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1.
Lancet Oncol ; 21(9): e419-e430, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888471

RESUMO

Notable advances have been achieved in the treatment of cancer since the advent of immunotherapy, and immune checkpoint inhibitors have shown clinical benefit across a wide variety of tumour types. Nevertheless, most patients still progress on these treatments, highlighting the importance of unravelling the underlying mechanisms of primary resistance to immunotherapy. A well described biomarker of non-responsiveness to immune checkpoint inhibitors is the absence or low presence of lymphocytes in the tumour microenvironment, so-called cold tumours. There are five mechanisms of action that have the potential to turn cold tumours into so-called hot and inflamed tumours, hence increasing the tumour's responsiveness to immunotherapy-increasing local inflammation, neutralising immunosuppression at the tumour site, modifying the tumour vasculature, targeting the tumour cells themselves, or increasing the frequency of tumour-specific T cells. In this Review, we discuss preclinical data that serves as the basis for ongoing immunotherapy clinical trials for the treatment of non-immunoreactive tumours, as well as reviewing clinical and translational data where available. We explain how improving our understanding of the underlying mechanisms of primary resistance to immunotherapy will help elucidate an increasingly granular view of the tumour microenvironment cellular composition, functional status, and cellular localisation, with the goal of further therapy refinement.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Imunoterapia/efeitos adversos , Inflamação/terapia , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunidade Celular/imunologia , Inflamação/imunologia , Inflamação/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Microambiente Tumoral/imunologia
2.
Nat Commun ; 11(1): 4457, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901017

RESUMO

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.


Assuntos
Ácidos Graxos Voláteis/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Interleucinas/biossíntese , Animais , Butiratos/imunologia , Butiratos/metabolismo , Butiratos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Citrobacter rodentium , Colite/imunologia , Colite/microbiologia , Colite/prevenção & controle , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Interleucinas/deficiência , Interleucinas/genética , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
4.
DNA Cell Biol ; 39(10): 1838-1849, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32876480

RESUMO

The breast cancer gene 1 (BRCA1) is a tumor suppressor, and mutations or epigenetic inactivation will increase the risk of breast cancer oncogenesis. The current research aimed to explore the relationship between BRCA1 expression, prognosis, and tumor immunity in hepatocellular carcinoma (HCC). In this study, BRCA1 expression was analyzed via multiple online databases and its association with clinical characteristics, prognosis and genetic alterations was identified using the original The Cancer Genome Atlas-liver hepatocellular carcinoma cohorts. DNA methylation sites and their prognostic values were analyzed using MethSurv. The correlations between BRCA1 and immune infiltration were investigated via Tumor Immune Estimation Resource. As results, BRCA1 was significantly upregulated in tumor tissues in multiple HCC cohorts. Besides, high BRCA1 expression was correlated with race, advanced T stage, clinical stage, poor tumor grade, MSI status, and worse prognosis. Notably, BRCA1 expression was positively correlated with infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. The current findings imply that BRCA1 is associated with prognosis and immune infiltration, laying foundations for in-depth research on the role of BRCA1 in HCC.


Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína BRCA1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Movimento Celular , Metilação de DNA , Células Dendríticas/imunologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Linfócitos/imunologia , Macrófagos/imunologia
5.
Nat Commun ; 11(1): 3798, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732867

RESUMO

Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis.


Assuntos
Células Endoteliais/citologia , Endotélio Vascular/citologia , Linfonodos/irrigação sanguínea , Linfócitos/imunologia , Células Mieloides/imunologia , Animais , Sequência de Bases , Movimento Celular/imunologia , Feminino , Perfilação da Expressão Gênica , Homeostase/imunologia , Inflamação/imunologia , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma/genética
6.
Blood ; 136(7): 914, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32790856
8.
Life Sci ; 258: 118167, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735885

