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1.
Viruses ; 12(9)2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967229

RESUMO

As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.


Assuntos
Fatores Imunológicos/imunologia , Viroses/imunologia , Vírus/imunologia , Animais , Antivirais/uso terapêutico , Doença Crônica , Humanos , Fatores Imunológicos/antagonistas & inibidores , Imunoterapia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Viroses/terapia , Vírus/classificação
2.
Lancet ; 396(10247): 345-360, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738956

RESUMO

Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and relatives, and is the leading cause of the global burden from skin disease. Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders. The pathophysiology is complex and involves a strong genetic predisposition, epidermal dysfunction, and T-cell driven inflammation. Although type-2 mechanisms are dominant, there is increasing evidence that the disorder involves multiple immune pathways. Currently, there is no cure, but increasing numbers of innovative and targeted therapies hold promise for achieving disease control, including in patients with recalcitrant disease. We summarise and discuss advances in our understanding of the disease and their implications for prevention, management, and future research.


Assuntos
Dermatite Atópica/epidemiologia , Dermatite Atópica/fisiopatologia , Inflamação/fisiopatologia , Linfócitos T/imunologia , Adolescente , Asma/epidemiologia , Criança , Pré-Escolar , Comorbidade , Dermatite Atópica/prevenção & controle , Dermatite Atópica/terapia , Eczema/patologia , Hipersensibilidade Alimentar/epidemiologia , Predisposição Genética para Doença/genética , Carga Global da Doença , Humanos , Lactente , Transtornos Mentais/epidemiologia , Microbiota/fisiologia , Terapia de Alvo Molecular/métodos , Fototerapia/métodos , Prevalência , Prurido/patologia , Qualidade de Vida , Rinite Alérgica/epidemiologia , Linfócitos T/patologia
3.
Nature ; 585(7823): 102-106, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848245

RESUMO

Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis1. Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)2,3, as well as human studies4-6, have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4+ T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease.


Assuntos
Encefalomielite Autoimune Experimental/microbiologia , Microbioma Gastrointestinal/imunologia , Inflamação/patologia , Medula Espinal/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Vida Livre de Germes , Inflamação/imunologia , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Lactobacillus reuteri/química , Lactobacillus reuteri/imunologia , Lactobacillus reuteri/patogenicidade , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/química , Glicoproteína Mielina-Oligodendrócito/imunologia , Medula Espinal/imunologia , Células Th17/imunologia , Células Th17/patologia
4.
Zool Res ; 41(5): 503-516, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32772513

RESUMO

As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques ( Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b + and CD8 + cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b + cells, and persistent infiltration of CD8 + cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.


Assuntos
Envelhecimento/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Macaca mulatta/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Fatores Etários , Envelhecimento/metabolismo , Animais , Betacoronavirus/fisiologia , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/veterinária , Inflamação/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta/virologia , Doenças dos Macacos/imunologia , Doenças dos Macacos/virologia , Pandemias/veterinária , Pneumonia Viral/veterinária , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/veterinária , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Carga Viral/imunologia , Carga Viral/veterinária , Replicação Viral/imunologia
5.
Int J Antimicrob Agents ; 56(4): 106129, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32755653

RESUMO

INTRODUCTION: The effect of anti-infective agents in COVID-19 is unclear. The impact of changes in practice on prognosis over time has not been evaluated. METHODS: Single center, retrospective study in adults hospitalized in a medicine ward for COVID-19 from March 5th to April 25th 2020. Patient characteristics were compared between two periods (before/after March 19th) considering French guidelines. The aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission to intensive care unit (ICU) and/or death. RESULTS: A total of 132 patients were admitted: mean age 59.0±16.3 years; mean C-reactive protein (CRP) level 84.0±71.1 mg/L; 46% had a lymphocyte count <1000/mm3. Prescribed anti-infective agents were lopinavir-ritonavir (n=12), azithromycin (AZI) (n=28) and AZI combined with hydroxychloroquine (HCQ) (n=52). There was a significant decrease in ICU admission, from 43% to 12%, between the two periods (P<0.0001). Delays until transfer to ICU were similar between periods (P=0.86). Pulmonary computerized tomography (CT)-scans were performed significantly more often with time (from 50% to 90%, P<0.0001), and oxygen-dependency (53% vs 80%, P=0.001) and prescription of AZI±HCQ (from 25% to 76%, P<0.0001) were also greater over time. Multivariate analyses showed a reduction of unfavorable outcome in patients receiving AZI±HCQ (hazard ratio [HR]=0.45, 95% confidence interval [CI: 0.21-0.97], P=0.04), particularly among an identified category of individuals (lymphocyte ≥1000/mm3 or CRP ≥100 mg/L). CONCLUSION: The present study showed a significant decrease in admission to ICU over time, which was probably related to multiple factors, including a better indication of pulmonary CT-scan, oxygen therapy, and a suitable prescription of anti-infective agents.


