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Recent evidence has demonstrated that both acute and chronic exposure to particulate air pollution are risk factors for respiratory tract infections and increased mortality from sepsis. There is therefore an urgent need to establish the impact of ambient particulate matter (PM) on innate immune cells and to establish potential strategies to mitigate against adverse effects. PM has previously been reported to have potential adverse effects on neutrophil function. In the present study, we investigated the impact of standard urban PM (SRM1648a, NIST) and PM2.5 collected from Chiang Mai, Thailand, on human peripheral blood neutrophil functions, including LPS-induced migration, IL-8 production, and bacterial killing. Both NIST and the PM2.5, being collected in Chiang Mai, Thailand, increased IL-8 production, but reduced CXCR2 expression and migration of human primary neutrophils stimulated with Escherichia coli LPS. Moreover, PM-pretreated neutrophils from vitamin D-insufficient participants showed reduced E. coli-killing activity. Furthermore, in vitro vitamin D3 supplementation attenuated IL-8 production and improved bacterial killing by cells from vitamin D-insufficient participants. Our findings suggest that provision of vitamin D to individuals with insufficiency may attenuate adverse acute neutrophilic responses to ambient PM.
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Colecalciferol , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Colecalciferol/farmacología , Neutrófilos , Escherichia coli , Interleucina-8 , Lipopolisacáridos , Vitamina D , VitaminasRESUMEN
Background: Vitamin D upregulates anti-inflammatory and antimicrobial pathways that promote respiratory health. Vitamin D synthesis is initiated following skin exposure to sunlight, however nutritional supplementation can be required to address deficiency, for example during the winter months or due to cultural constraints. We recently reported that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment induced alpha-1 antitrypsin (AAT) expression in CD4+, but not CD8+ T cells, with evidence supporting an immunoregulatory role. Research Question: To understand the relationship between vitamin D, lung AAT levels and T lymphocytes further we investigated whether TGF-ß is required as a co-factor for 1,25(OH)2D3-induced upregulation of AAT by vitamin D in CD8+ T cells in vitro and correlated circulating vitamin D levels with lung AAT levels in vivo. Results: 1,25(OH)2D3 in combination with TGF-ß1 increased AAT expression by CD8+ T cells, as well as VDR and RXRα gene expression, which may partly explain the requirement for TGF-ß. CD4+ T cells may also require autocrine stimulation with TGF-ß as a co-factor since 1,25(OH)2D3 was associated with increased TGF-ß bioactivity and neutralisation of TGF-ß partially abrogated 1,25(OH)2D3-induced SERPINA1 gene expression. Neither CD4+ nor CD8+ T cells responded to the circulating vitamin D precursor, 25-hydroxyvitamin D3 for induction of SERPINA1, suggesting that local generation of 1,25(OH)2D3 is required. Transcriptional gene profiling studies previously demonstrated that human bronchial epithelial cells rapidly increased TGF-ß2 gene expression in response to 1,25(OH)2D3. Here, human epithelial cells responded to precursor 25(OH)D3 to increase bioactive TGF-ß synthesis. CD8+ T cells responded comparably to TGF-ß1 and TGF-ß2 to increase 1,25(OH)2D3-induced AAT. However, CD8+ T cells from adults with AAT-deficiency, homozygous for the Z allele of SERPINA1, were unable to mount this response. AAT levels in the airways of children with asthma and controls correlated with circulating 25(OH)D3. Conclusions: Vitamin D increases AAT expression in human T cells and this response is impaired in T cells from individuals homozygous for the Z allele of SERPINA1 in a clinic population. Furthermore, a correlation between circulating vitamin D and airway AAT is reported. We propose that vitamin D-induced AAT contributes to local immunomodulation and airway health effects previously attributed to vitamin D.
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BACKGROUND: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412). CONCLUSIONS: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.
