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1.
PLoS One ; 18(1): e0280392, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36649304

RESUMO

For coronavirus disease 2019 (COVID-19), a pandemic disease characterized by strong immune dysregulation in severe patients, convenient and efficient monitoring of the host immune response is critical. Human hosts respond to viral and bacterial infections in different ways, the former is characterized by the activation of interferon stimulated genes (ISGs) such as IFI27, while the latter is characterized by the activation of anti-bacterial associated genes (ABGs) such as S100A12. This two-tiered innate immune response has not been examined in COVID-19. In this study, the activation patterns of this two-tiered innate immune response represented by IFI27 and S100A12 were explored based on 1421 samples from 17 transcriptome datasets derived from the blood of COVID-19 patients and relevant controls. It was found that IFI27 activation occurred in most of the symptomatic patients and displayed no correlation with disease severity, while S100A12 activation was more restricted to patients under severe and critical conditions with a stepwise activation pattern. In addition, most of the S100A12 activation was accompanied by IFI27 activation. Furthermore, the activation of IFI27 was most pronounced within the first week of symptom onset, but generally waned after 2-3 weeks. On the other hand, the activation of S100A12 displayed no apparent correlation with disease duration and could last for several months in certain patients. These features of the two-tiered innate immune response can further our understanding on the disease mechanism of COVID-19 and may have implications to the clinical triage. Development of a convenient two-gene protocol for the routine serial monitoring of this two-tiered immune response will be a valuable addition to the existing laboratory tests.


Assuntos
COVID-19 , Imunidade Inata , Humanos , COVID-19/genética , COVID-19/imunologia , Marcadores Genéticos , Imunidade Inata/genética , Interferons , Proteína S100A12/genética
2.
Cell Transplant ; 32: 9636897221149444, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36644879

RESUMO

Clinically, xenotransplantation often leads to T-cell-mediated graft rejection. Immunosuppressive agents including polyclonal regulatory T cells (poly-Tregs) promote global immunosuppression, resulting in serious infections and malignancies in patients. Xenoantigen-expanded Tregs (xeno-Tregs) have become a promising immune therapy strategy to protect xenografts with fewer side effects. In this study, we aimed to identify an efficient and stable subset of xeno-Tregs. We enriched CD27+ xeno-Tregs using cell sorting and evaluated their suppressive functions and stability in vitro via mixed lymphocyte reaction (MLR), real-time polymerase chain reaction, inflammatory induction assay, and Western blotting. A STAT5 inhibitor was used to investigate the relationship between the function and stability of CD27+ xeno-Tregs and the JAK3-STAT5 signaling pathway. A humanized xenotransplanted mouse model was used to evaluate the function of CD27+ xeno-Tregs in vivo. Our results show that CD27+ xeno-Tregs express higher levels of Foxp3, cytotoxic T-lymphocyte antigen-4 (CTLA4), and Helios and lower levels of interleukin-17 (IL-17) than their CD27- counterparts. In addition, CD27+ xeno-Tregs showed enhanced suppressive function in xeno-MLR at ratios of 1:4 and 1:16 of Tregs:responder cells. Under inflammatory conditions, a lower percentage of CD27+ xeno-Tregs secretes IL-17 and interferon-γ (IFN-γ). CD27+ xeno-Tregs demonstrated an upregulated JAK3-STAT5 pathway compared with that of CD27- xeno-Tregs and showed decreased Foxp3, Helios, and CTLA4 expression after addition of STAT5 inhibitor. Mice that received porcine skin grafts showed a normal tissue phenotype and less leukocyte infiltration after reconstitution with CD27+ xeno-Tregs. Taken together, these data indicate that CD27+ xeno-Tregs may suppress immune responses in a xenoantigen-specific manner, which might be related to the activation of the JAK3-STAT5 signaling pathway.


