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INTRODUCTION: Sepsis, a life-threatening organ dysfunction syndrome occurring in the context of severe infections, remains a major burden on global health with high morbidity and high mortality rates. Despite recent advances in the understanding of its pathophysiology, the treatment of sepsis remains supportive of nature with few interventions specifically designed for treating this complex syndrome. The focus of sepsis trials has increasingly shifted towards targeting excessive inflammation and immunosuppression using immunomodulatory agents. However, it remains uncertain how to identify patients that could benefit from such treatment, whether treatments can be tailored to an individual's immune profile, or at which stage of the disease the intervention should be initiated. In this scoping review, we provide a comprehensive overview of current available literature on immunostimulatory and immunosuppressive therapies against sepsis. METHODS AND ANALYSIS: The aim of this scoping review is to describe and summarise current literature evaluating immunotherapy in adult patients with sepsis. The review will be performed using the framework formulated by Arksey and O'Malley. A comprehensive literature and study collection will be executed by searching PubMed, Embase, Cochrane CENTRAL and ClinicalTrials.gov to identify clinical trials and cohort studies concerning immunotherapy in adult patients with sepsis. Screening will be performed independently and in duplicate by two reviewers who will also independently extract data into prespecified spreadsheets. We will summarise evidence in tabular format with descriptive statistics. The reported evidence will convey knowledge on the types of immunotherapies studied, and currently being studied, in adult patients with sepsis. ETHICS AND DISSEMINATION: Approval from a medical ethics committee is not required. Once completed, the review will be submitted for publication in a peer-reviewed journal. These results will be of value to clinicians and researchers with an interest in advancing sepsis care.
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Projetos de Pesquisa , Sepse , Adulto , Humanos , Imunoterapia , Revisão por Pares , Grupos Populacionais , Literatura de Revisão como Assunto , Sepse/terapiaRESUMO
INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.
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COVID-19 , Endotelina-1 , Estudos de Coortes , Humanos , Inflamação , Pandemias , SARS-CoV-2RESUMO
OBJECTIVES: Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1ß. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. METHODS: Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. RESULTS: High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. CONCLUSION: Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.
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Gota , Ácido Úrico , Animais , Epigênese Genética , Gota/genética , Humanos , Leucócitos Mononucleares , Proteínas de Membrana , Camundongos , Monócitos , Proteínas de Ligação a RNARESUMO
The dendritic cell (DC)-derived cytokine profile contributes to naive T cell differentiation, thereby directing the immune response. IL-37 is a cytokine with anti-inflammatory characteristics that has been demonstrated to induce tolerogenic properties in DC. In this study we aimed to evaluate the influence of IL-37 on DC-T cell interaction, with a special focus on the role of the chemokine CXCL1. DC were cultured from bone marrow of human IL-37 transgenic (hIL-37Tg) or WT mice. The phenotype of unstimulated and LPS-stimulated DC was analyzed (co-stimulatory molecules and MHCII by flow cytometry, cytokine profile by RT-PCR and ELISA), and T cell stimulatory capacity was assessed in mixed lymphocyte reaction. The role of CXCL1 in T cell activation was analyzed in T cell stimulation assays with anti-CD3 or allogeneic DC. The expression of the co-stimulatory molecules CD40, CD80 and CD86, and of MHCII in LPS-stimulated DC was not affected by endogenous expression of IL-37, whereas LPS-stimulated hIL-37Tg DC produced less CXCL1 compared to LPS-stimulated WT DC. T cell stimulatory capacity of LPS-matured hIL-37Tg DC was comparable to that of WT DC. Recombinant mouse CXCL1 did not increase T cell proliferation either alone or in combination with anti-CD3 or allogeneic DC, nor did CXCL1 affect the T cell production of interferon-γ and IL-17. Endogenous IL-37 expression does not affect mouse DC phenotype or subsequent T cell stimulatory capacity, despite a reduced CXCL1 production. In addition, we did not observe an effect of CXCL1 in T cell proliferation or differentiation.
