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1.
Front Immunol ; 13: 964910, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059521

RESUMO

Depression in childhood negatively affects the growth and development, school performance, and peer or family relationships of affected children, and may even lead to suicide. Despite this, its etiology and pathophysiology remain largely unknown. Increasing evidence supports that gut microbiota plays a vital role in the development of childhood depression. However, little is known about the underlying mechanisms, as most clinical studies investigating the link between gut microbiota and depression have been undertaken in adult cohorts. In present study, a total of 140 school-aged children (6-12 years) were enrolled, including 92 with depression (male/female: 42/50) and 48 healthy controls (male/female: 22/26) from Lishui, Zhejiang, China. Illumina sequencing of the V3-V4 region of the 16S rRNA gene was used to investigate gut microbiota profiles while Bio-Plex Pro Human Cytokine 27-plex Panel was employed to explore host immune response. We found that, compared with healthy controls, children with depression had greater bacterial richness and altered ß-diversity. Pro-inflammatory genera such as Streptococcus were enriched in the depression group, whereas anti-inflammatory genera such as Faecalibacterium were reduced, as determined by linear discriminant analysis effect size. These changes corresponded to altered bacterial functions, especially the production of immunomodulatory metabolites. We also identified the presence of a complex inflammatory condition in children with depression, characterized by increased levels of pro-inflammatory cytokines such as IL-17 and decreased levels of anti-inflammatory cytokines such as IFN-γ. Correlation analysis demonstrated that the differential cytokine abundance was closely linked to changes in gut microbiota of children with depression. In summary, key functional genera, such as Streptococcus and Faecalibacterium, alone or in combination, could serve as novel and powerful non-invasive biomarkers to distinguish between children with depression from healthy ones. This study was the first to demonstrate that, in Chinese children with depression, gut microbiota homeostasis is disrupted, concomitant with the activation of a complex pro-inflammatory response. These findings suggest that gut microbiota might play an important role in the pathogenesis of depression in school-aged children, while key functional bacteria in gut may serve as novel targets for non-invasive diagnosis and patient-tailored early precise intervention in children with depression.


Assuntos
Citocinas , Depressão , Microbioma Gastrointestinal , Bactérias/genética , Estudos de Casos e Controles , Criança , Citocinas/imunologia , Depressão/imunologia , Depressão/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Masculino , RNA Ribossômico 16S/genética
2.
PLoS Negl Trop Dis ; 16(8): e0010721, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35976976

RESUMO

Despite that the impact of different helminth species is not well explored, the current dogma states that helminths affect the Th1/Th2 balance which in turn affects the risk of tuberculosis (TB) reactivation and severity of disease. We investigated the influence of helminth species on cytokine profiles including IL-17A in TB patients and healthy community controls (CCs). In total, 104 newly diagnosed pulmonary TB patients and 70 HIV negative and QuantiFERON negative CCs in Gondar, Ethiopia were included following helminth screening by stool microscopy. Plasma samples and ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with purified protein derivative (PPD) and Staphylococcus enterotoxin B (SEB) was used to determine cytokine profiles by cytometric bead array. In CCs, Ascaris lumbricoides or Schistosoma mansoni infections were associated with an impaired Th1-type response (IFN-gamma, IL-6 and TNF-alpha) in PBMCs mainly with SEB stimulations, whereas in TB patients only hookworm infection showed a similar pattern. Among CCs, the IL-17A response in PBMCs stimulated with SEB was higher only for S. mansoni, whereas in TB patients, the elevated systemic IL-17A plasma level was significantly suppressed in hookworm infected TB patients compared to patients without helminth coinfection. Following treatment of TB and helminth infection there was a general decrease in ex vivio IL-10 and TNF-alpha production in unstimulated, PPD or SEB stimulated PBMCs that was the most pronounced and significant in TB patients infected with S. mansoni, whereas the follow-up levels of IFN-gamma and IL-17A was significantly increased only in TB patients without helminth coinfection from PBMCs stimulated mainly with SEB. In summary, in addition to confirming helminth specific effects on the Th1/Th2 response before and after TB treatment, our novel finding is that IL-17A was impaired in helminth infected TB patients especially for hookworm, indicating a helminth species-specific immunoregulatory effect on IL-17A which needs to be further investigated.