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Terapia de Reemplazo de Estrógeno/estadística & datos numéricos , Estrógenos/uso terapéutico , Menopausia/fisiología , Progestinas/uso terapéutico , Salud de la Mujer/estadística & datos numéricos , Femenino , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: The impact of hormone replacement therapy (HRT) on clinical outcomes in menopausal women is uncertain. OBJECTIVE: To investigate the association between use of HRT and severe asthma exacerbation in perimenopausal and postmenopausal women with asthma. METHODS: We used the Optimum Patient Care Research Database, a population-based longitudinal primary care database in the United Kingdom, to construct a 17-year (January 1, 2000, to December 31, 2016) cohort of perimenopausal and postmenopausal (46-70 years, N = 31,656) women. We defined use of HRT, its subtypes, and duration of HRT use. Severe asthma exacerbation was defined as an asthma-related hospitalization, emergency department visits due to asthma, and/or prescription of oral corticosteroids. Analyses were undertaken using multilevel mixed-effects Poisson regression. RESULTS: At baseline, 22% of women were using any HRT, 11% combined HRT, and 11% estrogen-only HRT. Previous, but not current, use of any (incidence rate ratio [IRR]: 1.24, 95% confidence interval [CI]: 1.22-1.26), combined (IRR: 1.28, 95% CI: 1.25-1.31), and estrogen-only HRT (IRR: 1.18, 95% CI: 1.14-1.21), and longer duration (1-2 years: IRR: 1.16, 95% CI: 1.13-1.19; 3-4 years: IRR: 1.43, 95% CI: 1.38-1.48; 5+ years: IRR: 1.32, 95% CI: 1.28-1.36) of HRT use were associated with increased risk of severe asthma exacerbation compared with nonuse. The risk estimates were greater among lean women (body mass index [BMI] <25 kg/m2) than among heavier women (BMI 25-29.9 kg/m2 and ≥30 kg/m2) and higher among smokers than nonsmokers. CONCLUSION: Use of HRT and subtypes, particularly previous, but not current, use and use for more than 2 years, is associated with an increased risk of severe asthma exacerbation in perimenopausal/postmenopausal women with established asthma. Lean women and smokers are at greater risk than heavier women and nonsmokers, respectively.
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Asma , Posmenopausia , Asma/tratamiento farmacológico , Asma/epidemiología , Estudios de Cohortes , Femenino , Terapia de Reemplazo de Hormonas , Humanos , Perimenopausia , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: There is uncertainty about the role of hormonal replacement therapy (HRT) in the development of asthma. OBJECTIVE: We investigated whether use of HRT and duration of use was associated with risk of development of asthma in perimenopausal and postmenopausal women. METHODS: We constructed a 17-year (from January 1, 2000, to December 31, 2016) open cohort of 353,173 women (aged 46-70 years) from the Optimum Patient Care Database, a longitudinal primary care database from across the United Kingdom. HRT use, subtypes, and duration of use; confounding variables; and asthma onset were defined by using the Read Clinical Classification System. We fitted multilevel Cox regression models to estimate hazard ratios (HRs) with 95% CIs. RESULTS: During the 17-year follow-up (1,340,423 person years), 7,614 new asthma cases occurred, giving an incidence rate of 5.7 (95% CI = 5.5-5.8) per 1,000 person years. Compared with nonuse of HRT, previous use of any (HR = 0.83; 95% CI = 0.76-0.88), estrogen-only (HR = 0.89; 95% CI = 0.84-0.95), or combined estrogen and progestogen (HR = 0.82; 95% CI = 0.76-0.88) HRT was associated with a reduced risk of asthma onset. This was also the case with current use of any (HR = 0.79; 95% CI = 0.74-0.85), estrogen-only (HR = 0.80; 95% CI = 0.73-0.87), and combined estrogen and progestogen (HR = 0.78; 95% CI = 0.70-0.87) HRT. Longer duration of HRT use (1-2 years [HR = 0.93; 95% CI = 0.87-0.99]; 3-4 years [HR = 0.77; 95% CI = 0.70-0.84]; and ≥5 years [HR = 0.71; 95% CI = 0.64-0.78]) was associated with a dose-response reduced risk of asthma onset. CONCLUSION: We found that HRT was associated with a reduced risk of development of late onset asthma in menopausal women. Further cohort studies are needed to confirm these findings.
