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AIMS: This study aimed to investigate the effect of interleukin-35 (IL-35) on inflamed lung tissue in a murine model of asthma. IL-35 was examined for its potential to induce regulatory lymphocytes during ovalbumin (OVA)-induced acute lung injury. METHODS: Female BALB/c mice sensitized with OVA and were treated with recombinant IL-35 (rIL-35) via intranasal or intraperitoneal routes and were administered 4 h before OVA challenge. The effects of rIL-35 treatment on the lung and blood levels of regulatory B cells (Bregs) and regulatory T cells (Tregs), as well as their production of immunosuppressive cytokines, were determined using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS: Treatment of OVA-sensitized asthmatic mice with rIL-35, whether administered intranasally or intraperitoneally, resulted in reduced lung inflammation and injury. This reduction was accompanied by an increase in the frequency of IL-35 producing Bregs, IL-35 and IL-10 producing Bregs, and conventional LAG3+ Tregs in the lung tissues and blood. This increase was more pronounced with intranasal rIL-35. Furthermore, there was a positive correlation between the levels of these regulatory cells and lung gene expression of IL-35 and IL-10, and an inverse correlation with both lung gene expression and plasma level of IL-17. CONCLUSIONS: The results of this study suggest that IL-35, through its ability to increase Bregs and Tregs, is effective in reversing lung inflammation in the context of asthma. Since the increase was more pronounced with intranasal administration, this highlights the therapeutic potential of its local intrapulmonary application in managing asthma-related inflammation.
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Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses.
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Hepatitis Viral Humana , Interleucina-10 , Humanos , Interleucina-10/genética , Hermanos , Interferón gamma/genéticaRESUMEN
Background: E-government platforms provide an opportunity to use a novel data source for population health surveillance (also known as e-health). Absher is a Saudi e-government platform with 23 million authenticated users, including residents and citizens in Saudi Arabia. All Absher users were invited to participate in a web-based survey to estimate the prevalence of noncommunicable diseases and their risk factors in Saudi Arabia. Objective: To assess the potential of using an e-government platform (Absher) to administer web-based health surveys. Methods: A cross-sectional, web-based health survey was administered to Absher users between April 2019 and March 2020. The survey instrument included eight items and took <5 min to complete. The respondents' data were compared to Saudi Arabia's 2016 census. Descriptive summary statistics of the prevalence of major noncommuncable diseases are presented and compared to population-based prevalence data from Saudi Arabia's World Health Survey (WHS) 2019. All analysis was conducted using Stata 13.0. Results: Overall, the Absher health survey had a 24.6% response rate, with most respondents being male (84%), Saudi (67%), and between 30 and 44 years of age (49%). Overall, the prevalence of noncommunicable diseases and risk factors among respondents was high for overweight (35%) and obesity (30%) and low for asthma (6%). The prevalence of diabetes, dyslipidemia, and hypertension was between 15 and 17% on average, and 26.5% were smokers. In comparison to population-based World Health Survey estimates, the Absher survey overestimated obesity, diabetes, dyslipidemia, hypertension, and smoking rates, and underestimated overweight, whereas asthma prevalence was similar for Absher and the WHS. Conclusions: With improvements in the study design, the use of e-government platforms can provide a useful and potentially low-cost data source for public health research.
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Asma , Hipertensión , Enfermedades no Transmisibles , Asma/epidemiología , Estudios Transversales , Femenino , Gobierno , Humanos , Hipertensión/epidemiología , Masculino , Enfermedades no Transmisibles/epidemiología , Obesidad/epidemiología , Sobrepeso , Arabia Saudita/epidemiología , Encuestas y CuestionariosRESUMEN
Cytokines are major players in orchestrating inflammation, disease pathogenesis and severity during COVID-19 disease. However, the role of IL-19 in COVID-19 pathogenesis remains elusive. Herein, through the analysis of transcriptomic datasets of SARS-CoV-2 infected lung cells, nasopharyngeal swabs, and lung autopsies of COVID-19 patients, we report that expression levels of IL-19 and its receptor, IL-20R2, were upregulated following SARS-CoV-2 infection. Of 202 adult COVID-19 patients, IL-19 protein level was significantly higher in blood and saliva of asymptomatic patients compared to healthy controls when adjusted for patients' demographics (P < 0.001). Interestingly, high saliva IL-19 level was also associated with COVID-19 severity (P < 0.0001), need for mechanical ventilation (P = 0.002), and/or death (P = 0.010) within 29 days of admission, after adjusting for patients' demographics, diabetes mellitus comorbidity, and COVID-19 serum markers of severity such as D-dimer, C-reactive protein, and ferritin. Moreover, patients who received interferon beta during their hospital stay had lower plasma IL-19 concentrations (24 pg mL-1) than those who received tocilizumab (39.2 pg mL-1) or corticosteroids (42.5 pg mL-1). Our findings indicate that high saliva IL-19 level was associated with COVID-19 infectivity and disease severity.