Assuntos
Coinfecção , Citocinas , Helmintíase , Interleucina-17 , Tuberculose , Animais , Citocinas/imunologia , Helmintíase/imunologia , Helmintos/classificação , Humanos , Interleucina-17/imunologia , Leucócitos Mononucleares/imunologia , Células Th1/imunologia , Células Th17/imunologia , Tuberculina , Tuberculose/complicações , Tuberculose/imunologia , Fator de Necrose Tumoral alfa
3.
Front Immunol ; 13: 951107, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967401

RESUMO

Although numerous clinical trials have been implemented, an absolutely effective treatment against coronavirus disease 2019 (COVID-19) is still elusive. Interleukin-22 (IL-22) has attracted great interest over recent years, making it one of the best-studied cytokines of the interleukin-10 (IL-10) family. Unlike most interleukins, the major impact of IL-22 is exclusively on fibroblasts and epithelial cells due to the restricted expression of receptor. Numerous studies have suggested that IL-22 plays a crucial role in anti-viral infections through significantly ameliorating the immune cell-mediated inflammatory responses, and reducing tissue injury as well as further promoting epithelial repair and regeneration. Herein, we pay special attention to the role of IL-22 in the lungs. We summarize the latest progress in our understanding of IL-22 in lung health and disease and further discuss maneuvering this cytokine as potential immunotherapeutic strategy for the effective manage of COVID-19.


Assuntos
COVID-19 , Interleucinas , Pulmão , COVID-19/tratamento farmacológico , COVID-19/imunologia , Citocinas/imunologia , Citocinas/uso terapêutico , Humanos , Interleucinas/imunologia , Interleucinas/uso terapêutico , Pulmão/imunologia
4.
Front Cell Infect Microbiol ; 12: 941939, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967844

RESUMO

Lymphostatin is a virulence factor of enteropathogenic E. coli (EPEC) and non-O157 serogroup enterohaemorrhagic E. coli. Previous studies using whole-cell lysates of EPEC showed that lymphostatin inhibits the mitogen-activated proliferation of bulk human peripheral blood mononuclear cells (PBMCs) and the production of cytokines IL-2, IL-4, IL-5, and IFN-γ. Here, we used highly purified lymphostatin and PBMC-derived T cells to show that lymphostatin inhibits anti-CD3/anti-CD28-activated proliferation of human CD4+ and CD8+ T cells and blocks the synthesis of IL-2, IL-4, IL-10 and IFN-γ without affecting cell viability and in a manner dependent on an N-terminal DTD glycosyltransferase motif. Such inhibition was not observed with T cells activated by phorbol 12-myristate 13-acetate and ionomycin, implying that lymphostatin targets T cell receptor signaling. Analysis of the expression of CD69 indicated that lymphostatin suppresses T cell activation at an early stage and no impacts on apoptosis or necrosis were observed. Flow cytometric analysis of the DNA content of lymphostatin-treated CD4+ and CD8+ T cells showed a concentration- and DTD-dependent accumulation of the cells in the G0/G1 phase of the cell cycle, and corresponding reduction of the percentage of cells in S phase. Consistent with this, we found a marked reduction in the abundance of cyclins D3, E and A and loss of phosphorylated Rb over time in activated T cells from 8 donors treated with lymphostatin. Moreover, the cyclin-dependent kinase (cdk) inhibitor p27kip1, which inhibits progression of the cell cycle at G1 by acting on cyclin E-cdk2 or cyclin D-cdk4 complexes, was found to be accumulated in lymphostatin-treated T cells. Analysis of the abundance of phosphorylated kinases involved in signal transduction found that 30 of 39 were reduced in abundance following lymphostatin treatment of T cells from 5 donors, albeit not significantly so. Our data provide novel insights into the mode of action of lymphostatin on human T lymphocytes.