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Asma/epidemiología , Terapia de Reemplazo de Hormonas , Menopausia , Anciano , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Longitudinal studies investigating impact of exogenous sex steroids on clinical outcomes of asthma in women are lacking. We investigated the association between use of hormonal contraceptives and risk of severe asthma exacerbation in reproductive-age women with asthma. METHODS: We used the Optimum Patient Care Research Database, a population-based, longitudinal, anonymised primary care database in the UK, to construct a 17-year (1 January 2000-31 December 2016) retrospective cohort of reproductive-age (16-45 years, n=83 084) women with asthma. Using Read codes, we defined use, subtypes and duration of use of hormonal contraceptives. Severe asthma exacerbation was defined according to recommendations of the European Respiratory Society/American Thoracic Society as asthma-related hospitalisation, accident and emergency department visits due to asthma and/or oral corticosteroid prescriptions. Analyses were done using multilevel mixed-effects Poisson regression with QR decomposition. RESULTS: The 17-year follow-up resulted in 456 803 person-years of follow-up time. At baseline, 34% of women were using any hormonal contraceptives, 25% combined (oestrogen/progestogen) and 9% progestogen-only contraceptives. Previous (incidence rate ratio (IRR) 0.94, 95% CI 0.92 to 0.97) and current (IRR 0.96, 95% CI 0.94 to 0.98) use of any, previous (IRR 0.92, 95% CI 0.87 to 0.97) and current use of combined (IRR 0.93, 95% CI 0.91 to 0.96) and longer duration of use (3-4 years: IRR 0.94, 95% CI 0.92 to 0.97; 5+ years: IRR 0.91, 95% CI 0.89 to 0.93) of hormonal contraceptives, but not progestogen-only contraceptives, were associated with reduced risk of severe asthma exacerbation compared with non-use. CONCLUSIONS: Use of hormonal contraceptives may reduce the risk of severe asthma exacerbation in reproductive-age women. Mechanistic studies investigating the biological basis for the influence of hormonal contraceptives on clinical outcomes of asthma in women are required. PROTOCOL REGISTRATION NUMBER: European Union electronic Register of Post-Authorisation Studies (EUPAS22967).
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Asma/fisiopatología , Anticoncepción Hormonal , Brote de los Síntomas , Adolescente , Adulto , Asma/epidemiología , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Reino UnidoRESUMEN
Allergens induce type-2 immunity, but unresolved questions remain about initiation of this response. In this issue, Perner et al. propose that cutaneous activation of TRPV1+ sensory neurons by protease allergens stimulates release of substance P to induce migration of Th2-skewing CD301b+ DC to draining lymph nodes.
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Alérgenos , Sustancia P , Movimiento Celular , Células Dendríticas/inmunología , Inmunidad , Células Receptoras Sensoriales , Células Th2/inmunologíaRESUMEN
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BACKGROUND: Despite well-described sex differences in asthma incidence, there remains uncertainty about the role of female sex hormones in the development of asthma. OBJECTIVE: We sought to investigate whether hormonal contraceptive use, its subtypes, and duration of use were associated with new-onset asthma in reproductive-age women. METHODS: Using the Optimum Patient Care Research Database, a UK national primary care database, we constructed an open cohort of 16- to 45-year-old women (N = 564,896) followed for up to 17 years (ie, January 1, 2000, to December 31, 2016). We fitted multilevel Cox regression models to analyze the data. RESULTS: At baseline, 26% of women were using any hormonal contraceptives. During follow-up (3,597,146 person-years), 25,288 women developed asthma, an incidence rate of 7.0 (95% CI, 6.9-7.1) per 1000 person-years. Compared with nonuse, previous use of any hormonal contraceptives (hazard ratio [HR], 0.70; 95% CI, 0.68-0.72), combined (HR, 0.70; 95% CI, 0.68-0.72), and progestogen-only therapy (HR, 0.70; 95% CI, 0.67-0.74) was associated with reduced risk of new-onset asthma. For current use, the estimates were as follows: any (HR, 0.63; 95% CI, 0.61-0.65), combined (HR, 0.65; 95% CI, 0.62-0.67), and progestogen-only therapy (HR, 0.59; 95% CI, 0.56-0.62). Longer duration of use (1-2 years: HR, 0.83; 95% CI, 0.81-0.86; 3-4 years: HR, 0.64; 95% CI, 0.61-0.67; 5+ years: HR, 0.46; 95% CI, 0.44-0.49) was associated with a lower risk of asthma onset than nonuse. CONCLUSIONS: Hormonal contraceptive use was associated with reduced risk of new-onset asthma in women of reproductive age. Mechanistic investigations to uncover the biological processes for these observations are required. Clinical trials investigating the safety and effectiveness of hormonal contraceptives for primary prevention of asthma will be helpful to confirm these results.