Assuntos
Interleucina-17 , Linfócitos T Reguladores , Transplante Heterólogo , Animais , Humanos , Camundongos , Antígenos Heterófilos/metabolismo , Antígeno CTLA-4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Interleucina-17/metabolismo , Ativação Linfocitária , Fator de Transcrição STAT5/metabolismo , Suínos , Linfócitos T Reguladores/imunologia
3.
Science ; 379(6627): 84-88, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36603070

RESUMO

The central nervous system is lined by meninges, classically known as dura, arachnoid, and pia mater. We show the existence of a fourth meningeal layer that compartmentalizes the subarachnoid space in the mouse and human brain, designated the subarachnoid lymphatic-like membrane (SLYM). SLYM is morpho- and immunophenotypically similar to the mesothelial membrane lining of peripheral organs and body cavities, and it encases blood vessels and harbors immune cells. Functionally, the close apposition of SLYM with the endothelial lining of the meningeal venous sinus permits direct exchange of small solutes between cerebrospinal fluid and venous blood, thus representing the mouse equivalent of the arachnoid granulations. The functional characterization of SLYM provides fundamental insights into brain immune barriers and fluid transport.


Assuntos
Encéfalo , Espaço Subaracnóideo , Animais , Humanos , Camundongos , Dura-Máter/citologia , Dura-Máter/fisiologia , Endotélio/citologia , Endotélio/fisiologia , Espaço Subaracnóideo/citologia , Espaço Subaracnóideo/fisiologia , Epitélio/fisiologia , Encéfalo/anatomia & histologia , Encéfalo/imunologia , Líquido Cefalorraquidiano/fisiologia
4.
Science ; 379(6627): 45-62, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36603072

RESUMO

Age-related macular degeneration is a prevalent neuroinflammatory condition and a major cause of blindness driven by genetic and environmental factors such as obesity. In diseases of aging, modifiable factors can be compounded over the life span. We report that diet-induced obesity earlier in life triggers persistent reprogramming of the innate immune system, lasting long after normalization of metabolic abnormalities. Stearic acid, acting through Toll-like receptor 4 (TLR4), is sufficient to remodel chromatin landscapes and selectively enhance accessibility at binding sites for activator protein-1 (AP-1). Myeloid cells show less oxidative phosphorylation and shift to glycolysis, ultimately leading to proinflammatory cytokine transcription, aggravation of pathological retinal angiogenesis, and neuronal degeneration associated with loss of visual function. Thus, a past history of obesity reprograms mononuclear phagocytes and predisposes to neuroinflammation.


Assuntos
Imunidade Inata , Degeneração Macular , Doenças Neuroinflamatórias , Obesidade , Animais , Camundongos , Citocinas/genética , Imunidade Inata/genética , Doenças Neuroinflamatórias/genética , Doenças Neuroinflamatórias/imunologia , Obesidade/genética , Fagócitos/imunologia , Transcrição Genética , Degeneração Macular/genética , Degeneração Macular/imunologia , Reprogramação Celular/genética , Receptor 4 Toll-Like/genética
5.
Science ; 379(6627): 28-29, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36603093
6.
Brief Bioinform ; 24(1)2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36611255

RESUMO

Accurate in silico prediction of conformational B-cell epitopes would lead to major improvements in disease diagnostics, drug design and vaccine development. A variety of computational methods, mainly based on machine learning approaches, have been developed in the last decades to tackle this challenging problem. Here, we rigorously benchmarked nine state-of-the-art conformational B-cell epitope prediction webservers, including generic and antibody-specific methods, on a dataset of over 250 antibody-antigen structures. The results of our assessment and statistical analyses show that all the methods achieve very low performances, and some do not perform better than randomly generated patches of surface residues. In addition, we also found that commonly used consensus strategies that combine the results from multiple webservers are at best only marginally better than random. Finally, we applied all the predictors to the SARS-CoV-2 spike protein as an independent case study, and showed that they perform poorly in general, which largely recapitulates our benchmarking conclusions. We hope that these results will lead to greater caution when using these tools until the biases and issues that limit current methods have been addressed, promote the use of state-of-the-art evaluation methodologies in future publications and suggest new strategies to improve the performance of conformational B-cell epitope prediction methods.


