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1.
Front Immunol ; 11: 560381, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072099

RESUMO

Background: Emerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind. Methods: Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group. Results: sCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not. Conclusions: Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.


Assuntos
Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Betacoronavirus , Infecções por Coronavirus , Receptores de Lipopolissacarídeos , Pandemias , Pneumonia Viral , Receptores de Superfície Celular , Corticosteroides/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos CD/sangue , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/sangue , Antígenos de Diferenciação Mielomonocítica/imunologia , Betacoronavirus/imunologia , Betacoronavirus/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Unidades de Terapia Intensiva , Interleucina-6/sangue , Interleucina-6/imunologia , Receptores de Lipopolissacarídeos/sangue , Receptores de Lipopolissacarídeos/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Admissão do Paciente , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Receptores de Superfície Celular/sangue , Receptores de Superfície Celular/imunologia , Fatores de Tempo
2.
Anticancer Res ; 40(11): 6473-6484, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109586

RESUMO

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is an intractable tumor that has a very poor prognosis despite intensive treatment with temozolomide plus radiotherapy. PATIENTS AND METHODS: Sixteen newly diagnosed patients with high-grade gliomas were enrolled in a phase II study of the α-type-1 DC vaccine. Briefly, DCs obtained from the culture of enriched monocytes in the presence of a cytokine cocktail, were pulsed with a cocktail of 5 synthetic peptides and cryopreserved until injection into patients. RESULTS: The amount of IL-12 produced by activated DCs was higher than that previously reported. Among 15 evaluable patients, 10 showed positive CTL responses to any peptides in an ELISPOT assay. After 6 years of observation, five patients were still alive, and two of these patients were relapse-free. Moreover, a significant survival-prolonging effect was verified in DC-treated glioma patients. CONCLUSION: Peptide-cocktail-pulsed α-type-1 DC vaccines have a potential therapeutic effect on survival when used in combination with the standard regimen, which is partly based on IL-12-IFN-γ-mediated T-cell activation.


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/imunologia , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Vacinas Anticâncer/imunologia , Polaridade Celular/imunologia , Intervalo Livre de Doença , Feminino , Glioma/imunologia , Glioma/patologia , Humanos , Interferon gama/genética , Interleucina-12/genética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Linfócitos T/imunologia , Vacinação/métodos
3.
Front Immunol ; 11: 573662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123152

RESUMO

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.


Assuntos
Senescência Celular/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Envelhecimento/imunologia , Betacoronavirus/imunologia , Diabetes Mellitus Tipo 2/imunologia , Feminino , Humanos , Masculino , Monócitos/imunologia , Neutrófilos/imunologia , Obesidade/imunologia , Pandemias , Fatores de Risco , Linfócitos T/imunologia
4.
Cells ; 9(10)2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003471

RESUMO

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host-pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Células Dendríticas/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Pneumonia Viral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Células Cultivadas , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia
5.
PLoS One ; 15(9): e0238509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32870935

RESUMO

Dendrobium bibenzyls and phenanthrenes such as chrysotoxine, cypripedin, gigantol and moscatilin have been reported to show promising inhibitory effects on lung cancer growth and metastasis in ex vivo human cell line models, suggesting their potential for clinical application in patients with lung cancer. However, it remains to be determined whether these therapeutic effects can be also seen in primary human cells and/or in vivo. In this study, we comparatively investigated the immune modulatory effects of bibenzyls and phenanthrenes, including a novel Dendrobium bibenzyl derivative, in primary human monocytes. All compounds were isolated and purified from a Thai orchid Dendrobium lindleyi Steud, a new source of therapeutic compounds with promising potential of tissue culture production. We detected increased frequencies of TNF- and IL-6-expressing monocytes after treatment with gigantol and cypripedin, whereas chrysotoxine and moscatilin did not alter the expression of these cytokines in monocytes. Interestingly, the new 4,5-dihydroxy-3,3',4'-trimethoxybibenzyl derivative showed dose-dependent immune modulatory effects in lipopolysaccharide (LPS)-treated CD14lo and CD14hi monocytes. Together, our findings show immune modulatory effects of the new bibenzyl derivative from Dendrobium lindleyi on different monocyte sub-populations. However, therapeutic consequences of these different monocyte populations on human diseases including cancer remain to be investigated.