RESUMO

AIMS: This study aimed to make a comparison between the clinical laboratory-related factors, complete blood count (CBC) indices, cytokines, and lymphocyte subsets in order to distinguish severe coronavirus disease 2019 (COVID-19) cases from the non-severe ones. MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, Scopus, and Web of Science databases until March 31, 2020. Cochrane's Q test and the I2 statistic were used to determine heterogeneity. We used the random-effect models to pool the weighted mean differences (WMDs) and 95% confidence intervals (CIs). KEY FINDINGS: Out of a total of 8557 initial records, 44 articles (50 studies) with 7865 patients (ranging from 13 to 1582), were included. Our meta-analyses with random-effect models showed a significant decrease in lymphocytes, monocyte, CD4+ T cells, CD8+ T cells, CD3 cells, CD19 cells, and natural killer (NK) cells and an increase in the white blood cell (WBC), neutrophils, neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP)/hs-CRP, erythrocyte sedimentation rate (ESR), ferritin, procalcitonin (PCT), and serum amyloid A (SAA), interleukin-2 (IL-2), IL-2R, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ) in the severe group compared to the non-severe group. However, no significant differences were found in IL-1ß, IL-17, and CD4/CD8 T cell ratio between the two groups. SIGNIFICANCE: Decrease in total lymphocytes and lymphocyte subsets as well as the elevation of CRP, ESR, SAA, PCT, ferritin, and cytokines, but not IL-1ß and IL-17, were closely associated with COVID-19 severity, implying reliable indicators of severe COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Citocinas/sangue , Linfócitos/imunologia , Pneumonia Viral/sangue , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Relação CD4-CD8 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Humanos , Contagem de Linfócitos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Prognóstico
9.
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
10.
World J Emerg Surg ; 15(1): 41, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605582

RESUMO

BACKGROUND: Iron metabolism and immune response to SARS-CoV-2 have not been described yet in intensive care patients, although they are likely involved in Covid-19 pathogenesis. METHODS: We performed an observational study during the peak of pandemic in our intensive care unit, dosing D-dimer, C-reactive protein, troponin T, lactate dehydrogenase, ferritin, serum iron, transferrin, transferrin saturation, transferrin soluble receptor, lymphocyte count and NK, CD3, CD4, CD8 and B subgroups of 31 patients during the first 2 weeks of their ICU stay. Correlation with mortality and severity at the time of admission was tested with the Spearman coefficient and Mann-Whitney test. Trends over time were tested with the Kruskal-Wallis analysis. RESULTS: Lymphopenia is severe and constant, with a nadir on day 2 of ICU stay (median 0.555 109/L; interquartile range (IQR) 0.450 109/L); all lymphocytic subgroups are dramatically reduced in critically ill patients, while CD4/CD8 ratio remains normal. Neither ferritin nor lymphocyte count follows significant trends in ICU patients. Transferrin saturation is extremely reduced at ICU admission (median 9%; IQR 7%), then significantly increases at days 3 to 6 (median 33%, IQR 26.5%, p value 0.026). The same trend is observed with serum iron levels (median 25.5 µg/L, IQR 69 µg/L at admission; median 73 µg/L, IQR 56 µg/L on days 3 to 6) without reaching statistical significance. Hyperferritinemia is constant during intensive care stay: however, its dosage might be helpful in individuating patients developing haemophagocytic lymphohistiocytosis. D-dimer is elevated and progressively increases from admission (median 1319 µg/L; IQR 1285 µg/L) to days 3 to 6 (median 6820 µg/L; IQR 6619 µg/L), despite not reaching significant results. We describe trends of all the abovementioned parameters during ICU stay. CONCLUSIONS: The description of iron metabolism and lymphocyte count in Covid-19 patients admitted to the intensive care unit provided with this paper might allow a wider understanding of SARS-CoV-2 pathophysiology.