Assuntos
Toxinas Bacterianas , Infecções por Escherichia coli , Proteínas de Escherichia coli , Escherichia coli , Linfócitos T , Apoptose , Toxinas Bacterianas/imunologia , Linfócitos T CD8-Positivos/imunologia , Pontos de Checagem do Ciclo Celular/imunologia , Divisão Celular , Proliferação de Células/fisiologia , Citocinas/biossíntese , Citocinas/imunologia , Escherichia coli Enteropatogênica/imunologia , Escherichia coli Enteropatogênica/patogenicidade , Escherichia coli/imunologia , Escherichia coli/patogenicidade , Infecções por Escherichia coli/imunologia , Proteínas de Escherichia coli/imunologia , Humanos , Interleucina-2 , Interleucina-4 , Leucócitos Mononucleares/imunologia , Necrose , Linfócitos T/imunologia , Fatores de Virulência/imunologia
5.
J Exp Med ; 219(8)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35819408

RESUMO

In certain instances, Th17 responses are associated with severe immunopathology. T cell-intrinsic mechanisms that restrict pathogenic effector functions have been described for type 1 and 2 responses but are less well studied for Th17 cells. Here, we report a cell-intrinsic feedback mechanism that controls the pathogenicity of Th17 cells. Th17 cells produce IL-24, which prompts them to secrete IL-10. The IL-10-inducing function of IL-24 is independent of the cell surface receptor of IL-24 on Th17 cells. Rather, IL-24 is recruited to the inner mitochondrial membrane, where it interacts with the NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 13 (also known as Grim19), a constituent of complex I of the respiratory chain. Together, Grim19 and IL-24 promote the accumulation of STAT3 in the mitochondrial compartment. We propose that IL-24-guided mitochondrial STAT3 constitutes a rheostat to blunt extensive STAT3 deflections in the nucleus, which might then contribute to a robust IL-10 response in Th17 cells and a restriction of immunopathology in experimental autoimmune encephalomyelitis.


Assuntos
Citocinas/imunologia , Interleucina-10 , Células Th17 , Animais , Diferenciação Celular , Interleucina-10/metabolismo , Camundongos , NADH NADPH Oxirredutases/metabolismo , Transdução de Sinais , Virulência
6.
Nature ; 608(7921): 161-167, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35896747

RESUMO

Invasive fungal pathogens are major causes of human mortality and morbidity1,2. Although numerous secreted effector proteins that reprogram innate immunity to promote virulence have been identified in pathogenic bacteria, so far, there are no examples of analogous secreted effector proteins produced by human fungal pathogens. Cryptococcus neoformans, the most common cause of fungal meningitis and a major pathogen in AIDS, induces a pathogenic type 2 response characterized by pulmonary eosinophilia and alternatively activated macrophages3-8. Here, we identify CPL1 as an effector protein secreted by C. neoformans that drives alternative activation (also known as M2 polarization) of macrophages to enable pulmonary infection in mice. We observed that CPL1-enhanced macrophage polarization requires Toll-like receptor 4, which is best known as a receptor for bacterial endotoxin but is also a poorly understood mediator of allergen-induced type 2 responses9-12. We show that this effect is caused by CPL1 itself and not by contaminating lipopolysaccharide. CPL1 is essential for virulence, drives polarization of interstitial macrophages in vivo, and requires type 2 cytokine signalling for its effect on infectivity. Notably, C. neoformans associates selectively with polarized interstitial macrophages during infection, suggesting a mechanism by which C. neoformans generates its own intracellular replication niche within the host. This work identifies a circuit whereby a secreted effector protein produced by a human fungal pathogen reprograms innate immunity, revealing an unexpected role for Toll-like receptor 4 in promoting the pathogenesis of infectious disease.