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Comunicação Celular/imunologia , Quimiocina CXCL1/metabolismo , Células Dendríticas/metabolismo , Interleucina-1/metabolismo , Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Proliferação de Células , Células Cultivadas , Quimiocina CXCL1/genética , Células Dendríticas/imunologia , Humanos , Interleucina-1/genética , Ativação Linfocitária , Masculino , Camundongos , Camundongos Transgênicos , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
OBJECTIVE: Acromegaly is characterized by an excess of growth hormone (GH) and insulin like growth-factor 1 (IGF1), and it is strongly associated with cardiovascular diseases (CVD). Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Previous results suggest the presence of systemic inflammation in treated patients. Here we assessed the association between treatment of acromegaly, systemic inflammation and vascular function. DESIGN: Ex vivo cytokine production and circulating inflammatory markers were assessed in peripheral blood from treated and untreated acromegaly patients (N = 120), and compared them with healthy controls. A more comprehensive prospective inflammatory and vascular assessment was conducted in a subgroup of six treatment-naive patients with follow-up during treatment. RESULTS: Circulating concentrations of VCAM1, E-selectin and MMP2 were higher in patients with uncontrolled disease, whereas the concentrations of IL18 were lower. In stimulated whole blood, cytokine production was skewed towards a more pro-inflammatory profile in patients, especially those with untreated disease. Prospective vascular measurements in untreated patients showed improvement of endothelial function during treatment. CONCLUSIONS: Acromegaly patients are characterized by a pro-inflammatory phenotype, most pronounced in those with uncontrolled disease. Treatment only partially reverses this pro-inflammatory bias. These findings suggest that systemic inflammation could contribute to the increased risk of CVD in acromegaly patients.
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Acromegalia/terapia , Adenoma/terapia , Antineoplásicos Hormonais/uso terapêutico , Endotélio Vascular/fisiopatologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Inflamação/metabolismo , Procedimentos Neurocirúrgicos , Radioterapia , Acromegalia/metabolismo , Acromegalia/fisiopatologia , Adenoma/metabolismo , Adenoma/fisiopatologia , Adulto , Idoso , Espessura Intima-Media Carotídea , Citocinas/metabolismo , Agonistas de Dopamina/uso terapêutico , Selectina E/metabolismo , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/fisiopatologia , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Inflamação/fisiopatologia , Interleucina-18/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Pessoa de Meia-Idade , Análise de Onda de Pulso , Somatostatina/análogos & derivados , Resultado do Tratamento , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Behçet's disease (BD) is an inflammatory disease mainly affecting men along the ancient Silk Route. In the present study we describe a Dutch family suffering from BD-like disease with extreme pathergic responses, but without systemic inflammation. Genetic assessment revealed a combination of the human leukocyte antigen (HLA)-B*51 risk-allele together with a rare heterozygous variant in the CSF2 gene (c.130A>C, p.N44H) encoding for granulocyte-macrophage colony-stimulating factor (GM-CSF) found by whole exome sequencing. We utilized an over-expression vector system in a human hepatocyte cell line to produce the aberrant variant of GM-CSF. Biological activity of the protein was measured by signal transducer and activator of transcription 5 (STAT-5) phosphorylation, a downstream molecule of the GM-CSF receptor, in wild-type peripheral mononuclear cells (PBMCs) using flow cytometry. Increased STAT-5 phosphorylation was observed in response to mutated GM-CSF when compared to the wild-type or recombinant protein. CSF2 p.N44H results in disruption of one of the protein's two N-glycosylation sites. Enzymatically deglycosylated wild-type GM-CSF also enhanced STAT-5 phosphorylation. The patient responded well to anti-tumor necrosis factor (TNF)-α treatment, which may be linked to the capacity of TNF-α to induce GM-CSF in phorbol 12-myristate 13-acetate (PMA)-treated PBMCs, while GM-CSF itself only induced dose-dependent interleukin (IL)-1Ra production. The identified CSF2 pathway could provide novel insights into the pathergic response of BD-like disease and offer new opportunities for personalized treatment.