Assuntos
Infecções por Coronavirus , Cuidados Críticos , Ferro/metabolismo , Linfócitos/imunologia , Pandemias , Pneumonia Viral , Idoso , Betacoronavirus/isolamento & purificação , Coagulação Sanguínea , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Correlação de Dados , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Itália/epidemiologia , Contagem de Linfócitos/métodos , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Mortalidade , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Índice de Gravidade de Doença , Transferrina/análise
11.
PLoS Pathog ; 16(7): e1008651, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32658914

RESUMO

Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain ill-defined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer. Anti-HMGB1 ablated lung ILC2 numbers and ASM growth in vivo, and inhibited ILC2-mediated ASM cell proliferation in a co-culture model. Furthermore, we identified that HMGB1/RAGE (receptor for advanced glycation endproducts) signalling mediates an ILC2-intrinsic IL-13 auto-amplification loop. In summary, therapeutic targeting of the HMGB1/RAGE signalling axis may act as a novel asthma preventative by dampening ILC2-mediated type-2 inflammation and associated ASM remodelling.


Assuntos
Remodelação das Vias Aéreas/imunologia , Proteína HMGB1/imunologia , Inflamação/imunologia , Linfócitos/imunologia , Músculo Liso/imunologia , Animais , Camundongos , Músculo Liso/patologia , Receptor para Produtos Finais de Glicação Avançada/imunologia
12.
Rev Med Virol ; 30(5): e2123, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32648313

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID-19 cases have been reported in 185 countries. Some patients with COVID-19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS-CoV-2 infection as well as immunotherapeutic strategies for COVID-19. Immune evasion by SARS-CoV-2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS-CoV-2 infection. Some potential immunotherapeutic strategies to control the progression of COVID-19, such as passive antibody therapy and use of interferon αß and IL-6 receptor (IL-6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID-19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Evasão da Resposta Imune/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Interferon Tipo I/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Progressão da Doença , Regulação da Expressão Gênica , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Imunização Passiva/métodos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Terapia de Alvo Molecular/métodos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Índice de Gravidade de Doença , Transdução de Sinais
13.
Rev Med Virol ; 30(5): e2130, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32656939

RESUMO

The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive-C-protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Coagulação Intravascular Disseminada/imunologia , Eritema/imunologia , Exantema/imunologia , Interações Hospedeiro-Patógeno/imunologia , Pneumonia Viral/imunologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Progressão da Doença , Coagulação Intravascular Disseminada/patologia , Coagulação Intravascular Disseminada/virologia , Eritema/patologia , Eritema/virologia , Exantema/patologia , Exantema/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata , Linfócitos/imunologia , Linfócitos/patologia , Linfócitos/virologia , Macrófagos/imunologia , Macrófagos/patologia , Macrófagos/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Receptores Virais/genética , Receptores Virais/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
14.
Nat Rev Immunol ; 20(9): 515-516, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728221

Assuntos
Antioxidantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Pulmão/imunologia , Neutrófilos/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Acetilcisteína/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Quimioterapia Combinada , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Regulação da Expressão Gênica , Glicina/análogos & derivados , Glicina/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/imunologia , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Sulfonamidas/uso terapêutico , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia
15.
Diabetes Res Clin Pract ; 166: 108340, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32707213

RESUMO

OBJECTIVE: To investigate the characteristics of lymphocytes in type 2 diabetic patients with coronavirus disease (COVID-19). METHODS: Patients with COVID-19 admitted to hospital in Wuxi, China from January 29 to March 15 were included in the study. Lymphocytes were measured and recorded at admission and during treatment. Hospitalization days, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid positive days, minimal lymphocyte count, and occurrence time were collected and comparatively analyzed. Correlations between minimal lymphocyte count and hospitalization days as well as SARS-CoV-2 nucleic acid positive days were analyzed. RESULTS: A total of 63 patients were included in the study, with 16 in the diabetic group and 47 in the non-diabetic group. After adjusting for potential confounding factors, we observed lower minimal lymphocyte count (0.67 ± 0.36 * 109/L vs. 1.30 ± 0.54 * 109/L, adjusted P = 0.001), earlier occurrence of the minimal lymphocyte count (2.68 ± 2.33 days vs. 5.29 ± 4.95 days, adjusted P = 0.042), and longer hospitalization time (20.44 ± 5.24 days vs. 17.11 ± 4.78 days, adjusted P = 0.047) in the diabetic group than in the non-diabetic group. There was a negative correlation between minimal lymphocyte count and hospitalization days (R = -0.600, P < 0.05) as well as SARS-CoV-2 nucleic acid positive days (R = -0.420, P < 0.05). CONCLUSIONS: The diabetic group with COVID-19 had lower lymphocyte count, reached the minimal count faster, and had longer hospital stays than the non-diabetic group. Hospitalization days and SARS-CoV-2 nucleic acid positive days were negatively correlated with the minimal lymphocyte count.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/imunologia , Diabetes Mellitus Tipo 2/imunologia , Linfócitos/imunologia , Pneumonia Viral/imunologia , Adulto , China/epidemiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/virologia , Feminino , Hospitalização , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Estudos Retrospectivos
16.
Rev Med Virol ; 30(5): e2134, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32618072
17.
J Vis Exp ; (160)2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32658195