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Asma/epidemiología , Agentes Anticonceptivos Hormonales/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Adolescente , Adulto , Asma/etiología , Estudios de Cohortes , Agentes Anticonceptivos Hormonales/efectos adversos , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Grupos de Población , Reproducción , Reino Unido/epidemiología , Adulto JovenRESUMEN
A well-functioning immune system is vital for a healthy body. Inadequate and excessive immune responses underlie diverse pathologies such as serious infections, metastatic malignancies and auto-immune conditions. Therefore, understanding the effects of ambient pollutants on the immune system is vital to understanding how pollution causes disease, and how that pathology could be abrogated. The immune system itself consists of multiple types of immune cell that act together to generate (or fail to generate) immune responses and in this article we review evidence of how air pollutants can affect different immune cell types such as particle-clearing macrophages, inflammatory neutrophils, dendritic cells that orchestrate adaptive immune responses and lymphocytes that enact those responses. Common themes that emerge are of the capacity of air pollutants to stimulate pro-inflammatory immune responses across multiple classes of immune cell. Air pollution can enhance T helper lymphocyte type 2 (Th2) and T helper lymphocyte type 17 (Th17) adaptive immune responses, as seen in allergy and asthma, and dysregulate anti-viral immune responses. The clinical effects of air pollution, in particular the known association between elevated ambient pollution and exacerbations of asthma and chronic obstructive pulmonary disease (COPD), are consistent with these identified immunological mechanisms. Further to this, as inhaled air pollution deposits primarily on the respiratory mucosa this review focuses on mechanisms of respiratory disease. However, as discussed in the article, air pollution also affects the wider immune system for example in the neonate and gastrointestinal tract. Whilst the many identified actions of air pollution on the immune system are notably diverse, immunological research does suggest potential strategies to ameliorate such effects, for example with vitamin D supplementation. An in-depth understanding of the immunological effects of ambient pollutants should hopefully yield new ideas on how to reduce the adverse health effects of air pollution.
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Contaminantes Atmosféricos , Contaminación del Aire , Asma , Enfermedad Pulmonar Obstructiva Crónica , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Asma/etiología , Humanos , Sistema Inmunológico , Recién Nacido , Material Particulado/análisis , Material Particulado/toxicidadRESUMEN
PURPOSE OF REVIEW: To review recent evidence on the capacity of vitamin D to prevent atopic disease, focussing on food allergy and asthma, and potential underlying mechanisms. RECENT FINDINGS: The incidence of allergic disease continues to increase worldwide. Vitamin D status is influenced by sun exposure and dietary intake. Vitamin D deficiency is linked to an increased incidence of allergic disease and asthma. These associations are generally strongest in early life. The capacity of vitamin D to enhance antimicrobial pathways, promote peripheral immunological tolerance and maintain mucosal barrier integrity may underlie these associations. Interventional studies have addressed the capacity of vitamin D supplementation in utero and early life to reduce the incidence of disease. Ancillary studies have provided insights into potential biological mechanisms linked to these effects. SUMMARY: Observational studies show an inverse association between vitamin D levels and development of food allergy and asthma. Secondary analyses of two recent interventional studies suggest that achieving vitamin D sufficiency throughout pregnancy reduces the incidence of asthma/recurrent wheeze at 3 years. Longitudinal studies of vitamin D requirements in utero and postnatally, better understanding of factors that influence bioavailability of vitamin D and mechanistic insights into vitamin D effects on neonatal-specific immune pathways are awaited.