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Síndrome de Behçet/genética , Mutação com Ganho de Função/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Linhagem Celular , Linhagem Celular Tumoral , Exoma/genética , Feminino , Células Hep G2 , Humanos , Fosforilação/genéticaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The Roma population is a European ethnic minority characterized by recent and multiple dispersals and founder effects. After their origin in South Asia around 1,500 years ago, they migrated West. In Europe, they diverged into ethnolinguistically distinct migrant groups that spread across the continent. Previous genetic studies based on genome-wide data and uniparental markers detected Roma founder events and West-Eurasian gene flow. However, to the best of our knowledge, it has not been assessed whether these demographic processes have equally affected both sexes in the population. The present study uses the largest and most comprehensive dataset of complete mitochondrial and Y chromosome Roma sequences to unravel the sex-biased patterns that have shaped their genetic history. The results show that the Roma maternal genetic pool carries a higher lineage diversity from South Asia, as opposed to a single paternal South Asian lineage. Nonetheless, the European gene flow events mainly occurred through the maternal lineages; however, a signal of this gene flow is also traceable in the paternal lineages. We also detect a higher female migration rate among European Roma groups. Altogether, these results suggest that sociocultural factors influenced the emergence of sex-biased genetic patterns at global and local scales in the Roma population through time.
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Etnicidade/genética , Genética Populacional , Migração Humana , Roma (Grupo Étnico)/genética , Povo Asiático/genética , Cromossomos Humanos Y/genética , DNA Mitocondrial/genética , Etnicidade/história , Feminino , Efeito Fundador , Fluxo Gênico/genética , Variação Genética/genética , Haplótipos/genética , História Antiga , Humanos , Masculino , Caracteres Sexuais , População Branca/genéticaRESUMO
BACKGROUND: Previous studies have reported on myocardial injury in patients with coronavirus infectious disease 19 (COVID-19) defined as elevated cardiac biomarkers. Whether elevated biomarkers truly represent myocardial dysfunction is not known. The aim of this study was to explore the incidence of ventricular dysfunction and assess its relationship with biomarker analyses. METHODS: This cross-sectional study ran from April 1 to May 12, 2020, and consisted of all consecutively admitted patients to the Radboud university medical centre nursing ward for COVID-19. Laboratory assessment included high-sensitivity Troponin T and Nterminal pro-B-type natriuretic peptide (NT-proBNP). Echocardiographic evaluation focused on left and right ventricular systolic function and global longitudinal strain (GLS). RESULTS: In total, 51 patients were included, with a median age of 63 years (range 51-68 years) of whom 80% was male. Troponin T was elevated (>14â¯ng/l) in 47%, and a clinically relevant Troponin T elevation (10â¯× URL) was found in three patients (6%). NT-proBNP was elevated (>300â¯pg/ml) in 24 patients (47%), and in four (8%) the NT-proBNP concentration was >1,000â¯pg/ml. Left ventricular dysfunction (ejection fraction <52% and/or GLS >-18%) was observed in 27%, while right ventricular dysfunction (TAPSE <17â¯mm and/or RV S'â¯< 10â¯cm/s) was seen in 10%. There was no association between elevated Troponin T or NT-proBNP and left or right ventricular dysfunction. Patients with confirmed pulmonary embolism had normal right ventricular function. CONCLUSIONS: In hospitalised patients, it seems that COVID-19 predominantly affects the respiratory system, while cardiac dysfunction occurs less often. Based on a single echocardiographic evaluation, we found no relation between elevated Troponin T or NT-proBNP, and ventricular dysfunction. Echocardiography has limited value in screening for ventricular dysfunction.
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The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.