RESUMO

Naïve lymphocytes recirculate from the blood to the lymphoid tissues under physiological condition and it is commonly recognized as an important phenomenon in the gut immunity. The stroma of secondary lymphoid organs, such as Peyer's patches (PPs) or mesenteric lymph nodes, are where naïve lymphocytes sense antigens. Naïve lymphocytes circulate through the bloodstream to reach high endothelial venules, the portal of entry into PPs. Some immunomodulators are estimated to influence lymphocyte migration, but the precise evaluation of microcirculation dynamics is very difficult, and establishing a method to observe lymphocyte migration in vivo can contribute to the clarification of the precise mechanisms. We refined the method of collecting lymphocytes from the lymph duct and observing the detailed dynamics of gut-tropic lymphocytes in rat PPs. We chose confocal laser scanning microscopy to observe rat PPs in vivo and recorded it using time-lapse photography. We can now obtain clear images that can contribute to the analysis of lymphocyte dynamics.


Assuntos
Linfócitos/citologia , Microscopia Confocal , Nódulos Linfáticos Agregados/imunologia , Animais , Movimento Celular , Linfonodos/imunologia , Linfócitos/imunologia , Masculino , Ratos
18.
PLoS One ; 15(7): e0236744, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730309

RESUMO

Repeated exposures to environmental allergens in susceptible individuals drive the development of type 2 inflammatory conditions such as asthma, which have been traditionally considered to be mainly mediated by Th2 cells. However, emerging evidence suggest that a new innate cell type, group 2 innate lymphoid cells (ILC2), plays a central role in initiating and amplifying a type 2 response, even in the absence of adaptive immunity. At present, the regulatory mechanisms for controlling ILC2 activation remain poorly understood. Here we report that respiratory delivery of immunogenic extracellular RNA (exRNAs) derived from RNA- and DNA-virus infected cells, was able to activate a protective response against acute type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus, in mice. Mechanistically, we found that the innate immune responses triggered by exRNAs had a potent suppressive effect in vivo on the proliferation and function of ILC2 without the involvement of adaptive immunity. We further provided the loss-of-function genetic evidence that the TLR3- and MAVS-mediated signaling axis is essential for the inhibitory effects of exRNAs in mouse lungs. Thus, our results indicate that the host detection of extracellular immunostimulatory RNAs generated during respiratory viral infections have an important function in the regulation of ILC2-driven acute lung inflammation.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , RNA/imunologia , Hipersensibilidade Respiratória/imunologia , Imunidade Adaptativa , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Alérgenos/imunologia , Alérgenos/metabolismo , Animais , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-33/imunologia , Interleucina-33/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Pneumonia/patologia , RNA/metabolismo , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais , Células Th2/imunologia , Células Th2/metabolismo , Receptor 3 Toll-Like/fisiologia
19.
Exp Parasitol ; 216: 107944, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619431