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Asma/prevención & control , Suplementos Dietéticos , Hipersensibilidad a los Alimentos/prevención & control , Deficiencia de Vitamina D/complicaciones , Vitamina D/administración & dosificación , Asma/sangre , Asma/epidemiología , Asma/inmunología , Disponibilidad Biológica , Ensayos Clínicos como Asunto , Epidemias/prevención & control , Femenino , Hipersensibilidad a los Alimentos/sangre , Hipersensibilidad a los Alimentos/epidemiología , Hipersensibilidad a los Alimentos/inmunología , Microbioma Gastrointestinal/inmunología , Carga Global de Enfermedades , Humanos , Incidencia , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Intercambio Materno-Fetal , Atención Perinatal/métodos , Permeabilidad , Atención Posnatal/métodos , Embarazo , Resultado del Tratamiento , Vitamina D/sangre , Vitamina D/metabolismo , Deficiencia de Vitamina D/dietoterapia , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/inmunologíaRESUMEN
Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH)2D3) in human CD4+ T cells revealed that 1,25(OH)2D3 potently induced expression of the gene SERPINA1, encoding the anti-protease α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH)2D3-treated CD4+ T cells, but not in CD8+ T cells or monocytes. α-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell populations. We therefore investigated its immune-regulatory effects in CD4+ T cells. Plasma-derived α-1-antitrypsin drove IL-10 synthesis by CD4+ T cells, which was not dependent on anti-protease activity, but appeared to require a serum-binding factor, since this could not be achieved with recombinant protein. α-1-Antitrypsin is reported to bind complement components, which regulate T cell function. A role for this interaction was therefore probed. Plasma-derived, but not recombinant α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4+ T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH)2D3-driven CD4+ T cell IL-10 synthesis, we treated cells from healthy or α-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH)2D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4+ T cells, which was absent in cells from α-1-antitrypsin-deficient individuals. Therefore, α-1-antitrypsin is required for 1,25(OH)2D3-induced IL-10 expression in CD4+ T cells, interacting with C3a to drive IL-10 expression.
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Linfocitos T CD4-Positivos/efectos de los fármacos , Calcitriol/farmacología , Interleucina-10/inmunología , Vitaminas/farmacología , alfa 1-Antitripsina/inmunología , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Humanos , Factores Inmunológicos/farmacologíaRESUMEN
Glucocorticoids are known to increase production of the anti-inflammatory cytokine IL-10, and this action is associated with their clinical efficacy in asthmatics. However, glucocorticoids also enhance the synthesis of IL-17A by PBMCs, which, in excess, is associated with increased asthma severity and glucocorticoid-refractory disease. In this study, we show that the glucocorticoid dexamethasone significantly increased IL-10 production by human memory CD4+ T cells from healthy donors, as assessed by intracellular cytokine staining. In addition, dexamethasone increased production of IL-17A, IL-17F, and IL-22, with the most striking enhancement in cells coproducing Th17-associated cytokines together with IL-10. Of note, an increase in IFN-γ+IL-10+ cells was also observed despite overall downregulation of IFN-γ production. These dexamethasone-driven IL-10+ cells, and predominantly the IL-17+IL-10+ double-producing cells, were markedly refractory to the inhibitory effect of dexamethasone on proliferation and IL-2Rα expression, which facilitated their preferential IL-2-dependent expansion. Although lower concentrations of exogenous IL-2 promoted IL-10+ cells coproducing proinflammatory cytokines, higher IL-2 doses, both alone and in combination with dexamethasone, increased the proportion of single IL-10+ T cells. Thus, glucocorticoid-induced IL-10 is only accompanied by an increase of IL-17 in a low IL-2 setting, which is, nevertheless, likely to be protective owing to the induction of regulatory IL-17+IL-10+-coproducing cells. These findings open new avenues of investigation with respect to the role of IL-2 in glucocorticoid responsiveness that have potential implications for optimizing the benefit/risk ratio of glucocorticoids in the clinic.