Assuntos
Bibenzilas/farmacologia , Dendrobium , Fatores Imunológicos/farmacologia , Monócitos/efeitos dos fármacos , Fenantrenos/farmacologia , Extratos Vegetais/farmacologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Bibenzilas/química , Células Cultivadas , Dendrobium/química , Guaiacol/análogos & derivados , Guaiacol/química , Guaiacol/farmacologia , Humanos , Fatores Imunológicos/química , Monócitos/imunologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Fenantrenos/química , Extratos Vegetais/química
6.
PLoS One ; 15(9): e0239488, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946496

RESUMO

The immunopathogenesis of H5N1 virus has been studied intensively since it caused cross-species infection and induced high mortality to human. We previously observed the interaction between monocytes and B cells, which increased the susceptibility of B cell to H5N1 virus infection after a co-culture. Levels of α2,3 sialic acid (avian flu receptor) were also significantly increased on B cell surface in this co-culture model with unclear explanation. In this study, we aimed to determine the possible mechanism that responded for this increase in α2,3 sialic acid on B cells. Acquisition of α2,3 SA by B cells via cell contact-dependent trogocytosis was proposed. Results showed that the lack of α2,3 SA was detected on B cell surface, and B cells acquired membrane-bound α2,3 SA molecules from monocytes in H5N1-infected co-cultures. Occurrence of membrane exchange mainly relied on H5N1 infection and cell-cell contact as opposed to a mock infection and transwell. The increase in α2,3 SA on B cell surface mediated by trogocytosis was associated with the enhanced susceptibility to H5N1 infection. These observations thus provide the evidence that H5N1 influenza virus may utilize trogocytosis to expand its cell tropism and spread to immune cells despite the lack of avian flu receptor.


Assuntos
Linfócitos B/imunologia , Linfócitos B/virologia , Virus da Influenza A Subtipo H5N1/imunologia , Virus da Influenza A Subtipo H5N1/patogenicidade , Influenza Humana/imunologia , Influenza Humana/virologia , Monócitos/imunologia , Ácido N-Acetilneuramínico/imunologia , Animais , Apresentação do Antígeno , Linfócitos B/metabolismo , Aves , Comunicação Celular/imunologia , Técnicas de Cocultura , Humanos , Influenza Aviária/imunologia , Influenza Aviária/virologia , Monócitos/metabolismo , Monócitos/virologia , Ácido N-Acetilneuramínico/metabolismo , Receptores Virais/imunologia , Receptores Virais/metabolismo
7.
Anesth Analg ; 131(4): 993-999, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32925314

RESUMO

BACKGROUND: The cellular immune system is of pivotal importance with regard to the response to severe infections. Monocytes/macrophages are considered key immune cells in infections and downregulation of the surface expression of monocytic human leukocyte antigen-DR (mHLA-DR) within the major histocompatibility complex class II reflects a state of immunosuppression, also referred to as injury-associated immunosuppression. As the role of immunosuppression in coronavirus disease 2019 (COVID-19) is currently unclear, we seek to explore the level of mHLA-DR expression in COVID-19 patients. METHODS: In a preliminary prospective monocentric observational study, 16 COVID-19-positive patients (75% male, median age: 68 [interquartile range 59-75]) requiring hospitalization were included. The median Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score in 9 intensive care unit (ICU) patients with acute respiratory failure was 30 (interquartile range 25-32). Standardized quantitative assessment of HLA-DR on monocytes (cluster of differentiation 14+ cells) was performed using calibrated flow cytometry at baseline (ICU/hospital admission) and at days 3 and 5 after ICU admission. Baseline data were compared to hospitalized noncritically ill COVID-19 patients. RESULTS: While normal mHLA-DR expression was observed in all hospitalized noncritically ill patients (n = 7), 89% (8 of 9) critically ill patients with COVID-19-induced acute respiratory failure showed signs of downregulation of mHLA-DR at ICU admission. mHLA-DR expression at admission was significantly lower in critically ill patients (median, [quartiles]: 9280 antibodies/cell [6114, 16,567]) as compared to the noncritically ill patients (30,900 antibodies/cell [26,777, 52,251]), with a median difference of 21,508 antibodies/cell (95% confidence interval [CI], 14,118-42,971), P = .002. Reduced mHLA-DR expression was observed to persist until day 5 after ICU admission. CONCLUSIONS: When compared to noncritically ill hospitalized COVID-19 patients, ICU patients with severe COVID-19 disease showed reduced mHLA-DR expression on circulating CD14+ monocytes at ICU admission, indicating a dysfunctional immune response. This immunosuppressive (monocytic) phenotype remained unchanged over the ensuing days after ICU admission. Strategies aiming for immunomodulation in this population of critically ill patients should be guided by an immune-monitoring program in an effort to determine who might benefit best from a given immunological intervention.