Assuntos
Epitopos de Linfócito B , Glicoproteína da Espícula de Coronavírus , Humanos , Biologia Computacional/métodos , Epitopos de Linfócito B/imunologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia
7.
Mem Inst Oswaldo Cruz ; 117: e220072, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36700578

RESUMO

BACKGROUND: Patients with severe coronavirus disease 2019 (COVID-19) often present with coagulopathies and have high titres of circulating antibodies against viral proteins. OBJECTIVES: Herein, we evaluated the association between D-dimer and circulating immunoglobulin levels against viral proteins in patients at different clinical stages of COVID-19. METHODS: For this, we performed a cross-sectional study involving patients of the first wave of COVID-19 clinically classified as oligosymptomatic (n = 22), severe (n = 30), cured (n = 27) and non-infected (n = 9). Next, we measured in the plasma samples the total and fraction of immunoglobulins against the nucleoprotein (NP) and the receptor-binding domain (RBD) of the spike proteins by enzyme-linked immunosorbent assay (ELISA) assays. FINDINGS: Patients with severe disease had a coagulation disorder with high levels of D-dimer as well as circulating IgG against the NP but not the RBD compared to other groups of patients. In addition, high levels of D-dimer and IgG against the NP and RBD were associated with disease severity among the patients in this study. MAIN CONCLUSIONS: Our data suggest that IgG against NP and RBD participates in the worsening of COVID-19. Although the humoral response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is partially understood, and more efforts are needed to clarify gaps in the knowledge of this process.


Assuntos
Transtornos da Coagulação Sanguínea , COVID-19 , Imunidade Humoral , Humanos , Anticorpos Antivirais/sangue , COVID-19/imunologia , Estudos Transversais , Imunoglobulina G/sangue , SARS-CoV-2 , Proteínas Virais
10.
Respir Res ; 24(1): 26, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694181

RESUMO

BACKGROUND: Severe bronchiolitis is often associated with subsequent respiratory morbidity, mainly recurrent wheezing and asthma. However, the underlying immune mechanisms remain unclear. The main goal of this study was to investigate the association of nasal detection of periostin and thymic stromal lymphopoietin (TSLP) during severe bronchiolitis with the development of asthma at 4 years of age. METHODS: Observational, longitudinal, post-bronchiolitis, hospital-based, follow-up study. Children hospitalized for bronchiolitis between October/2013 and July/2017, currently aged 4 years, included in a previous study to investigate the nasal airway secretion of TSLP and periostin during bronchiolitis, were included. Parents were contacted by telephone, and were invited to a clinical interview based on a structured questionnaire to obtain information on the respiratory evolution. The ISAAC questionnaire for asthma symptoms for 6-7-year-old children, was also employed. RESULTS: A total of 248 children were included (median age 4.4 years). The mean age at admission for bronchiolitis was 3.1 (IQR: 1.5-6.5) months. Overall, 21% had ever been diagnosed with asthma and 37% had wheezed in the last 12 months. Measurable nasal TSLP was detected at admission in 27(11%) cases and periostin in 157(63%). The detection of nasal TSLP was associated with the subsequent prescription of maintenance asthma treatment (p = 0.04), montelukast (p = 0.01), and the combination montelukast/inhaled glucocorticosteroids (p = 0.03). Admissions for asthma tended to be more frequent in children with TSLP detection (p = 0.07). In the multivariate analysis, adjusting for potential confounders, the detection of TSLP remained independently associated with chronic asthma treatment prescription (aOR:2.724; CI 1.051-7.063, p:0.04) and with current asthma (aOR:3.41; CI 1.20-9.66, p:0.02). Nasal detection of periostin was associated with lower frequency of ever use of short-acting beta2-agonists (SABA) (p = 0.04), lower prevalence of current asthma (p = 0.02), less prescription of maintenance asthma treatment in the past 12 months (p = 0.02, respectively). In the multivariate analysis, periostin was associated with lower risk of asthma at 4 years, independently of the atopic status (aOR:0.511 CI 95% 0.284-0.918, p:0.025). CONCLUSIONS: Our results show a positive correlation between nasal TSLP detection in severe bronchiolitis and the presence of current asthma, prescription of asthma maintenance treatment and respiratory admissions up to the age of 4 years. By contrast, we found a protective association between nasal periostin detection and current asthma at 4 years, ever diagnosis of asthma, maintenance asthma treatment prescription, and respiratory admissions.