Assuntos
Anti-Infecciosos/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Lopinavir/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ritonavir/uso terapêutico , Adulto , Idoso , Betacoronavirus/patogenicidade , Proteína C-Reativa/metabolismo , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Progressão da Doença , Combinação de Medicamentos , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pandemias , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Linfócitos T/patologia , Linfócitos T/virologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
6.
Int J Antimicrob Agents ; 56(4): 106143, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32853672

RESUMO

As no specific pharmacological treatment has been validated for use in coronavirus disease 2019 (COVID-19), we aimed to assess the effectiveness of azithromycin (AZM) in these patients at a referral centre in Iran. An open-label, randomised controlled trial was conducted on patients with laboratory-confirmed COVID-19. A total of 55 patients in the control group receiving hydroxychloroquine (HCQ) and lopinavir/ritonavir (LPV/r) were compared with 56 patients in the case group who in addition to the same regimen also received AZM. Patients with prior cardiac disease were excluded from the study. Furthermore, patients from the case group were assessed for cardiac arrythmia risk based on the American College of Cardiology (ACC) risk assessment for use of AZM and HCQ. The main outcome measures were vital signs, SpO2 levels, duration of hospitalisation, need for and length of intensive care unit admission, mortality rate and results of 30-day follow-up after discharge. Initially, there was no significant difference between the general conditions and vital signs of the two groups. The SpO2 levels at discharge were significantly higher, the respiratory rate was lower and the duration of admission was shorter in the case group. There was no significant difference in the mortality rate between the two groups. Patients who received AZM in addition to HCQ and LPV/r had a better general condition. HCQ+AZM combination may be beneficial for individuals who are known to have a very low underlying risk for cardiac arrhythmia based on the ACC criteria.


Assuntos
Anti-Infecciosos/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Lopinavir/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ritonavir/uso terapêutico , Adulto , Idoso , Betacoronavirus/patogenicidade , Proteína C-Reativa/metabolismo , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Progressão da Doença , Combinação de Medicamentos , Feminino , Frequência Cardíaca/fisiologia , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Segurança do Paciente , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Prognóstico , Testes de Função Respiratória , Análise de Sobrevida , Linfócitos T/patologia , Linfócitos T/virologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
7.
Int J Antimicrob Agents ; 56(4): 106144, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32853673

RESUMO

Hydroxychloroquine (HCQ) has been largely used and investigated as therapy for COVID-19 across various settings at a total dose usually ranging from 2400 mg to 9600 mg. In Belgium, off-label use of low-dose HCQ (total 2400 mg over 5 days) was recommended for hospitalised patients with COVID-19. We conducted a retrospective analysis of in-hospital mortality in the Belgian national COVID-19 hospital surveillance data. Patients treated either with HCQ monotherapy and supportive care (HCQ group) were compared with patients treated with supportive care only (no-HCQ group) using a competing risks proportional hazards regression with discharge alive as competing risk, adjusted for demographic and clinical features with robust standard errors. Of 8075 patients with complete discharge data on 24 May 2020 and diagnosed before 1 May 2020, 4542 received HCQ in monotherapy and 3533 were in the no-HCQ group. Death was reported in 804/4542 (17.7%) and 957/3533 (27.1%), respectively. In the multivariable analysis, mortality was lower in the HCQ group compared with the no-HCQ group [adjusted hazard ratio (aHR) = 0.684, 95% confidence interval (CI) 0.617-0.758]. Compared with the no-HCQ group, mortality in the HCQ group was reduced both in patients diagnosed ≤5 days (n = 3975) and >5 days (n = 3487) after symptom onset [aHR = 0.701 (95% CI 0.617-0.796) and aHR = 0.647 (95% CI 0.525-0.797), respectively]. Compared with supportive care only, low-dose HCQ monotherapy was independently associated with lower mortality in hospitalised patients with COVID-19 diagnosed and treated early or later after symptom onset.