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Linfocitos T CD4-Positivos/efectos de los fármacos , Dexametasona/farmacología , Glucocorticoides/farmacología , Memoria Inmunológica , Interleucina-10/inmunología , Interleucina-17/inmunología , Interleucina-2/farmacología , Proliferación Celular , Femenino , Humanos , Masculino , FenotipoRESUMEN
BACKGROUND: Particulate matter (PM) pollutant exposure, which induces oxidative stress and inflammation, and vitamin D insufficiency, which compromises immune regulation, are detrimental in asthma. OBJECTIVES: Mechanistic cell culture experiments were undertaken to ascertain whether vitamin D abrogates PM-induced inflammatory responses of human bronchial epithelial cells (HBECs) through enhancement of antioxidant pathways. METHODS: Transcriptome analysis, PCR and ELISA were undertaken to delineate markers of inflammation and oxidative stress; with comparison of expression in primary HBECs from healthy and asthmatic donors cultured with reference urban PM in the presence/absence of vitamin D. RESULTS: Transcriptome analysis identified over 500 genes significantly perturbed by PM-stimulation, including multiple pro-inflammatory cytokines. Vitamin D altered expression of a subset of these PM-induced genes, including suppressing IL6. Addition of vitamin D suppressed PM-stimulated IL-6 production, although to significantly greater extent in healthy versus asthmatic donor cultures. Vitamin D also differentially affected PM-stimulated GM-CSF, with suppression in healthy HBECs and enhancement in asthmatic cultures. Vitamin D increased HBEC expression of the antioxidant pathway gene G6PD, increased the ratio of reduced to oxidised glutathione, and in PM-stimulated cultures decreased the formation of 8-isoprostane. Pre-treatment with vitamin D decreased CXCL8 and further decreased IL-6 production in PM-stimulated cultures, an effect abrogated by inhibition of G6PD with DHEA, supporting a role for this pathway in the anti-inflammatory actions of vitamin D. CONCLUSIONS: In a study using HBECs from 18 donors, vitamin D enhanced HBEC antioxidant responses and modulated the immune response to PM, suggesting that vitamin D may protect the airways from pathological pollution-induced inflammation.
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Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Bronquios/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Material Particulado/efectos adversos , Vitamina D/farmacología , Adulto , Contaminantes Atmosféricos/efectos adversos , Asma/tratamiento farmacológico , Asma/inmunología , Bronquios/inmunología , Células Cultivadas , Exposición a Riesgos Ambientales/efectos adversos , Células Epiteliales/inmunología , Femenino , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , Transcriptoma/efectos de los fármacos , Adulto JovenRESUMEN
INTRODUCTION: Female sex steroid hormones have been implicated in sex-related differences in the development and clinical outcomes of asthma. The role of exogenous sex steroids, however, remains unclear. Our recent systematic review highlighted the lack of high-quality population-based studies investigating this subject. We aim to investigate whether the use of hormonal contraception and hormone replacement therapy (HRT), subtypes and route of administration are associated with asthma onset and clinical outcomes in reproductive age and perimenopausal/postmenopausal females. METHODS AND ANALYSIS: Using the Optimum Patient Care Research Database (OPCRD), a national primary care database in the UK, we will construct a retrospective longitudinal cohort of reproductive age (16-45 years) and perimenopausal/postmenopausal (46-70 years) females. We will estimate the risk of new-onset asthma using Cox regression and multilevel modelling for repeated asthma outcomes, such as asthma attacks. We will adjust for confounding factors in all analyses. We will evaluate interactions between the use of exogenous sex hormones and body mass index and smoking by calculating the relative excess risk due to interaction and the attributable proportion due to interaction. With 90% power, we need 23 700 reproductive age females to detect a 20% reduction (risk ratio 0.8) in asthma attacks for use of any hormonal contraception and 6000 perimenopausal/postmenopausal females to detect a 40% (risk ratio 1.40) increased risk of asthma attacks for use of any HRT. ETHICS AND DISSEMINATION: We have obtained approval (ADEPT1317) from the Anonymised Data Ethics and Protocol Transparency Committee which grants project-specific ethics approvals for the use of OPCRD data. Optimum Patient Care has an existing NHS Health Research Authority ethics approval for the use of OPCRD data for research (15/EM/150). We will present our findings at national and international scientific meetings and publish the results in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: EUPAS22967.