Assuntos
Asma , Bronquiolite , Infecções por Vírus Respiratório Sincicial , Criança , Pré-Escolar , Humanos , Lactente , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/epidemiologia , Asma/imunologia , Bronquiolite/complicações , Bronquiolite/diagnóstico , Bronquiolite/epidemiologia , Bronquiolite/imunologia , Citocinas , Seguimentos , Infecções por Vírus Respiratório Sincicial/epidemiologia
11.
Nature ; 613(7945): 639-649, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36697862

RESUMO

Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.


Assuntos
Biomassa , Contaminação por DNA , Feto , Microbiota , Animais , Feminino , Humanos , Gravidez , Líquido Amniótico/imunologia , Líquido Amniótico/microbiologia , Mamíferos , Microbiota/genética , Placenta/imunologia , Placenta/microbiologia , Feto/imunologia , Feto/microbiologia , Reprodutibilidade dos Testes
13.
Dev Comp Immunol ; 140: 104626, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36587712

RESUMO

One of the most studied defense mechanisms against invading pathogens, including viruses, are Toll-like receptors (TLRs). Among them, TLR3, TLR7, TLR8 and TLR9 detect different forms of viral nucleic acids in endosomal compartments, whereas TLR2 and TLR4 recognize viral structural and nonstructural proteins outside the cell. Although many different TLRs have been shown to be involved in SARS-CoV-2 infection and detection of different structural proteins, most studies have been performed in vitro and the results obtained are rather contradictory. In this study, we report using the unique advantages of the zebrafish model for in vivo imaging and gene editing that the S1 domain of the Spike protein from the Wuhan strain (S1WT) induced hyperinflammation in zebrafish larvae via a Tlr2/Myd88 signaling pathway and independently of interleukin-1ß production. In addition, S1WT also triggered emergency myelopoiesis, but in this case through a Tlr2/Myd88-independent signaling pathway. These results shed light on the mechanisms involved in the fish host responses to viral proteins.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Receptor 2 Toll-Like , Animais , COVID-19/imunologia , Fator 88 de Diferenciação Mieloide/genética , SARS-CoV-2 , Receptor 2 Toll-Like/genética , Peixe-Zebra/genética
16.
In Vivo ; 37(1): 70-78, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593041

RESUMO

BACKGROUND/AIM: The manifestation and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections show a clear correlation to the age of a patient. The younger a person, the less likely the infection results in significant illness. To explore the immunological characteristics behind this phenomenon, we studied the course of SARS-CoV-2 infections in 11 households, including 8 children and 6 infants/neonates of women who got infected with SARS-CoV-2 during pregnancy. MATERIALS AND METHODS: We investigated the immune responses of peripheral blood mononuclear cells (PBMCs), umbilical cord blood mononuclear cells (UCBCs), and T cells against spike and nucleocapsid antigens of SARS-COV-2 by flow cytometry and cytokine secretion assays. RESULTS: Upon peptide stimulation, UCBC from neonates showed a strongly reduced IFN-γ production, as well as lower levels of IL-5, IL-13, and TNF-α alongside with decreased frequencies of surface CD137/PD-1 co-expressing CD4+ and CD+8 T cells compared with adult PBMCs. The PBMC response of older children instead was characterized by elevated frequencies of IFN-γ+ CD4+ T cells, but significantly lower levels of multiple cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, and TNF-α) and a marked shift of the CD4+/CD8+ T-cell ratio towards CD8+ T cells in comparison to adults. CONCLUSION: The increased severity of SARS-CoV-2 infections in adults could result from the strong cytokine production and lower potential to immunomodulate the excessive inflammation, while the limited IFN-γ production of responding T cells in infants/neonates and the additional higher frequencies of CD8+ T cells in older children may provide advantages during the course of a SARS-CoV-2 infection.