Assuntos
Antimaláricos/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Proteína C-Reativa/metabolismo , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Progressão da Doença , Cálculos da Dosagem de Medicamento , Reposicionamento de Medicamentos , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Segurança do Paciente , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Linfócitos T/patologia , Linfócitos T/virologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
8.
PLoS One ; 15(8): e0236966, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776968

RESUMO

Platelet-leukocyte aggregates (PLAs) are associated with increased thrombosis risk. The influence of PLA formation is especially important for cancer patients, since thrombosis accounts for approximately 10% of cancer-associated deaths. Our objective was to characterize and quantify PLAs in whole blood samples from lung cancer patients compared to healthy volunteers with the intent to analyze PLA formation in the context of lung cancer-associated thrombosis. Consenting lung cancer patients (57) and healthy volunteers (56) were enrolled at the Dana Cancer Center at the University of Toledo Health Science Campus. Peripheral blood samples were analyzed by flow cytometry. Patient medical history was reviewed through electronic medical records. Most importantly, we found lung cancer patients to have higher percentages of platelet-T cell aggregates (PTCAs) than healthy volunteers among both CD4+ T lymphocyte and CD8+ T lymphocyte populations. Our findings demonstrate that characterization of PTCAs may have clinical utility in differentiating lung cancer patients from healthy volunteers and stratifying lung cancer patients by history of thrombosis.


Assuntos
Plaquetas/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/complicações , Linfócitos T/patologia , Trombose/sangue , Trombose/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Agregação Celular , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
9.
Rev Med Virol ; 30(5): e2144, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32671966

RESUMO

The significantly higher mortality rates seen in the elderly compared with young children during the coronavirus disease 2019 (Covid-19) pandemic is likely to be driven in part by an impaired immune response in older individuals. Cytomegalovirus (CMV) seroprevalence approaches 80% in the elderly. CMV has been shown to accelerate immune ageing by affecting peripheral blood T cell phenotypes and increasing inflammatory mediated cytokines such as IL-6. The elderly with pre-existing but clinically silent CMV infection may therefore be particularly susceptible to severe Covid-19 disease and succumb to a cytokine storm which may have been promoted by CMV. Here, we evaluate the potential role of CMV in those with severe Covid-19 disease and consider how this relationship can be investigated in current research studies.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/epidemiologia , Infecções por Citomegalovirus/epidemiologia , Citomegalovirus/patogenicidade , Imunossenescência , Pandemias , Pneumonia Viral/epidemiologia , Fatores Etários , Idoso , Betacoronavirus/imunologia , Criança , Coinfecção , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/virologia , Progressão da Doença , Humanos , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Estudos Soroepidemiológicos , Índice de Gravidade de Doença , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/patologia , Linfócitos T/virologia
10.
Anticancer Res ; 40(8): 4729-4740, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727799

RESUMO

BACKGROUND/AIM: In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cell vaccination in combination with standard therapies in terms of the survival of patients with advanced or recurrent endometrial and cervical cancers of the uterus. PATIENTS AND METHODS: A total of 187 patients with advanced or recurrent uterine cancer were enrolled in this study. The correlation between overall survival and various clinical factors was examined by univariate and multivariate analyses. RESULTS: Univariate analysis revealed that the prognosis was improved in uterine cancer patients who received immune-cell therapy without prior chemotherapy or without distant metastasis. Multivariate analysis demonstrated that the absence of prior chemotherapy for endometrial cancer and liver/lung metastasis of cervical cancer are indications for immune-cell therapy. CONCLUSION: Survival benefit in uterine cancer patients could be potentially obtained by a combination of immune-cell therapy with other therapies.


Assuntos
Neoplasias do Endométrio/patologia , Neoplasias do Colo do Útero/patologia , Neoplasias Uterinas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Linfócitos T/patologia , Resultado do Tratamento , Útero/patologia
11.
Front Immunol ; 11: 1625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719685

RESUMO

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus , Sistemas de Liberação de Medicamentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Pandemias , Pneumonia Viral , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
12.
J Allergy Clin Immunol ; 146(2): 315-324.e7, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531372

RESUMO

BACKGROUND: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019. OBJECTIVE: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection. METHODS: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets. RESULTS: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes. CONCLUSIONS: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.


Assuntos
Asma/epidemiologia , Asma/genética , Infecções por Coronavirus/epidemiologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Receptores Virais/genética , Adolescente , Adulto , Asma/classificação , Asma/imunologia , Betacoronavirus/genética , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Brônquios/imunologia , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Coortes , Infecções por Coronavirus/virologia , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/virologia , Mapeamento de Interação de Proteínas , Receptores Virais/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Linfócitos T/classificação , Linfócitos T/imunologia , Linfócitos T/patologia , Transcriptoma , Estados Unidos/epidemiologia
13.
PLoS Pathog ; 16(6): e1008621, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544188

