Background: CD8 type 2 cytotoxic T (T2) cells undergo transcriptional reprogramming to IL-13 production in the presence of IL-4 to become potent, steroid-insensitive, pathogenic effector cells in asthmatic patients and in mice in a model of experimental asthma. However, no studies have described the effects of hypoxia exposure on T2 cell differentiation.
Objective: We determined the effects of hypoxia exposure on IL-13-producing CD8 T2 cells.
Methods: CD8 transgenic OT-1 cells differentiated with IL-2 and IL-4 (T2 cells) were exposed to normoxia (21% oxygen) or hypoxia (3% oxygen), and IL-13 production in vitro was monitored. After differentiation under these conditions, cells were adoptively transferred into CD8-deficient mice, and lung allergic responses, including airway hyperresponsiveness to inhaled methacholine, were assessed. The effects of pharmacologic inhibitors of hypoxia-inducible factor (HIF) 1α and HIF-2α were determined, as were responses in HIF-1α-deficient OT-1 cells.
Results: Under hypoxic conditioning, CD8 T2 cell differentiation was significantly enhanced, with increased numbers of IL-13 T cells and increased production of IL-13 in vitro. Adoptive transfer of T2 cells differentiated under hypoxic conditioning restored lung allergic responses in sensitized and challenged CD8-deficient recipients to a greater degree than seen in recipients of T2 cells differentiated under normoxic conditioning. Pharmacologic inhibition of HIF-1α or genetic manipulation to reduce HIF-1α expression reduced the hypoxia-enhanced differentiation of T2 cells, IL-13 production, and the capacity of transferred cells to restore lung allergic responses in vivo. IL-4-dependent, hypoxia-mediated increases in HIF-1α and T2 cell differentiation were shown to be mediated through activation of Janus kinase 1/3 and GATA-3.
Conclusions: Hypoxia enhances CD8 T2 cell-dependent airway hyperresponsiveness and inflammation through HIF-1α activation. These findings coupled with the known insensitivity of CD8 T cells to corticosteroids suggests that activation of the IL-4-HIF-1α-IL-13 axis might play a role in the development of steroid-refractory asthma.
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http://dx.doi.org/10.1016/j.jaci.2018.11.049 | DOI Listing |
Rev Alerg Mex
December 2024
Master's in economics, HS Pharmacoeconomic Research, Mexico City, Mexico.
Objective: to perform a cost-effectiveness analysis of asthma treatment with budesonide/formoterol against other treatment options used at Mexico's National Institute for Respiratory Diseases.
Methods: A complete economic evaluation of cost-effectiveness from a public health perspective, comparing the use of budesonide/formoterol as maintenance therapy with fluticasone/vilanterol in 103 female asthma patients managed at INER between 2015 and 2021.
Results: Average cost per patient was $743.
Clin Rev Allergy Immunol
December 2024
Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Olfactory dysfunction (OD) can have serious consequences as it hinders individuals from detecting important warning signals like smoke, spoiled food, and gas leaks. This can significantly impact their nutritional status, eating satisfaction, and overall quality of life. Allergic rhinitis (AR) is a common disease that greatly affects the quality of life and can lead to a decrease, distortion, or complete loss of olfactory ability.
View Article and Find Full Text PDFClin Rev Allergy Immunol
December 2024
Division of Allergy and Clinical Immunology, The Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Room 3B.71, Baltimore, MD, 21224, USA.
Asthma is a chronic airway inflammatory disease that affects millions globally. Although glucocorticoids are a mainstay of asthma treatment, a subset of patients show resistance to these therapies, resulting in poor disease control and increased morbidity. The complex mechanisms underlying steroid-resistant asthma (SRA) involve Th1 and Th17 lymphocyte activity, neutrophil recruitment, and NLRP3 inflammasome activation.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of North Dakota, Grand Forks, ND, USA.
Background: Alzheimer's disease (AD) is an age-related neurodegenerative disorder affecting nearly 50 million individuals worldwide. Besides aging, various comorbidities can increase the risk of AD, such as asthma. However, the molecular mechanism(s) underlying this asthma-associated AD exacerbation is unknown.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Centre for Precision Health, Edith Cowan University, Joondalup, Western Australia, Australia.
Background: Observational studies have suggested a co-occurring relationship between Alzheimer's disease (AD) and asthma. However, the aetiology and biological mechanisms underlying AD and its potential association with asthma, an autoimmune condition, remain unclear.
Method: We examine the genetic relationship between AD and asthma by analysing large-scale genome-wide association study (GWAS) summary data from international research consortia and groups.
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