Assuntos
Antígenos Virais , COVID-19 , Citocinas , Adulto , Criança , Feminino , Humanos , Recém-Nascido , Gravidez , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Citocinas/imunologia , Leucócitos Mononucleares/imunologia , Nucleocapsídeo/imunologia , SARS-CoV-2 , Fatores Etários , Antígenos Virais/imunologia , Linfócitos T CD4-Positivos/imunologia
17.
In Vivo ; 37(1): 286-293, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593062

RESUMO

BACKGROUND/AIM: Vitamin D3 (VD3) affects the regulation of the immune system, including the differentiation and function of regulatory T-cells (Tregs). Tregs play an important role in maintaining immune homeostasis in patients with colorectal cancer (CRC). The effects of VD3 on Treg-associated immune function were investigated in Thai patients in the early stages of CRC. MATERIALS AND METHODS: Twenty-eight patients were randomized to one of two groups: Untreated or treatment with VD3 for 3 months. Whole blood samples were collected at baseline, and at 1 and 3 months. Peripheral blood mononuclear cells were isolated and the populations of forkhead box P3-positive Treg cells was analyzed by flow cytometry. The levels of Treg-associated cytokines, interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-ß1), were measured by enzyme-linked immunosorbent assays. RESULTS: Serum VD3 levels of the VD3-treated group were significantly increased at 1 (p=0.017) and 3 months (p<0.001) compared to the untreated control group. The mean percentage of Tregs was maintained between 1 and 3 months in the VD3-treated group. At 3 months, the untreated group had significantly lower Treg levels than the VD3-treated group (p=0.043). Serum IL-10 levels of the VD3-treated group were statistically increased at 1 month compared to the control group (p=0.032). No significant difference in serum TGF-ß1 levels was observed between the two groups. However, the TGF-ß1 level in the VD3-treated group at 1 month was lower than that of the control. CONCLUSION: Our findings suggest that VD3 supplementation can maintain immune responses in the early stages of CRC, helping to control Treg function. Therefore, VD3 should be supplemented to maintain immune homeostasis, especially in patients with vitamin D deficiency.


Assuntos
Colecalciferol , Neoplasias Colorretais , Linfócitos T Reguladores , Humanos , Colecalciferol/administração & dosagem , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/cirurgia , Suplementos Nutricionais , Homeostase , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/imunologia
19.
Elife ; 122023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36648132

RESUMO

Background: Both sex and prior exposure to pathogens are known to influence responses to immune challenges, but their combined effects are not well established in humans, particularly in early innate responses critical for shaping subsequent outcomes. Methods: We employed systems immunology approaches to study responses to a replication-defective, herpes simplex virus (HSV) 2 vaccine in men and women either naive or previously exposed to HSV. Results: Blood transcriptomic and cell population profiling showed substantial changes on day 1 after vaccination, but the responses depended on sex and whether the vaccinee was naive or previously exposed to HSV. The magnitude of early transcriptional responses was greatest in HSV naive women where type I interferon (IFN) signatures were prominent and associated negatively with vaccine-induced neutralizing antibody titers, suggesting that a strong early antiviral response reduced the uptake of this replication-defective virus vaccine. While HSV seronegative vaccine recipients had upregulation of gene sets in type I IFN (IFN-α/ß) responses, HSV2 seropositive vaccine recipients tended to have responses focused more on type II IFN (IFN-γ) genes. Conclusions: These results together show that prior exposure and sex interact to shape early innate responses that then impact subsequent adaptive immune phenotypes. Funding: Intramural Research Program of the NIH, the National Institute of Allergy and Infectious Diseases, and other institutes supporting the Trans-NIH Center for Human Immunology, Autoimmunity, and Inflammation. The vaccine trial was supported through a clinical trial agreement between the National Institute of Allergy and Infectious Diseases and Sanofi Pasteur. Clinical trial number: NCT01915212.


Assuntos
Vacinas contra Herpesvirus , Imunidade Inata , Fatores Sexuais , Feminino , Humanos , Masculino , Anticorpos Neutralizantes , Herpesvirus Humano 2 , Vacinas contra Herpesvirus/imunologia , Vacinas Atenuadas , Herpes Simples/prevenção & controle
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