Assuntos
Infecções por Coronavirus/imunologia , Estado Terminal , Antígenos HLA-DR/biossíntese , Antígenos HLA-DR/imunologia , Tolerância Imunológica/imunologia , Pneumonia Viral/imunologia , APACHE , Idoso , Anticorpos/análise , Anticorpos/imunologia , Infecções por Coronavirus/terapia , Cuidados Críticos , Regulação para Baixo/imunologia , Feminino , Humanos , Imunoterapia , Receptores de Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Pandemias , Pneumonia Viral/terapia , Estudos Prospectivos , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/fisiopatologia
8.
J Cancer Res Ther ; 16(4): 731-736, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930111

RESUMO

Background: Chronic state of inflammation is an important factor in advanced cancer which is used by tumor cells for maintaining survival and growth. Hematological parameters such as neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), and lymphocyte/monocyte ratio (LMR) are reliable indicators of systemic inflammation. We aimed to elucidate the effect of hematological parameters and clinical features of patients on the prognosis of advanced-stage non-small cell lung cancer (NSCLC). Methods: We included 102 Stage IV NSCLC patients who presented to the oncology clinic between 2010 and 2016. Pretreatment clinical parameters and NLR, TLR, and LMR were retrieved from the medical records. The cutoff values, calculated with receiver operating curve analysis, for NLR, LMR, and TLR were 2.5, 3, and 183, respectively. All patients were divided into two groups according to cutoff values and analyzed accordingly. Results: Median overall survival and progression-free survival were 10 and 6 months, respectively. In univariate analysis, high NLR, high TLR, and low LMR were found to be significantly associated with survival. Among clinical parameters having eastern cooperative oncology group performance score 0-1, older age (≥70 years) single metastatic disease was prognostic. In multivariate Cox regression analysis, only the number of metastatic lesions and LMR were found to be independent predictors for survival. Conclusion: Among hematological parameters, only LMR was found to be an independent predictor of survival in patients with advanced-stage NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Inflamação/sangue , Neoplasias Pulmonares/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Plaquetas/imunologia , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Inflamação/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos
9.
Sci Immunol ; 5(51)2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943497

RESUMO

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Monócitos/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Biomarcadores/sangue , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Reino Unido/epidemiologia
10.
Biomed Pharmacother ; 131: 110622, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32890967

RESUMO

Propolis, a resinous material produced by honey bees from plant exudates, has long been used in traditional herbal medicine and is widely consumed as a health aid and immune system booster. The COVID-19 pandemic has renewed interest in propolis products worldwide; fortunately, various aspects of the SARS-CoV-2 infection mechanism are potential targets for propolis compounds. SARS-CoV-2 entry into host cells is characterized by viral spike protein interaction with cellular angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2. This mechanism involves PAK1 overexpression, which is a kinase that mediates coronavirus-induced lung inflammation, fibrosis, and immune system suppression. Propolis components have inhibitory effects on the ACE2, TMPRSS2 and PAK1 signaling pathways; in addition, antiviral activity has been proven in vitro and in vivo. In pre-clinical studies, propolis promoted immunoregulation of pro-inflammatory cytokines, including reduction in IL-6, IL-1 beta and TNF-α. This immunoregulation involves monocytes and macrophages, as well as Jak2/STAT3, NF-kB, and inflammasome pathways, reducing the risk of cytokine storm syndrome, a major mortality factor in advanced COVID-19 disease. Propolis has also shown promise as an aid in the treatment of various of the comorbidities that are particularly dangerous in COVID-19 patients, including respiratory diseases, hypertension, diabetes, and cancer. Standardized propolis products with consistent bioactive properties are now available. Given the current emergency caused by the COVID-19 pandemic and limited therapeutic options, propolis is presented as a promising and relevant therapeutic option that is safe, easy to administrate orally and is readily available as a natural supplement and functional food.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Própole/farmacologia , Animais , Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Suplementos Nutricionais , Alimento Funcional , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Própole/administração & dosagem
11.
Nat Commun ; 11(1): 3924, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764665