RESUMO

During tuberculosis, lung myeloid cells have two opposing roles: they are an intracellular niche occupied by Mycobacterium tuberculosis, and they restrict bacterial replication. Lung myeloid cells from mice infected with yellow-fluorescent protein expressing M. tuberculosis were analyzed by flow cytometry and transcriptional profiling to identify the cell types infected and their response to infection. CD14, CD38, and Abca1 were expressed more highly by infected alveolar macrophages and CD11cHi monocyte-derived cells compared to uninfected cells. CD14, CD38, and Abca1 "triple positive" (TP) cells had not only the highest infection rates and bacterial loads, but also a strong interferon-γ signature and nitric oxide synthetase-2 production indicating recognition by T cells. Despite evidence of T cell recognition and appropriate activation, these TP macrophages are a cellular compartment occupied by M. tuberculosis long-term. Defining the niche where M. tuberculosis resists elimination promises to provide insight into why inducing sterilizing immunity is a formidable challenge.


Assuntos
Antígenos CD11/imunologia , Macrófagos Alveolares , Monócitos , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/imunologia , Animais , Antígenos CD11/genética , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Mycobacterium tuberculosis/genética , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , Tuberculose/genética , Tuberculose/patologia
14.
PLoS Pathog ; 16(6): e1008568, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32516328

RESUMO

Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus worldwide. However, whether and how HHV-6 infection influences the metabolic machinery of the host cell to provide the energy and biosynthetic resources for virus propagation remains unknown. In this study, we identified that HHV-6A infection promotes glucose metabolism in infected T cells, resulting in elevated glycolytic activity with an increase of glucose uptake, glucose consumption and lactate secretion. Furthermore, we explored the mechanisms involved in HHV-6A-mediated glycolytic activation in the infected T cells. We found increased expressions of the key glucose transporters and glycolytic enzymes in HHV-6A-infected T cells. In addition, HHV-6A infection dramatically activated AKT-mTORC1 signaling in the infected T cells and pharmacological inhibition of mTORC1 blocked HHV-6A-mediated glycolytic activation. We also found that direct inhibition of glycolysis by 2-Deoxy-D-glucose (2-DG) or inhibition of mTORC1 activity in HHV-6A-infected T cells effectively reduced HHV-6 DNA replication, protein synthesis and virion production. These results not only reveal the mechanism of how HHV-6 infection affects host cell metabolism, but also suggest that targeting the metabolic pathway could be a new avenue for HHV-6 therapy.


Assuntos
Glicólise , Herpesvirus Humano 6/metabolismo , Infecções por Roseolovirus/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , DNA Viral/biossíntese , Desoxiglucose/farmacologia , Glucose/metabolismo , Humanos , Ácido Láctico/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Infecções por Roseolovirus/tratamento farmacológico , Infecções por Roseolovirus/patologia , Linfócitos T/patologia , Linfócitos T/virologia , Proteínas Virais/biossíntese , Vírion/metabolismo
15.
Immunology ; 160(3): 261-268, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460357

RESUMO

Coronavirus disease 2019 (COVID-19) is a respiratory disorder caused by the highly contagious severe acute respiratory syndrome coronavirus 2. The immunopathological characteristics of patients with COVID-19, either systemic or local, have not been thoroughly studied. In the present study, we analysed both the changes in the number of various immune cell types as well as cytokines important for immune reactions and inflammation. Our data indicate that patients with severe COVID-19 exhibited an overall decline of lymphocytes including CD4+ and CD8+ T cells, B cells and natural killer cells. The number of immunosuppressive regulatory T cells was moderately increased in patients with mild COVID-19. Interleukin-6 (IL-6), IL-10 and C-reactive protein were remarkably up-regulated in patients with severe COVID-19. In conclusion, our study shows that the comprehensive decrease of lymphocytes, and the elevation of IL-6, IL-10 and C-reactive protein are reliable indicators of severe COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Idoso , Linfócitos B/imunologia , Linfócitos B/patologia , Betacoronavirus/fisiologia , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Linfócitos/patologia , Masculino , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/patologia , Linfócitos T Reguladores/patologia
16.
Cancer Immunol Immunother ; 69(10): 1989-1999, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32393998

RESUMO

Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno CTLA-4/sangue , Neoplasias Colorretais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/sangue , Receptores Imunológicos/sangue , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Antígeno CTLA-4/genética , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/genética , Receptores Imunológicos/genética , Linfócitos T/metabolismo , Linfócitos T/patologia , Adulto Jovem
17.
J Vasc Res ; 57(4): 236-244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32434199