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Asma/sangre , Asma/etiología , Anticonceptivos Hormonales Orales/efectos adversos , Hormonas Esteroides Gonadales/administración & dosificación , Terapia de Reemplazo de Hormonas/efectos adversos , Proyectos de Investigación , Adolescente , Adulto , Anciano , Índice de Masa Corporal , Bases de Datos Factuales , Femenino , Hormonas Esteroides Gonadales/sangre , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Atención Primaria de Salud , Estudios Retrospectivos , Fumar/epidemiología , Reino Unido , Adulto JovenAsunto(s)
Activación de Complemento/inmunología , Proteínas del Sistema Complemento/inmunología , Fibrinólisis/inmunología , Mucosa Nasal/inmunología , Rinitis Alérgica Estacional/inmunología , Adulto , Femenino , Humanos , Cinética , Masculino , Mastocitos/inmunología , Metaloproteinasa 9 de la Matriz/inmunología , Persona de Mediana Edad , Adulto JovenRESUMEN
Epidemiological studies have consistently shown associations between elevated concentrations of urban particulate matter (UPM) air pollution and exacerbations of asthma and chronic obstructive pulmonary disease, which are both associated with viral respiratory infections. The effects of UPM on dendritic cell (DC) -stimulated CD4 T lymphocytes have been investigated previously, but little work has focused on CD8 T-lymphocyte responses despite their importance in anti-viral immunity. To address this, we examined the effects of UPM on DC-stimulated naive CD8 T-cell responses. Expression of the maturation/activation markers CD83, CCR7, CD40 and MHC class I on human myeloid DCs (mDCs) was characterized by flow cytometry after stimulation with UPMin vitro in the presence/absence of granulocyte-macrophage colony-stimulating factor (GM-CSF). The capacity of these mDCs to stimulate naive CD8 T-lymphocyte responses in allogeneic co-culture was then assessed by measuring T-cell cytokine secretion using cytometric bead array, and proliferation and frequency of interferon-γ (IFN-γ)-producing T lymphocytes by flow cytometry. Treatment of mDCs with UPM increased expression of CD83 and CCR7, but not MHC class I. In allogeneic co-cultures, UPM treatment of mDCs enhanced CD8 T-cell proliferation and the frequency of IFN-γ+ cells. The secretion of tumour necrosis factor-α, interleukin-13, Granzyme A and Granzyme B were also increased. GM-CSF alone, and in concert with UPM, enhanced many of these T-cell functions. The PM-induced increase in Granzyme A was confirmed in a human experimental diesel exposure study. These data demonstrate that UPM treatment of mDCs enhances priming of naive CD8 T lymphocytes and increases production of pro-inflammatory cytokines. Such UPM-induced stimulation of CD8 cells may potentiate T-lymphocyte cytotoxic responses upon concurrent airway infection, increasing bystander damage to the airways.
Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/efectos de los fármacos , Material Particulado/farmacología , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Proliferación Celular , Células Cultivadas , Células Dendríticas/inmunología , Voluntarios Sanos , Humanos , Inmunoglobulinas/biosíntesis , Inmunoglobulinas/inmunología , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/inmunología , Material Particulado/química , Receptores CCR7/biosíntesis , Receptores CCR7/inmunología , Antígeno CD83RESUMEN
There is increasing interest in the therapeutic utility of vitamin D in asthma, which is supported by a significant body of evidence on epidemiologic associations between vitamin D insufficiency and worse asthma control. In support of a causal relationship, vitamin D beneficially modulates diverse immunologic pathways in heterogeneous asthma endotypes, regulating the actions of lymphocytes, mast cells, antigen-presenting cells, and structural cells to dampen excessive inflammatory responses. Allergic asthma is characterized by a failure of immune tolerance and the development of pathologic responses to inhaled aeroallergens, and vitamin D has been extensively shown to support immune regulation. Alarmin cytokines are increasingly implicated in nonallergic eosinophilic inflammation, which vitamin D also regulates. Steroid resistance and pathologic interleukin (IL)-17 responses are features of severe asthma, and vitamin D beneficially enhances the response to steroids in these individuals. Additionally, vitamin D enhances antimicrobial pathways, which is of relevance to infection-precipitated asthma exacerbations. These mechanisms support a role for vitamin D as secondary prevention to reduce exacerbations and inflammation in asthma. Similar mechanisms, and effects on fetal lung development, likely underlie a primary prevention therapeutic role in pregnancy for vitamin D to reduce the development of asthma in children. However, randomized controlled trials of variable design show inconsistent positive outcomes for vitamin D interventions in asthma. Increased understanding of the biological characteristics of vitamin D reveals methodological issues that might explain certain negative outcomes. Importantly, on systematic review of the trials to date, vitamin D is shown to be beneficial in asthma. The evidence discussed in this review supports the importance of optimizing vitamin D in holistic asthma care.