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Suscetibilidade a Doenças , Variação Genética , Imunidade/genética , Leucemia Mieloide Aguda/etiologia , Adulto , Idoso , Alelos , Biomarcadores Tumorais , Suscetibilidade a Doenças/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Imunomodulação/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Esteroides/metabolismoRESUMO
OBJECTIVE: In invasive aspergillosis (IA), monitoring response to antifungal treatment is challenging. We aimed to explore if routine blood parameters help to anticipate outcomes following IA. METHODS: Post hoc secondary analysis of two multicenter randomized trials was performed. The Global Comparative Aspergillosis Study (GCA, n = 123) and the Combination Antifungal Study (CAS, n = 251) constituted the discovery and validation cohorts respectively. The outcome measures were response to treatment and survival to 12 weeks. Interval platelet, galactomannan index (GMI) and C-reactive protein (CRP) levels prior and during antifungal treatment were analysed using logistic regression, Kaplan-Meier survival and receiver operating characteristic (ROC) analyses. RESULTS: The 12-week survival was 70.7% and 63.7% for the GCA and CAS cohorts respectively. In the GCA cohort, every 10 × 109/L platelet count increase at week 2 and 4 improved 12-week survival odds by 6-18% (odds ratio (OR) 1.06-1.18, 95% confidence interval (CI) 1.02-1.33). Survival odds also improved 13% with every 10 mg/dL CRP drop at week 1 and 2 (OR 0.87, 95% CI 0.78-0.97). In the CAS cohort, week 2 platelet count was also associated with 12-week survival with 10% improved odds for every 10 × 109/L platelet increase (OR, 1.10, 95% CI 1.04-1.15). A GMI drop of 0.1 unit was additionally found to increase the odds of treatment response by 3% at the baseline of week 0 (OR 0.97, 95% CI 0.95-0.99). Week 2 platelet and CRP levels performed better than GMI on ROC analyses for survival (area under ROC curve 0.76, 0.87 and 0.67 respectively). A baseline platelet count higher than 30 × 109/L clearly identified patients with >75% survival probability. CONCLUSIONS: Higher serial platelets were associated with overall survival while GMI trends were linked to IA treatment response. Routine and simple laboratory indices may aid follow-up of response in IA patients.
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Antifúngicos/uso terapêutico , Aspergilose Pulmonar Invasiva/sangue , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Mananas/sangue , Adolescente , Adulto , Idoso , Análise Química do Sangue , Proteína C-Reativa/análise , Criança , Estudos de Coortes , Feminino , Galactose/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Curva ROC , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Candida vaginitis is a frequent clinical diagnosis with up to 8% of women experiencing recurrent vulvovaginal candidiasis (RVVC) globally. RVVC is characterized by at least three episodes per year. Most patients with RVVC lack known risk factors, suggesting a role for genetic risk factors in this condition. Through integration of genomic approaches and immunological studies in two independent cohorts of patients with RVVC and healthy individuals, we identified genes and cellular processes that contribute to the pathogenesis of RVVC, including cellular morphogenesis and metabolism, and cellular adhesion. We further identified SIGLEC15, a lectin expressed by various immune cells that binds sialic acid-containing structures, as a candidate gene involved in RVVC susceptibility. Candida stimulation induced SIGLEC15 expression in human peripheral blood mononuclear cells (PBMCs) and a polymorphism in the SIGLEC15 gene that was associated with RVVC in the patient cohorts led to an altered cytokine profile after PBMC stimulation. The same polymorphism led to an increase in IL1B and NLRP3 expression after Candida stimulation in HeLa cells in vitro. Last, Siglec15 expression was induced by Candida at the vaginal surface of mice, where in vivo silencing of Siglec15 led to an increase in the fungal burden. Siglec15 silencing was additionally accompanied by an increase in polymorphonuclear leukocytes during the course of infection. Identification of these pathways and cellular processes contributes to a better understanding of RVVC and may open new therapeutic avenues.
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Candida albicans/patogenicidade , Genômica/métodos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/microbiologia , Animais , Candidíase Vulvovaginal/genética , Candidíase Vulvovaginal/metabolismo , Citocinas/metabolismo , Feminino , Predisposição Genética para Doença/genética , Humanos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
Hospital-acquired pneumonia is a major cause of morbidity and mortality. The incidence of hospital-acquired pneumonia remains high globally and treatment can often be ineffective. Here, we review the available data and unanswered questions surrounding hospital-acquired pneumonia, discuss alterations of the respiratory microbiome and of the mucosal immunity in patients admitted to hospital, and explore potential approaches to stratify patients for tailored treatments. The lungs have been considered a sterile organ for decades because microbiological culture techniques had shown negative results. Culture-independent techniques have shown that healthy lungs harbour a diverse and dynamic ecosystem of bacteria, changing our comprehension of respiratory physiopathology. Understanding dysbiosis of the respiratory microbiome and altered mucosal immunity in patients with critical illness holds great promise to develop targeted host-directed immunotherapy to reduce ineffective treatment, to improve patient outcomes, and to tackle the global threat of resistant bacteria that cause these infections.