RESUMO

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Monócitos/imunologia , Pneumonia Viral/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Biologia Computacional , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/sangue , Humanos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Receptores de Interleucina-6/imunologia , Análise de Célula Única/métodos
12.
EBioMedicine ; 59: 102964, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32861199

RESUMO

Mononuclear phagocytes are a widely distributed family of cells contributing to innate and adaptive immunity. Circulating monocytes and tissue macrophages participate in all stages of SARS COVID-19. They contribute to comorbidities predisposing to clinical infection, virus resistance and dissemination, and to host factors that determine disease severity, recovery and sequelae. Assays are available to detect viral infection and antibody responses, but no adequate tests have been developed to measure the activation level of monocytes and tissue macrophages, and the risk of progression to a fatal hyperinflammatory syndrome. Blood monocytes provide a window on the systemic immune response, from production to tissue recruitment, reflecting the impact of infection on the host. Ready availability of blood makes it possible to monitor severity and the risk of potentially lethal complications, by developing tests to assess the status of monocyte activation and its potential for further inflammatory dysregulation after recruitment to tissues and during recovery.


Assuntos
Infecções por Coronavirus/patologia , Monócitos/imunologia , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Imunidade Inata , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença
13.
PLoS One ; 15(8): e0237754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804985

RESUMO

A strain of lactic acid bacteria, Lactobacillus paracasei KW3110 (KW3110), activates M2 macrophages with anti-inflammatory reactions and mitigates aging-related chronic inflammation and blue-light exposure-induced retinal inflammation in mice. However, the mechanism underlying the anti-inflammatory effects of KW3110 remains unclear. In this study, we investigated the anti-inflammatory effects of KW3110 using both mouse and human immune cells and evaluated the suppressive effect of KW3110 on the inflammatory reactions of the cells stimulated with lipopolysaccharide and adenosine 5'-triphosphate (LPS/ATP). KW3110 treatment induced anti-inflammatory cytokine interleukin (IL)-10 production in the supernatants of murine macrophage-like cells, J774A.1, and suppressed IL-1ß production in the supernatants of LPS/ATP-stimulated cells. The influence of KW3110 on the production of these cytokines was inhibited by pre-treatment with phagocytosis blocker or transfection with siRNAs for IL-10 signaling components. KW3110 treatment also suppressed activation of caspase-1, an active component of inflammasome complexes, in LPS/ATP-stimulated J774A.1 cells, and its effect was inhibited by transfection with siRNAs for IL-10 signaling components. In addition to the effects of KW3110 on J774A.1 cells, KW3110 treatment induced IL-10 production in the supernatants of human monocytes, and KW3110 or IL-10 treatment suppressed caspase-1 activation and IL-1ß production in the supernatants of LPS/ATP-stimulated cells. These results suggest that KW3110 suppresses LPS/ATP stimulation-induced caspase-1 activation and IL-1ß production by promoting IL-10 production in mouse and human immune cells. Our findings reveal a novel anti-inflammatory mechanism of LAB and the effect of KW3110 on caspase-1 activation is expected to contribute to constructing future preventive strategies for inflammation-related disorders using food ingredients.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/terapia , Lactobacillus paracasei/imunologia , Probióticos/farmacologia , Animais , Caspase 1/metabolismo , Linhagem Celular , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/imunologia , Interleucina-10/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
14.
Proc Natl Acad Sci U S A ; 117(34): 20729-20740, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32796104

RESUMO

Tissue-resident macrophages can originate from embryonic or adult hematopoiesis. They play important roles in a wide range of biological processes including tissue remodeling during organogenesis, organ homeostasis, repair following injury, and immune response to pathogens. Although the origins and tissue-specific functions of resident macrophages have been extensively studied in many other tissues, they are not well characterized in skeletal muscle. In the present study, we have characterized the ontogeny of skeletal muscle-resident macrophages by lineage tracing and bone marrow transplant experiments. We demonstrate that skeletal muscle-resident macrophages originate from both embryonic hematopoietic progenitors located within the yolk sac and fetal liver as well as definitive hematopoietic stem cells located within the bone marrow of adult mice. Single-cell-based transcriptome analyses revealed that skeletal muscle-resident macrophages are distinctive from resident macrophages in other tissues as they express a distinct complement of transcription factors and are composed of functionally diverse subsets correlating to their origins. Functionally, skeletal muscle-resident macrophages appear to maintain tissue homeostasis and promote muscle growth and regeneration.


