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1.
Nat Immunol ; 25(5): 902-915, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38589618

RESUMEN

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.


Asunto(s)
Factor Nuclear 1-alfa del Hepatocito , Hipersensibilidad , Factor de Unión 1 al Potenciador Linfoide , Células Madre Multipotentes , Factor 1 de Transcripción de Linfocitos T , Células Th2 , Humanos , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Factor de Unión 1 al Potenciador Linfoide/genética , Células Th2/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Hipersensibilidad/inmunología , Células Madre Multipotentes/metabolismo , Células Madre Multipotentes/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Diferenciación Celular , Citocinas/metabolismo , Linfopoyetina del Estroma Tímico , Animales , Células Cultivadas , Ratones
2.
J Allergy Clin Immunol ; 153(2): 527-532, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37898408

RESUMEN

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis. OBJECTIVE: We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP. METHODS: NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing. RESULTS: Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA, IGHE, and cell cycle- and proliferation-related transcripts (CCND2, MKI67, CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes. CONCLUSION: NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP.


Asunto(s)
Asma Inducida por Aspirina , Pólipos Nasales , Rinitis , Sinusitis , Humanos , Pólipos Nasales/metabolismo , Interleucina-5 , Rinitis/metabolismo , Asma Inducida por Aspirina/metabolismo , Aspirina/efectos adversos , Enfermedad Crónica , Células Productoras de Anticuerpos/metabolismo , Sinusitis/metabolismo , Proliferación Celular , Proteínas de Neoplasias , Proteínas Tirosina Fosfatasas
3.
bioRxiv ; 2023 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-37904989

RESUMEN

Background: The airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood. Objective: We hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation. Methods: Ethmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and ex vivo functional analysis of sinus EpCs were used to validate our findings. Results: Analysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and ex vivo inhibition demonstrated that mTOR is critical for EpC generation of CXCL8, IL-33, and CXCL2. Across patient samples, the degree of glycolytic activity was associated with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in severe asthma. Conclusions: Together, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma.

4.
Artículo en Inglés | MEDLINE | ID: mdl-37742089

RESUMEN

KEY POINTS: Mast cell numbers were reduced in samples cryopreserved as whole tissue chunks. Thawed epithelial cells had reduced proliferation rates when preserved as dissociated cell suspensions. The right cryopreservation method to choose may depend on the goals and cell-type focus of the project.

6.
J Allergy Clin Immunol ; 151(6): 1536-1549, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36804595

RESUMEN

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown. OBJECTIVE: We sought to determine the role of T2 cytokines in regulating airway BCs. METHODS: Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration. RESULTS: Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhi BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/IL-13 increases the expression of BCAM and TP63 through an insulin receptor substrate-dependent signaling pathway that is increased in CRSwNP. CONCLUSIONS: These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.


Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Humanos , Animales , Ratones , Receptor de Insulina/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Inflamación/metabolismo , Sinusitis/metabolismo , Células Epiteliales/metabolismo , Transducción de Señal , Enfermedad Crónica , Pólipos Nasales/metabolismo , Rinitis/metabolismo
8.
Otol Neurotol Open ; 1(2): e004, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38550356

RESUMEN

Objective: To evaluate whether augmented reality microscopy surgical fluorescence technology, already Food and Drug Administration approved for vascular neurosurgery, can aid in lateral skull base surgery during cerebellopontine (CPA) tumor resection and microvascular decompression. Study Design: Pilot prospective uncontrolled observational cohort study. Setting: An academic tertiary care hospital. Patients: Those who underwent retrosigmoid craniotomy for CPA tumor resection or microvascular decompression for hemifacial spasm, trigeminal neuralgia or pulsatile tinnitus. 11 patients were recruited: 4 underwent CPA tumor resection and 7 underwent microvascular decompression. Interventions: Augmented reality microscopy with fluorescence imaging was utilized to visualize vascular flow intraoperatively. A postoperative surgeon questionnaire was administered to assess the intraoperative efficacy of this technology. Main Outcome Measures: Efficacy of technology in aiding with CPA tumor resection and microvascular decompression. Results: For all 7 microvascular decompression cases, surgeons agreed that the technology aided in identifying areas where disease was affecting tissues with no cases of vascular occlusion identified. In 3 of the 4 CPA tumor resection cases, surgeons agreed that the technology identified areas of vascular flow within the CPA and the tumor. Vascular patency of the sigmoid-transverse sinus was also confirmed. No significant adverse effects were noted except 1 instance of severe-to-profound sensorineural hearing loss. Conclusions: Our study shows that the augmented reality fluorescence technology works during lateral skull base surgery as it can confirm intraoperative vascular integrity. Our data also suggest that this technology may improve visualization of ambiguous vasculature and blood flow to diseased tissue.

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