Asunto(s)
Asma/prevención & control , Deficiencia de Vitamina D/complicaciones , Vitamina D/uso terapéutico , Vitaminas/uso terapéutico , Asma/etiología , Humanos , Deficiencia de Vitamina D/prevención & controlRESUMEN
Urban particulate matter (UPM) air pollution and vitamin D deficiency are detrimentally associated with respiratory health. This is hypothesized to be due in part to regulation of IL-17A, which UPM is reported to promote. Here, we used a myeloid dendritic cell (DC)-memory CD4+ T cell co-culture system to characterize UPM-driven IL-17A+ cells, investigate the mechanism by which UPM-primed DCs promote this phenotype, and address evidence for cross-regulation by vitamin D. CD1c+ myeloid DCs were cultured overnight with or without a reference source of UPM and/or active vitamin D (1,25[OH]2D3) before they were co-cultured with autologous memory CD4+ T cells. Supernatants were harvested for cytokine analysis on Day 5 of co-culture, and intracellular cytokine staining was performed on Day 7. UPM-primed DCs increased the proportion of memory CD4+ T cells expressing the T helper 17 cell (Th17)-associated cytokines IL-17A, IL-17F, and IL-22, as well as IFN-γ, granulocyte-macrophage colony-stimulating factor, and granzyme B. Notably, a large proportion of the UPM-driven IL-17A+ cells co-expressed these cytokines, but not IL-10, indicative of a proinflammatory Th17 profile. UPM-treated DCs expressed elevated levels of il23 mRNA and increased secretion of IL-23p40. Neutralization of IL-23 in culture reduced the frequency of IL-17A+IFN-γ+ cells without affecting cell proliferation. 1,25(OH)2D3 counteracted the UPM-driven DC maturation and inhibited the frequency of IL-17A+IFN-γ+ cells, most prominently when DCs were co-treated with the corticosteroid dexamethasone, while maintaining antiinflammatory IL-10 synthesis. These data indicate that UPM might promote an inflammatory milieu in part by inducing an IL-23-driven proinflammatory Th17 response. Restoring vitamin D sufficiency may counteract these UPM-driven effects without obliterating important homeostatic immune functions.
Asunto(s)
Ciudades , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Material Particulado/toxicidad , Vitamina D/farmacología , Calcitriol/farmacología , Diferenciación Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Dexametasona/farmacología , Humanos , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Fenotipo , Células Th17/inmunología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Type 1 regulatory T (Tr1) cells play a pivotal role in restraining human T-cell responses toward environmental allergens and protecting against allergic diseases. Still, the precise molecular cues that underlie their transcriptional and functional specification remain elusive. Here, we show that the cytokine activin-A instructs the generation of CD4+ T cells that express the Tr1-cell-associated molecules IL-10, inducible T-Cell costimulator (ICOS), lymphocyte activation gene 3 protein (LAG-3), and CD49b, and exert strongly suppressive functions toward allergic responses induced by naive and in vivo-primed human T helper 2 cells. Moreover, mechanistic studies reveal that activin-A signaling induces the activation of the transcription factor interferon regulatory factor (IRF4), which, along with the environmental sensor aryl hydrocarbon receptor, forms a multipartite transcriptional complex that binds in IL-10 and ICOS promoter elements and controls gene expression in human CD4+ T cells. In fact, IRF4 silencing abrogates activin-A-driven IL10 and ICOS up-regulation and impairs the suppressive functions of human activin-A-induced Tr1-like (act-A-iTr1) cells. Importantly, using a humanized mouse model of allergic asthma, we demonstrate that adoptive transfer of human act-A-iTr1 cells, both in preventive and therapeutic protocols, confers significant protection against cardinal asthma manifestations, including pulmonary inflammation. Overall, our findings uncover an activin-A-induced IRF4-aryl hydrocarbon receptor (AhR)-dependent transcriptional network, which generates suppressive human Tr1 cells that may be harnessed for the control of allergic diseases.