Assuntos
Macrófagos/imunologia , Músculo Esquelético/imunologia , Animais , Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Diferenciação Celular/genética , Linhagem da Célula/genética , Desenvolvimento Embrionário , Feminino , Heterogeneidade Genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Homeostase , Macrófagos/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Organogênese/genética
15.
Nat Immunol ; 21(11): 1327-1335, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32839612

RESUMO

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Imunidade Inata/imunologia , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Pneumonia/patologia , Animais , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Interferon Tipo I/imunologia , Interferon gama/imunologia , Queratina-18/genética , Leucócitos/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , NF-kappa B/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Pandemias , Pneumonia/genética , Pneumonia/virologia , Pneumonia Viral/imunologia , Regiões Promotoras Genéticas/genética , Linfócitos T/imunologia , Células Vero , Replicação Viral/imunologia
16.
Exp Parasitol ; 218: 107970, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32828829

RESUMO

Visceral leishmaniasis (VL) is an anthropozoonosis endemic in Brazil. We included 20 patients with confirmed diagnosis of VL and 20 healthy individuals to evaluate the expression levels of complement receptor 1 (CR1)/CD35 and CR3/CD11b on leukocytes in the peripheral blood and determine their correlation with the clinical state of patients. CR1/CD35 expression increased on CD11b+CD35+granulocytes of patients, while CR1/CD35 and CR3/CD11b expression levels increased on CD14+CD11b+CD35+ monocytes. Among patients, those with severe clinical state had higher expression of CR3/CD11b on CD14+monocytes. The count of CD19+CD35+B lymphocytes reduced in the blood samples from patients. These observed changes may indicate the modulation in CR1/CD35 and CR3/CD11b complement receptor expressionlevels on granulocyte and monocyte populations in response to Leishmania sp.


Assuntos
Antígeno CD11b/metabolismo , Leishmaniose Visceral/imunologia , Leucócitos/metabolismo , Antígeno de Macrófago 1/metabolismo , Receptores de Complemento 3b/metabolismo , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Doenças Endêmicas/estatística & dados numéricos , Feminino , Citometria de Fluxo , Granulócitos/imunologia , Granulócitos/patologia , Humanos , Hipertrofia , Leishmaniose Visceral/sangue , Leishmaniose Visceral/epidemiologia , Leucócitos/imunologia , Fígado/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Pancitopenia , População Rural , Baço/patologia , População Urbana , Adulto Jovem
17.
Immunity ; 53(4): 864-877.e5, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32791036

RESUMO

The SARS-CoV-2 pandemic has resulted in millions of infections, yet the role of host immune responses in early COVID-19 pathogenesis remains unclear. By investigating 17 acute and 24 convalescent patients, we found that acute SARS-CoV-2 infection resulted in broad immune cell reduction including T, natural killer, monocyte, and dendritic cells (DCs). DCs were significantly reduced with functional impairment, and ratios of conventional DCs to plasmacytoid DCs were increased among acute severe patients. Besides lymphocytopenia, although neutralizing antibodies were rapidly and abundantly generated in patients, there were delayed receptor binding domain (RBD)- and nucleocapsid protein (NP)-specific T cell responses during the first 3 weeks after symptoms onset. Moreover, acute RBD- and NP-specific T cell responses included relatively more CD4 T cells than CD8 T cells. Our findings provided evidence that impaired DCs, together with timely inverted strong antibody but weak CD8 T cell responses, could contribute to acute COVID-19 pathogenesis and have implications for vaccine development.