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Disbiose/fisiopatologia , Pneumonia Associada a Assistência à Saúde/fisiopatologia , Pulmão/microbiologia , Pulmão/fisiopatologia , Microbiota , HumanosRESUMO
Vaccines are applied to large populations, but only recently has research into immunologic responses and mechanisms started to increase exponentially. Some live vaccines, such as the tuberculosis vaccine bacillus Calmette-Guérin, protect against other infections nonspecifically by eliciting complex immune responses which are not specific antibody related. These heterologous effects are explained by the concept of trained immunity. This editorial introduces five narrative reviews offering recent insights on innate and adaptive immune memory towards a variety of pathogens.
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Imunidade Heteróloga/imunologia , Vacinação , Imunidade Adaptativa , Vacina BCG/imunologia , Humanos , Imunidade Inata , Memória Imunológica , Infecções/imunologiaRESUMO
BACKGROUND: Some strains of Bacillus Calmette-Guérin (BCG) vaccine not only confer protection against disseminated forms of tuberculosis, but also reduce all-cause mortality by the induction of protection against infections with non-related pathogens. OBJECTIVES: We review evidence for non-specific protection induced by BCG vaccination against viral infections, discuss possible mechanisms of action, and summarize implications for vaccination policies and vaccine discovery. SOURCES: Relevant studies retrieved from PubMed and clinicaltrials.gov. CONTENT: Numerous epidemiological, clinical and immunological studies demonstrate that BCG vaccination impacts the immune response to subsequent infections, resulting in reduced morbidity and mortality. Important lines of evidence indicating that BCG protects against viral pathogens comes from experimental studies in mice showing that BCG offers protection against various DNA and RNA viruses, including herpes and influenza viruses. Recently, the effect of BCG on an experimental viral infection in humans has been demonstrated. These effects are thought to be mediated via the induction of innate immune memory and heterologous lymphocyte activation, resulting in enhanced cytokine production, macrophage activity, T-cell responses and antibody titres. IMPLICATIONS: The discovery of innate immune memory has greatly improved our understanding of the mechanisms underlying the non-specific effects induced by BCG vaccination. However, a full understanding of the molecular mechanisms that underlie this phenomenon is still evolving. By identifying the factors that impact the non-specific effects of BCG, we will take an important step towards novel therapeutic options and vaccination strategies, which might lead to a reduction in severe morbidity and mortality associated with viral infections.
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Vacina BCG/imunologia , Proteção Cruzada/imunologia , Viroses/prevenção & controle , Animais , Vacina BCG/administração & dosagem , Resistência à Doença/imunologia , Humanos , Imunidade Heteróloga/imunologia , Imunidade Inata , Memória Imunológica , Ativação Linfocitária , Viroses/epidemiologia , Viroses/mortalidadeRESUMO
BACKGROUND: Some individuals, even when heavily exposed to an infectious tuberculosis patient, develop neither active nor latent tuberculosis infection (LTBI). This 'early clearance' of Mycobacterium tuberculosis is associated with a history of bacillus Calmette-Guérin (BCG) vaccination. As BCG vaccination can boost innate immune responses through a process termed 'trained immunity', we hypothesize that BCG-induced trained innate immunity contributes to early clearance of M. tuberculosis. OBJECTIVES: We describe the epidemiological evidence and biological concepts of early clearance and trained immunity, and the possible relation between these two processes through BCG vaccination. SOURCES: Relevant data from published reports up to November 2018 were examined in the conduct of this review. CONTENT: Several observational studies and one recent randomized trial support the concept that boosting innate immunity contributes to protection against M. tuberculosis infection, with BCG vaccination providing approximately 50% protection. The molecular mechanisms mediating early clearance remain largely unknown, but we propose that trained immunity, characterized by epigenetic and metabolic reprogramming of innate immune cells such as monocytes or macrophages, is at least partially responsible for eliminating the mycobacteria and inducing early clearance. IMPLICATIONS: Future studies should examine if BCG revaccination increases early clearance of M. tuberculosis through induction of trained immunity. Epigenetic or metabolic modulation may further boost BCG-induced trained innate immunity to promote tuberculosis prevention. New tuberculosis vaccine candidates should also be examined for their capacity to improve protection against M. tuberculosis infection and induce trained immunity.