RESUMO

INTRODUCTION AND OBJECTIVE: Interleukin (IL)-32 is a pro-inflammatory cytokine not previously studied in relation to abdominal aortic aneurysm (AAA). The aim of this study was to elucidate the expression and localization of IL-32 in AAA. METHODS: Expression and localization of IL-32 in human aortic tissue was studied with immunohistochemical analysis and Western blot (AAA: n = 5; controls: n = 4). ELISA was used to measure IL-32 in human plasma samples (AAA: n = 140; controls: n = 37) and in media from cultured peripheral blood mononuclear cells (PBMCs) from 3 healthy donors. IL-32 mRNA in PBMCs, endothelial cells, aortic smooth muscle cells (SMCs), and aortic tissue samples of AAA (n = 16) and control aortas (n = 9) was measured with qPCR. RESULTS: IL-32 was predominantly expressed in SMCs and T-cell-rich areas. Highest mRNA expression was observed in the intima/media layer of the AAA. A weaker protein expression was detected in non-aneurysmal aortas. Expression of IL-32 was confirmed in isolated T cells, macrophages, endothelial cells, and SMCs, where expression was also inducible by cytokines such as interferon-γ. There was no difference in IL-32 expression in plasma between patients and controls. CONCLUSION: IL-32 signaling is altered locally in AAA and could potentially play an important role in aneurysm development. Further studies using animal models would be helpful to study its potential role in AAA disease.


Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Interleucinas/metabolismo , Adulto , Idoso , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Interleucinas/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Regulação para Cima , Adulto Jovem
18.
Nat Genet ; 52(6): 594-603, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32451460

RESUMO

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.


Assuntos
Linhagem da Célula , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Colorretais/patologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Humanos , Análise de Sequência de RNA , Análise de Célula Única , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
19.
Int J Legal Med ; 134(4): 1271-1274, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32458044

RESUMO

In the setting of the coronavirus disease 2019 (COVID-19) pandemic, only few data regarding lung pathology induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is available, especially without medical intervention interfering with the natural evolution of the disease. We present here the first case of forensic autopsy of a COVID-19 fatality occurring in a young woman, in the community. Diagnosis was made at necropsy and lung histology showed diffuse alveolar damage, edema, and interstitial pneumonia with a geographically heterogeneous pattern, mostly affecting the central part of the lungs. This death related to COVID-19 pathology highlights the heterogeneity and severity of central lung lesions after natural evolution of the disease.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Adenoviridae/genética , Adenoviridae/isolamento & purificação , Adulto , Autopsia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Bocavirus/genética , Bocavirus/isolamento & purificação , Proteína C-Reativa/análise , Coronavirus/genética , Coronavirus/isolamento & purificação , Feminino , Humanos , Influenzavirus A/genética , Influenzavirus A/isolamento & purificação , Influenzavirus B/genética , Influenzavirus B/isolamento & purificação , Macrófagos/patologia , Megacariócitos/patologia , Metapneumovirus/genética , Metapneumovirus/isolamento & purificação , Neutrófilos/patologia , Obesidade Mórbida , Pandemias , Pró-Calcitonina/sangue , Reação em Cadeia da Polimerase em Tempo Real , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rhinovirus/genética , Rhinovirus/isolamento & purificação , Suíça , Linfócitos T/patologia
20.
J Nippon Med Sch ; 87(2): 100-103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32418941

RESUMO

A 39-year-old Japanese woman presented with a pruritic infiltrated erythematous plaque on the right cheek. Histopathologic analysis of the erythema showed dermal edema, separation of collagen bundles, and nodular perivascular and periadnexal infiltration of lymphocytes in the whole dermis, without epidermal changes. Alcian blue staining intensity was elevated between the collagen bundles, indicating dermal mucinosis. The nodular infiltrates consisted of CD3+ T cell clusters and CD20+ B cell clusters (ratio, approximately 3:1) and included numerous CD123+ cells, indicative of plasmacytoid dendritic cells. Blood analysis revealed serum antinuclear antibody at a titer of 1:160 (homogeneous, speckled pattern). Lupus erythematosus tumidus with pseudolymphomatous infiltrates was diagnosed. Hydroxychloroquine treatment partially improved symptoms; however, the addition of prednisolone was required for complete resolution. Lupus erythematosus tumidus is sometimes accompanied by pseudolymphomatous infiltrates. Dermal mucinosis and the presence of numerous plasmacytoid dendritic cells are useful in differentiating lupus erythematosus tumidus from pseudolymphoma.


Assuntos
Linfócitos B/patologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Pseudolinfoma/imunologia , Pseudolinfoma/patologia , Linfócitos T/patologia , Adulto , Antígenos CD20 , Linfócitos B/imunologia , Complexo CD3 , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Subunidade alfa de Receptor de Interleucina-3 , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pseudolinfoma/tratamento farmacológico , Linfócitos T/imunologia
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