRS) mucosal inflammation is characterized by an accumulation of effector-memory T cells, but their immune regulatory potential has not been adequately examined. Coexpression of transcription factor, forkhead box P3 (Foxp3), and interleukin-2 receptor, CD25, in CD4+ and CD8+ T cells is linked with regulatory function in humans. The aim of this study was to investigate the regulatory T cell (Treg) phenotype of CD4+ (CD4Treg) and CD8+ (CD8Treg) T cells in peripheral blood (PB) and sinus mucosa of CRS patients. METHODS: Prospective study was performed involving 32 CRS with nasal polyp (CRSwNP), 14 CRS without nasal polyp (CRSsNP), and 8 control patients. Sinus and PB T lymphocytes were stained with CD3, CD4, CD8, CD25, and Foxp3 and analyzed using flow cytometry. Relevant clinical characteristics, sinus bacterial culture results, and eosinophilic mucus were examined. RESULTS: Sinus mucosa had a higher percentage of CD4Treg (CD3+CD4+CD25+Foxp3+) population compared with PB in all patients. The percentage of PB CD4Treg and CD8Treg (CD3+CD8+CD25+Foxp3+) was not significantly different between the study groups. CRS mucosal tissue had a higher percentage of CD4Treg and activated T-helper cells than controls. There was no significant difference in PB and mucosal CD4Treg populations in CRS patients based on the presence of allergy, sinus culture results, or eosinophilic mucus. In controls, increased mucosal CD4Treg correlated with coexisting allergy. Although overall CD4Treg numbers were higher, the regulatory potential of activated CD4+ T cells (CD4Treg/activated T-helper cell ratio) was significantly lower in CRS mucosa compared with controls. The CD8Treg subset was also significantly reduced in CRSwNP mucosa compared with controls. CONCLUSION: A higher percentage of CD4Treg and activated T-helper cells in CRS mucosa suggests increased inflammation in CRS, independent of the presence of allergy, microbial culture results, or eosinophilic mucus. However, the decreased ratio of CD4Treg versus activated T-helper cells in CRS and reduced CD8Treg population in CRSwNPs indicates an inflammatory bias and the inability to control mucosal disease.