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Vacina BCG/imunologia , Imunidade Inata/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Vacina BCG/administração & dosagem , Resistência à Doença/imunologia , Humanos , Modelos Biológicos , Tuberculose/microbiologia , Tuberculose/prevenção & controleRESUMO
BACKGROUND: Acute gouty arthritis currently is the most common form of inflammatory arthritis in developed countries. Treatment is still suboptimal. Dosage of urate-lowering therapy is often too low to reach target urate levels, and adherence to therapy is poor. In this study, we therefore explore a new treatment option to limit inflammation in acute gout: specific histone deacetylase (HDAC) inhibition. METHODS: Peripheral blood mononuclear cells (PBMCs) were cultured with a combination of monosodium urate crystals (MSU) and palmitic acid (C16.0) in order to activate the NLRP3 inflammasome and induce IL-1ß production. HDAC inhibitors and other compounds were added beforehand with a 1-h pre-incubation period. RESULTS: The HDAC1/2 inhibitor romidepsin was most potent in lowering C16.0+MSU-induced IL-1ß production compared to other specific class I HDAC inhibitors. At 10 nM, romidepsin decreased IL-1ß, IL-1Ra, IL-6, and IL-8 production. IL-1ß mRNA was significantly decreased at 25 nM. Although romidepsin increased PTEN expression, PBMCs from patients with germline mutations in PTEN still responded well to romidepsin. Romidepsin also increased SOCS1 expression and blocked STAT1 and STAT3 activation. Furthermore, experiments with bortezomib showed that blocking the proteasome reverses the cytokine suppression by romidepsin. CONCLUSIONS: Our results show that romidepsin is a very potent inhibitor of C16.0+MSU-induced cytokines in vitro. Romidepsin upregulated transcription of SOCS1, which was shown to directly target inflammatory signaling molecules for proteasomal degradation. Inhibiting the proteasome therefore reversed the cytokine-suppressive effects of romidepsin. HDAC1/2 dual inhibition could therefore be a highly potent new treatment option for acute gout, although safety has to be determined in vivo.
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Artrite Gotosa/metabolismo , Citocinas/metabolismo , Depsipeptídeos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Ácido Úrico/farmacologia , Antineoplásicos/farmacologia , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/genética , Células Cultivadas , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Ácido Palmítico/farmacologia , Proteína 1 Supressora da Sinalização de Citocina/genéticaRESUMO
OBJECTIVES: Chronic Q fever is a persistent infection, mostly of aortic aneurysms, vascular prostheses or damaged heart valves, caused by the intracellular bacterium Coxiella burnetii. Only a fraction of C. burnetii-infected individuals at risk develop chronic Q fever. In these individuals, a defective innate immune response may contribute to the development of chronic Q fever. We assessed whether genetic variations in genes involved in the killing machinery for C. burnetii by macrophages, contribute to the progression to chronic Q fever. METHODS: The prevalence of 66 single nucleotide polymorphisms (SNPs) in 31 genes pivotal in phagolysosomal maturation, bacterial killing and autophagy, was determined in 173 chronic Q fever patients and 184 controls with risk factors for chronic Q fever and serological evidence of a C. burnetii infection. Associations were detected with univariate logistic regression models. To assess the effect of these SNPs on innate responses to C. burnetii, the C. burnetii-induced cytokine production and basal reactive oxygen species production of healthy volunteers was determined. RESULTS: RAB7A (rs13081864) and P2RX7 loss-of-function SNP (rs3751143) were more common in chronic Q fever patients than in controls. RAB5A (rs8682), P2RX7 gain-of-function SNP (rs1718119), MAP1LC3A (rs1040747) and ATG5 (rs2245214) were more common in controls. In healthy volunteers, RAB7A (rs13081864) and MAP1LC3A (rs1040747) influenced the C. burnetii-induced cytokine production. RAB7A (rs13081864) modulated basal reactive oxygen species production. CONCLUSIONS: RAB7A (rs13081864) and P2RX7 (rs3751143) are associated with the development of chronic Q fever, whereas RAB5A (rs8682), P2RX7 (rs1718119), MAP1LC3A (rs1040747) and ATG5 (rs2245214) may have protective effects.