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COVID-19 , Adulto , Biomarcadores , Proteína C-Reactiva , Citocinas , Ferritinas , Humanos , Interferón beta , Interleucinas/genética , SARS-CoV-2 , Saliva , Regulación hacia ArribaRESUMEN
BACKGROUNDS: Treating asthmatic rheumatoid arthritis patients with abatacept has been shown to associate with better control of asthma symptoms. However, the mechanism behind that is not investigated. METHODS: Ovalbumin (OVA)- sensitized BALB/c female mice were treated intranasally (IN) or intraperitoneally (IP) with abatacept 4 hrs before the OVA challenge. The effects of abatacept IN or IP on the lungs and blood levels of Tregs and Bregs and their production of immunosuppressive cytokines, were determined using FACS analysis and ELISA assay. RESULTS: Treating OVA- sensitized asthmatic mice model with abatacept, IN or IP, reduced lung inflammation. IN treatment with abatacept increased the frequency of IL-35 and IL-10 producing Bregs in the lung tissues to a higher level compared to IP treatment. Moreover, the frequency of lungs LAG3+ Tregs was significantly increased following treatment. This was also associated with a reduction in lung tissue and serum IL-17 levels of treated mice. CONCLUSIONS: These results suggest that abatacept by enhancing IL-35+IL-10+ Bregs and LAG3+ Tregs might reverse IL-17 induced lung inflammation during asthma.
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Asma , Interleucina-10 , Abatacept/farmacología , Abatacept/uso terapéutico , Administración Intranasal , Animales , Asma/inducido químicamente , Asma/tratamiento farmacológico , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Femenino , Interleucina-17 , Pulmón , Ratones , Ratones Endogámicos BALB C , OvalbúminaRESUMEN
Objective: To evaluate COVID19 patients' clinical characteristics, risk factors, and COVID-19 severity at baseline and over one month following hospitalization. Design setting and participants: This prospective cohort study of 598 Saudi COVID19 patients recruited from 4 major medical institutions nationwide between June 01, 2020, and February 28, 2021. Patients were stratified into different demographic characteristics and COVID-19 severity scale. Results: Of the 598 hospitalized adult COVID19 patients (mean [range] age, 57 [46 to 65] years; 59% male), 300 (50.16%) had severe clinical COVID-19. Comorbidity was high among hospitalized patients (73.5 %), with diabetes mellitus (n=; 46%) and hypertension (n=; 41%) being the most common prevalent. In a multivariate logistic regression model, patient demographics and clinical factors such as age (odds ratio [OR], 1.014 per year; 95% CI, 1.003-1.025), male sex (OR, 1.63; 95% CI, 1.02-2.62), diabetes mellitus (OR, 1.63; 95% CI, 1.06-2.49), obesity (OR, 1.93; 95% CI, 1.26-2.94), oxygen saturation<92% (OR, 4.83; 95% CI, 2.96-7.86), and high neutrophil to lymphocyte ratio (OR, 3.74 per unit; 95% CI, 1.96-7.14) were independently associated with higher COVID-19 severity. Moreover, more than 60% of male patients and middle-aged patients (40-60 years) were associated with the use of COVID-19 medications, including favipiravir and dexamethasone, during their hospital stay. Additionally, the rate of invasive mechanical ventilation was the highest in female patients (61.5%) and in middle-aged patients (46.2%). However, the death rate was slightly higher in males (56%) than in female patients and in elderly patients (52%). In Cox proportional analysis, age associated with increased risk of 60-days mortality (Hazard ratio; HR, 1.05 per year; 95% CI, 1.018-1.098). Additionally, the Riyadh region associated with more COVID-19 cases required invasive respiratory support (57.7%) and Jeddah was associated with more deceased COVID-19 cases (44%). Conclusions: The data shows that comorbidity is associated with hospitalization among COVID-19 patients, which indicates the level of severity. Infection during the winter season (November), male gender, elderly, and those with pre-existing diabetes mellitus or obesity were associated with higher COVID-19 clinical severity.