Assuntos
Betacoronavirus/patogenicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus/imunologia , Hipertensão/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Convalescença , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Complicações do Diabetes , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/virologia , Progressão da Doença , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/virologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Monócitos/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Índice de Gravidade de Doença
18.
Clin Immunol ; 218: 108524, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659373

RESUMO

The outbreak of SARS-CoV-2-associated pneumonia, a disease called COVID-19, has caused a pandemic worldwide. To investigate the immune responses after infection of SARS-CoV-2 in non-critical patients may help to better understand the disease progression. We collected 334 confirmed COVID-19 cases including 212 still in hospital with nucleic acid test positive on halfway for SARS-CoV-2 and 122 discharged from hospital, compared specific antibodies, immune cells, and cytokine changes between the hospitalized and discharged patients. The hospitalized patients had a longer illness time compared with discharged patients. Analysis of viral loads explained long-term or persistent infection of SARS-CoV-2, which existed with the median time of 18.5 days of the positive nucleic acid test. Serum analysis showed that the specific anti-N IgG antibody was positive in all detected patients after infection of two weeks. Neutrophils, Monocytes, NK cells, and CD4+ T cells significantly increased, while total lymphocytes and CD8+ T cells decreased from non-critical hospitalized patients after longer-term infection. Further analysis of the cytokines showed that IL-6, TNF-α, IFN-γ, IL-2, IL-4, and IL-10 from the hospitalized patients were significantly higher, indicating a potential of the increased CD4+ T cell differentiation.


Assuntos
Betacoronavirus/patogenicidade , Doenças Cardiovasculares/imunologia , Infecções por Coronavirus/imunologia , Diabetes Mellitus/imunologia , Imunidade Inata , Pneumopatias/imunologia , Neoplasias/imunologia , Pneumonia Viral/imunologia , Idoso , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/virologia , China/epidemiologia , Comorbidade , Convalescença , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/sangue , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Diabetes Mellitus/virologia , Feminino , Hospitalização , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Pneumopatias/epidemiologia , Pneumopatias/patologia , Pneumopatias/virologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/patologia , Subpopulações de Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Monócitos/virologia , Neoplasias/epidemiologia , Neoplasias/patologia , Neoplasias/virologia , Neutrófilos/imunologia , Neutrófilos/patologia , Neutrófilos/virologia , Pandemias , Alta do Paciente , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Fatores de Tempo , Carga Viral/imunologia
19.
Cytometry A ; 97(9): 887-890, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32654350

RESUMO

In patients with severe SARS-CoV-2 infection, the development of cytokine storm induces extensive lung damage, and monocytes play a role in this pathological process. Non-classical (NC) and intermediate (INT) monocytes are known to be involved during viral and bacterial infections. In this study, 30 patients with different manifestations of acute SARS-CoV-2 infection were investigated with a flow cytometric study of NC, INT, and classical (CL) monocytes. Significantly reduced NC and INT monocytes and a downregulated HLA-DR were found in acute patients with severe SARS-CoV-2 symptoms. Conversely in patients with moderate symptoms NC and INT monocytes and CD11b expression were increased. © 2020 International Society for Advancement of Cytometry.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Monócitos/imunologia , Pneumonia Viral/imunologia , Idoso , Betacoronavirus/patogenicidade , Biomarcadores/análise , Antígeno CD11b/análise , Separação Celular , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Citometria de Fluxo , Interações entre Hospedeiro e Microrganismos , Humanos , Leucócitos , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Pandemias , Fenótipo , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Índice de Gravidade de Doença
20.
Anticancer Res ; 40(8): 4763-4771, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727803

RESUMO

BACKGROUND/AIM: Chemoimmunotherapy is a promising treatment for various malignant diseases. In this study, we examined whether first-line chemoimmunotherapy using adoptive immune-cell therapy was effective for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The therapeutic efficacy and safety of the standard first-line chemoimmunotherapy with adoptive αß T cell therapy and bevacizumab were assessed using thirty-two patients with mCRC in our hospital. Immunological status after this chemoimmunotherapy was also evaluated. RESULTS: The response and disease control rates were 68.8% and 87.5%, respectively. Further, median progression-free and overall survival were 14.2 and 35.3 months. Immunotherapy-associated toxicity was minimal. Significant decrease in the change of monocyte number (p=0.006) and increase in the change of rate of lymphocyte-to-monocyte ratio (p=0.039) were seen in the complete response group. CONCLUSION: First-line chemoimmunotherapy with adoptive αß T cell therapy may be useful for mCRC.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Imunoterapia/métodos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Intervalo Livre de Progressão
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