Assuntos
Coxiella burnetii/imunologia , Predisposição Genética para Doença , Imunidade Inata , Febre Q/genética , Febre Q/patologia , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A hallmark of obesity is chronic low-grade inflammation, which plays a major role in the process of atherosclerotic cardiovascular disease (ACVD). Gut microbiota is one of the factors influencing systemic immune responses, and profound changes have been found in its composition and metabolic function in individuals with obesity. This systematic review assesses the association between the gut microbiota and markers of low-grade inflammation in humans. We identified 14 studies which were mostly observational and relatively small (n = 10 to 471). The way in which the microbiome is analysed differed extensively between these studies. Lower gut microbial diversity was associated with higher white blood cell counts and high sensitivity C-reactive protein (hsCRP) levels. The abundance of Bifidobacterium, Faecalibacterium, Ruminococcus and Prevotella were inversely related to different markers of low-grade inflammation such as hsCRP and interleukin (IL)-6. In addition, this review speculates on possible mechanisms through which the gut microbiota can affect low-grade inflammation and thereby ACVD. We discuss the associations between the microbiome and the inflammasome, the innate immune system, bile acids, gut permeability, the endocannabinoid system and TMAO. These data reinforce the importance of human research into the gut microbiota as potential diagnostic and therapeutic strategy to prevent ACVD.
Assuntos
Aterosclerose/microbiologia , Microbioma Gastrointestinal , Inflamação/microbiologia , Obesidade/microbiologia , HumanosRESUMO
Signal transducer and activator of transcription 1 (STAT-1) gain-of-function (GOF) mutations cause chronic mucocutaneous candidiasis (CMC), a disease associated with Candida albicans and Staphylococcus aureus infection. Patients suffer from dysegulated immune responses due to aberrant cell programming and function. We investigated the effect of inhibitory molecules targeting histone deacetylases (HDACi) on the immune responses of peripheral blood mononuclear cells (PBMCs) of healthy controls and patients with CMC towards microbes relevant for CMC. PBMCs cells were pretreated with HDACi and challenged with C. albicans or S. aureus. Innate and adaptive cytokines were measured in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). We assessed the effect of HDAC inhibitors on T helper type 1 (Th1) and Th17 cells and measured STAT-1 and STAT-3 phosphorylation using flow cytometry. Panobinostat, a pan-HDAC inhibitor, strongly inhibits innate and adaptive cytokines upon challenge with C. albicans or S. aureus. Specific inhibitors (entinostat or RGFP966) also had a tendency to lower production of most innate cytokines in CMC patient cells. Entinostat and RGFP966 increased the production of interleukin (IL)-22 specifically after S. aureus challenge in patient cells. In healthy and control cells, entinostat and RGFP966 treatment down-regulated STAT-1 phosphorylation while pSTAT-3 levels remained stable. HDACi modulate cytokine production in response to C. albicans and S. aureus. Pan-inhibitors lower overall cytokine production, whereas specific inhibitors confer a selective effect. Entinostat and RGFP966 are promising therapeutic candidates to treat STAT-1 GOF due to their capacity to restore IL-22 production and decrease STAT-1 phosphorylation; however, their inhibition of innate cytokines poses a possible risk to secondary infections.