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Objectives: There are limited data on the efficacy and safety of favipiravir antiviral in coronavirus disease 2019 (COVID-19), particularly in the more progressed disease phase. This study aims to evaluate the favipiravir effect on reducing the length of hospital stay and in-hospital mortality among moderate and severe hospitalized COVID-19 patients. Methods: A prospective, multicenter observational study was conducted that included moderate and severe hospitalized adult COVID-19 patients in four major regions (Riyadh (Riyadh), Eastern (Dammam), Al-Qassem (Buraydah), and Macca (Jeddah) of Saudi Arabia. For the primary outcome of all-cause mortality, a Cox proportional hazard analysis was performed. While the association between favipiravir use and length of hospital stay was determined using adjusted generalized linear model. This study was approved by the Central Institutional Review Board in The Saudi Ministry of Health (MoH) with the approval number IRB # 20-85-M. Results: This study included 598 moderate and severe COVID-19 patients, of whom 156 (26%) received favipiravir. Favipiravir treatment was associated with more extended hospital stays (14 vs. 10 median days, P = 0.034) and higher mortality rate (aHR 3.63; 95% CI 1.06-12.45) compared to no favipiravir regimen. Despite lack of effectiveness, favipiravir use was only associated with higher diarrhea adverse effects (12 vs. 5%, P = 0.002), but it did not affect the renal and liver profiles of patients. Conclusion: Favipiravir was ineffective in reducing the length of hospital stay and in-hospital mortality in patients with moderate and severe COVID-19.
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Memory T cells play a central role in regulating inflammatory responses during asthma. However, tissue distribution of effector memory (TEM) and central memory (TCM) T-cell subtypes, their differentiation, and their contribution to the persistence of lung tissue inflammation during asthma are not well understood. Interestingly, an increase in survival and persistence of memory T cells was reported in asthmatic lungs, which may suggest a shift toward the more persistent TCM phenotype. In this report, we investigated the differential distribution of memory T-cell subtypes during allergic lung inflammation and the mechanism regulating that. Using an OVA-sensitized asthma mouse model, we observed a significant increase in the frequency of TCM cells in inflamed lungs compared to healthy controls. Interestingly, adoptive transfer techniques confirmed substantial infiltration of TCM cells to lung tissues during allergic airway inflammation. Expression levels of TCM homing receptors, CD34 and GlyCAM-1, were also significantly upregulated in the lung tissues of OVA-sensitized mice, which may facilitate the increased TCM infiltration into inflamed lungs. Moreover, a substantial increase in the relative expression of TCM profile-associated genes (EOMES, BCL-6, ID3, TCF-7, BCL-2, BIM, and BMI-1) was noted for TEM cells during lung inflammation, suggesting a shift for TEM into the TCM state. To our knowledge, this is the first study to report an increased infiltration of TCM cells into inflamed lung tissues and to suggest differentiation of TEM to TCM cells in these tissues. Therapeutic interference at TCM infiltration or differentiations could constitute an alternative treatment approach for lung inflammation.
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Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Animales , Asma/etiología , Asma/metabolismo , Asma/patología , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Expresión Génica , Hipersensibilidad/patología , Inmunohistoquímica , Inmunofenotipificación , Mediadores de Inflamación , Pulmón/patología , Recuento de Linfocitos , RatonesRESUMEN
PURPOSE: We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause. METHODS: Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed. RESULTS: We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes. CONCLUSION: We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.
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Fibrosis Quística , Mucoproteínas/genética , Proteínas Oncogénicas/genética , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Exoma , Humanos , Mutación , FenotipoRESUMEN
BACKGROUND: A growing number of experiments have suggested potential cross-reactive immunity between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and previous human coronaviruses. We conducted the present retrospective cohort study to investigate the relationship between previous Middle East respiratory syndrome-coronavirus (MERS-CoV) infection and the risk of SARS-CoV-2 infection as well as the relationship between previous MERS-CoV and COVID-19-related hospitalization and mortality. METHODS: Starting in March 2020, we prospectively followed two groups of individuals who tested negative for COVID-19 infection. The first group had a previously confirmed MERS-CoV infection, which was compared to a control group of MERS-negative individuals. The studied cohort was then followed until November 2020 to track evidence of contracting COVID-19 infection. FINDINGS: A total of 82 (24%) MERS-positive and 260 (31%) MERS-negative individuals had COVID-19 infection. Patients in the MERS-positive group had a lower risk of COVID-19 infection than those in the MERS-negative group (Risk ratio [RR] 0.696, 95% confidence interval [CI] 0.522-0.929; p =0.014). The risk of COVID-19-related hospitalization in the MERS-positive group was significantly higher (RR 4.036, 95% CI 1.705-9.555; p =0.002). The case fatality rate (CFR) from COVID-19 was 4.9% in the MERS-positive group and 1.2% in the MERS-negative group (p =0.038). The MERS-positive group had a higher risk of death than the MERS-negative group (RR 6.222, 95% CI 1.342-28.839; p =0.019). However, the risk of mortality was similar between the two groups when death was adjusted for age (p =0.068) and age and sex (p =0.057). After controlling for all the independent variables, only healthcare worker occupation and >1 comorbidity were independent predictors of SARS-CoV-2 infection. INTERPRETATION: Individuals with previous MERS-CoV infection can exhibit a cross-reactive immune response to SARS-CoV-2 infection. Our study demonstrated that patients with MERS-CoV infection had higher risks of COVID-19-related hospitalization and death than MERS-negative individuals.