RESUMO

Evaluation of the murine isotype antibodies is essential in subunit vaccine development because inbred mouse strains with diverse genetic backgrounds respond different to recombinant proteins. In this regard, the main goal of this study was to measuring and comparing the profile of IgG isotype responses in C57BL/6 mice. For this purpose, the extracellular region of plasmodium vivax thrombospondin-related adhesive protein (PvTRAP) gene was expressed in Escherichia coli Rosetta (DE3)-pET23a. Then, the recombinant PvTRAP alone or emulsified with Freund's complete adjuvant were applied for immunization of the C57BL/6 mice. The role of antibodies and cellular immune responses induced by recombinant PvTRAP were evaluated. The results showed the level of anti-rPvTRAP IgG2c was significantly higher than IgG2a in the groups that received rPvTRAP alone (mean OD490 = 0.798 ± 0.12 and 0.39 ± 0.1, respectively) and emulsified with CFA/IFA (mean OD490 = 1.48 ± 0.07 and 0.605 ± 0.13, respectively; P < 0.05, independent sample t-test). Additionally, the immunized mice with rPvTRAP and rPvTRAP + CFA/IFA had an intermediate-avidity IgG2a antibody but high-avidity IgG2c antibody as well as the mean of serum antibody titers results exhibited that in both rPvTRAP and rPvTRAP + CFA/IFA mouse groups, IgG2a end-point titer (1:3200 and 1:25,600, respectively) was noteworthy lower than IgG2c (1:25,600 and 1:102,400, respectively). Moreover, the results revealed the eliciting significant levels of IFN-γ (P < 0.05, independent sample t-test) and no detectable level of IL-4 in the mouse groups received rPvTRAP alone and emulsified with CFA/IFA as compared to the mouse control groups. In general, our results showed that for correctly interpreting of Th1 immune responses in C57BL/6 mouse strain it is critical to measure IgG2c instead of IgG2a along with IFN-γ.


Assuntos
Imunoglobulina G/sangue , Plasmodium vivax/imunologia , Proteínas de Protozoários/imunologia , Vacinas Protozoárias/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Afinidade de Anticorpos , Dicroísmo Circular , Feminino , Imunofluorescência , Imunoglobulina G/classificação , Interferon gama/análise , Interleucina-4/análise , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/imunologia , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/imunologia
20.
Cardiovasc Pathol ; 49: 107260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32683240

RESUMO

PURPOSE: to study the effect of immunosupressive therapy (IST) in the virus-negative and virus-positive patients with immune-mediated myocarditis. METHODS: in 60 patients (45 male, 46.7 ± 11.8 years, mean LV EDD, 6.7 ± 0.7 cm, EF 26.2 ± 9.1%) active/borderline myocarditis was verified by endomyocardial biopsy (n = 38), intraoperative biopsy (n = 10), examination of explanted heart (n = 3) and autopsy (n = 9). Indications for IST determined based on histological, immune activity. The follow-up was 19.0 [7.25; 40.25] months. RESULTS: The viral genome in the myocardium was detected in 32 patients (V+ group), incl. parvovirus B19 in 23. The anti-heart antibody level was equally high in the V+ and V- patients. Antiviral therapy was administered in 24 patients. IST (in 22 V+ and 24 V- patients) include steroids (n = 40), hydroxychloroquine (n = 20), azathioprine (n = 21). The significant decrease of LV EDD (6.7 ± 0.7 to 6.4 ± 0.8), PAP (48.9 ± 15.5 to 39.4 ± 11.5 mm Hg, р<0,01), increase of EF (26.5 ± 0.9 to 36.0 ± 10.8), and lower lethality (23.9% and 64.3%; RR 0.37, 95% CI 0.19-0.71), p<0.01, were found only in IST group. Significant improvement due to IST were achieved not only in V-, but also in V+ patients. CONCLUSIONS: IST in patients with immune-mediated lymphocytic myocarditis is effective and is associated with lower lethality both in virus-negative and virus-positive patients.


Assuntos
Antivirais/uso terapêutico , Autoanticorpos/sangue , Imunossupressores/uso terapêutico , Linfócitos/efeitos dos fármacos , Miocardite/tratamento farmacológico , Miocárdio/imunologia , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos , Adulto , Idoso , Biópsia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Linfócitos/imunologia , Linfócitos/patologia , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Miocardite/imunologia , Miocardite/patologia , Miocardite/virologia , Miocárdio/patologia , Resultado do Tratamento , Viroses/imunologia , Viroses/patologia , Viroses/virologia , Vírus/imunologia , Adulto Jovem
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