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COVID-19/epidemiología , COVID-19/mortalidad , Reacciones Cruzadas/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Arabia Saudita/epidemiología , Adulto JovenRESUMEN
The efficacy of corticosteroids and its use for the treatment of SARS-CoV-2 infections is controversial. In this study, using data sets of SARS-CoV-2 infected lung tissues and nasopharyngeal swabs, as well as in vitro experiments, we show that SARS-CoV-2 infection significantly downregulates DUSP1 expression. This downregulation of DUSP1 could be the mechanism regulating the enhanced activation of MAPK pathway as well as the reported steroid resistance in SARS-CoV-2 infection. Moreover, chloroquine, an off labeled COVID-19 drug is able to induce DUSP1 and attenuate MAPK pathway; and is expected to improve sensitivity to steroid treatment. However, further mechanistic studies are required to confirm this effect.
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Tratamiento Farmacológico de COVID-19 , Cloroquina/farmacología , Fosfatasa 1 de Especificidad Dual/genética , Glucocorticoides/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adulto , Anciano , COVID-19/patología , COVID-19/virología , Estudios de Casos y Controles , Células Cultivadas , Cloroquina/uso terapéutico , Conjuntos de Datos como Asunto , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Medicamentos/efectos de los fármacos , Resistencia a Medicamentos/genética , Sinergismo Farmacológico , Fosfatasa 1 de Especificidad Dual/metabolismo , Fibroblastos , Glucocorticoides/uso terapéutico , Voluntarios Sanos , Humanos , Pulmón/citología , Pulmón/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Persona de Mediana Edad , Nasofaringe/virología , Uso Fuera de lo Indicado , Cultivo Primario de Células , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidadRESUMEN
Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.
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Trasplante de Células Madre Hematopoyéticas , Linfohistiocitosis Hemofagocítica , Infecciones por Mycobacterium , Mycobacterium bovis , Humanos , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismoRESUMEN
Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.
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Antígenos de Neoplasias/genética , Leucocitosis/genética , Infecciones por Mycobacterium no Tuberculosas/genética , Células A549 , Adolescente , Antígenos de Neoplasias/metabolismo , Células Cultivadas , Niño , Gránulos Citoplasmáticos/metabolismo , Femenino , Células HEK293 , Células HeLa , Homocigoto , Humanos , Lactante , Interferón gamma/metabolismo , Leucocitosis/patología , Masculino , Mutación , Infecciones por Mycobacterium no Tuberculosas/patología , Linaje , Células THP-1 , Adulto JovenRESUMEN
Abatacept, an inhibitor of CD28 mediated T-cell activation, has been shown to be effective in controlling inflammation during rheumatoid arthritis (RA). However, its effects on immune regulatory B and T cells (Bregs and Tregs) has not been fully explored. Thirty-one RA patients treated with abatacept for ≥ 6 months along with 31 RA patients treated with other modalities as well as 30 healthy controls were recruited. Of these 62 RA patient, 49 (79%) were females with a mean age of 54 ± 12 years and disease duration of 10 ± 6 years. The blood levels of Tregs and Bregs and their production of immunosuppressive cytokines, were determined using FACS analysis and Luminex Multiplex assay. Treatment with abatacept significantly enhanced the blood level of IL-35+ IL-10+ Bregs (P = 0.0007). Their levels were higher in the blood of remitted patients (DAS28-CRP < 2.6) compared to the unremitted ones (P = 0.0173), 6 months following abatacept treatment initiation. Moreover, abatacept treatment significantly enhanced the blood levels of LAG3+ conventional and unconventional Tregs of RA patients. This increase in the blood levels of Bregs and Tregs was accompanied with an elevated serum level of IL-35 and IFN-ß in abatacept-treated patients. Therefore, Abatacept efficiency to achieve remittance in RA could be attributed, in part, to its ability to enhance immune regulatory cells, especially IL-135+ IL-10+ Bregs.
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Abatacept/uso terapéutico , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Linfocitos B Reguladores/inmunología , Abatacept/farmacología , Antígenos CD/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Femenino , Humanos , Interferón beta/sangre , Interleucina-10/metabolismo , Interleucinas/sangre , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Inducción de Remisión , Linfocitos T Reguladores/inmunología , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
It is still controversial whether chronic lung inflammation increases the risk for COVID-19. One of the risk factors for acquiring COVID-19 is the level of expression of SARS-CoV-2 entry receptors, ACE2 and TMPRSS2, in lung tissue. It is, however, not clear how lung tissue inflammation affects expression levels of these receptors. We hence aimed to determine the level of SARS-CoV-2 receptors in lung tissue of asthmatic relative to age, gender, and asthma severity, and to investigate the factors regulating that. Therefore, gene expression data sets of well-known asthmatic cohorts (SARP and U-BIOPRED) were used to evaluate the association of ACE2 and TMPRSS2 with age, gender of the asthmatic patients, and also the type of the underlying lung tissue inflammatory cytokines. Notably, ACE2 and to less extent TMPRSS2 expression were upregulated in the lung tissue of asthmatics compared to healthy controls. Although a differential expression of ACE2, but not TMPRSS2 was observed relative to age within the moderate and severe asthma groups, our data suggest that age may not be a key regulatory factor of its expression. The type of tissue inflammation, however, associated significantly with ACE2 and TMPRSS2 expression levels following adjusting with age, gender and oral corticosteroids use of the patient. Type I cytokine (IFN-γ), IL-8, and IL-19 were associated with increased expression, while Type II cytokines (IL-4 and IL-13) with lower expression of ACE2 in lung tissue (airway epithelium and/or lung biopsies) of moderate and severe asthmatic patients. Of note, IL-19 was associated with ACE2 expression while IL-17 was associated with TMPRSS2 expression in sputum of asthmatic subjects. In vitro treatment of bronchial fibroblasts with IL-17 and IL-19 cytokines confirmed the regulatory effect of these cytokines on SARS-CoV-2 entry receptors. Our results suggest that the type of inflammation may regulate ACE2 and TMPRSS2 expression in the lung tissue of asthmatics and may hence affect susceptibility to SARS-CoV-2 infection.
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Enzima Convertidora de Angiotensina 2/inmunología , Asma/inmunología , COVID-19/inmunología , Citocinas/inmunología , Regulación de la Expresión Génica/inmunología , Pulmón/inmunología , SARS-CoV-2/inmunología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Serina Endopeptidasas/inmunologíaRESUMEN
OBJECTIVES: To map research production by Saudi-affiliated investigators in order to identify areas of strength and weakness. Method: We followed the Arksey and O'Malley (2005) framework. Medline and Cochrane databases were searched with a focus on identifying articles related to COVID-19 and Saudi Arabia following the PRISMA protocol. The study was conducted at King Saud University, Riyadh, Saudi Arabia between March and May 2020. Results: A total of 53 articles were ultimately included. Most of the research production from Saudi Arabia was opinion and narrative reviews related to the clinicopathological features of COVID-19 as well as control and prevention of virus spread. Conclusion: The results of this scoping review identify a relative deficiency in original research, which requires further investigation.
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Betacoronavirus , Investigación Biomédica , Infecciones por Coronavirus , Pandemias , Neumonía Viral , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/terapia , Humanos , Neumonía Viral/diagnóstico , Neumonía Viral/terapia , SARS-CoV-2 , Arabia SauditaRESUMEN
PURPOSE: Combined immunodeficiency (CID), due to mutations in TFRC gene that encodes the transferrin receptors (TfR1), is a rare monogenic disorder. In this study, we further characterize the clinical and immunological phenotypes in a cohort of eight patients. METHODS: A retrospective review of clinical and immunological features of patients diagnosed with a TFRC gene mutation between 2015 and 2019 in three tertiary centers. RESULTS: Eight patients from six unrelated families were enrolled. The patients had a median age of 7 years (4-32 years). All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms. All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia. Anemia was found in 62%. All patients had hypogammaglobinemia and one had a persistent high IgM level. All patients had impaired function of T cells. The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients. Stem cell transplantation from matched donors was successful in two patients. Five patients did not receive stem cell transplantation, and they are on prophylactic treatment. One patient died due to severe sepsis and neurological complications. CONCLUSION: This report provides a large cohort with a long follow up of patients with this disease. Our cohort showed variable disease severity.