Assuntos
Criptococose , Cryptococcus neoformans , Proteínas Fúngicas , Hipersensibilidade , Inflamação , Receptor 4 Toll-Like , Fatores de Virulência , Animais , Criptococose/imunologia , Criptococose/microbiologia , Criptococose/patologia , Cryptococcus neoformans/imunologia , Cryptococcus neoformans/patogenicidade , Citocinas/imunologia , Proteínas Fúngicas/imunologia , Proteínas Fúngicas/metabolismo , Hipersensibilidade/imunologia , Hipersensibilidade/microbiologia , Imunidade Inata , Inflamação/imunologia , Inflamação/microbiologia , Lipopolissacarídeos/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Virulência , Fatores de Virulência/imunologia
7.
Front Immunol ; 13: 901273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844527

RESUMO

Background: Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients. Methods: A cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks. Results: Monocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density. Conclusions: Dampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.


Assuntos
Antígenos HLA-DR , Transplante de Rim , Monócitos , Células Supressoras Mieloides , Neoplasias , Estudos de Coortes , Citocinas/imunologia , Antígenos HLA-DR/imunologia , Humanos , Monócitos/imunologia , Monócitos/patologia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/patologia , Transplantados
8.
Front Immunol ; 13: 864632, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844540

RESUMO

IL-17 is a cytokine produced by innate and acquired immunity cells that have an action against fungi and bacteria. However, its action in helminth infections is unclear, including in Toxocara canis infection. Toxocariasis is a neglected zoonosis representing a significant public health problem with an estimated seroprevalence of 19% worldwide. In the present study, we describe the immunopathological action of IL-17RA in acute T. canis infection. C57BL/6j (WT) and IL-17RA receptor knockout (IL-17RA-/-) mice were infected with 1000 T. canis eggs. Mice were evaluated 3 days post-infection for parasite load and white blood cell count. Lung tissue was harvested for histopathology and cytokine expression. In addition, we performed multiparametric flow cytometry in the BAL and peripheral blood, evaluating phenotypic and functional changes in myeloid and lymphoid populations. We showed that IL-17RA is essential to control larvae load in the lung; however, IL-17RA contributed to pulmonary inflammation, inducing inflammatory nodular aggregates formation and presented higher pulmonary IL-6 levels. The absence of IL-17RA was associated with a higher frequency of neutrophils as a source of IL-4 in BAL, while in the presence of IL-17RA, mice display a higher frequency of alveolar macrophages expressing the same cytokine. Taken together, this study indicates that neutrophils may be an important source of IL-4 in the lungs during T. canis infection. Furthermore, IL-17/IL-17RA axis is important to control parasite load, however, its presence triggers lung inflammation that can lead to tissue damage.


Assuntos
Pneumonia , Receptores de Interleucina-17 , Toxocara canis , Toxocaríase , Animais , Citocinas/imunologia , Interleucina-17/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Pneumonia/parasitologia , Receptores de Interleucina-17/imunologia , Toxocara canis/imunologia , Toxocaríase/imunologia , Toxocaríase/parasitologia
9.
Nature ; 608(7921): 168-173, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35896748

RESUMO

Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1-3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity4-7. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer9,10. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.


Assuntos
Akkermansia , Homeostase , Imunidade , Fosfatidiletanolaminas , Akkermansia/química , Akkermansia/citologia , Akkermansia/imunologia , Membrana Celular/química , Membrana Celular/imunologia , Citocinas/imunologia , Homeostase/imunologia , Humanos , Mediadores da Inflamação/síntese química , Mediadores da Inflamação/química , Mediadores da Inflamação/imunologia , Fosfatidiletanolaminas/síntese química , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/imunologia , Relação Estrutura-Atividade , Receptor 1 Toll-Like/imunologia , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/imunologia
10.
Eur J Immunol ; 52(9): 1441-1451, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35775327

RESUMO

Natural Killer (NK) cells are important innate lymphocytes for effective immune responses against intracellular pathogens and tumors. CD56 is a well-known marker for human NK cells, but there is very limited information about a functional role of this surface receptor. Here, we show that engagement of CD56 can induce NK cell activation resulting in degranulation, IFN-γ secretion and morphological changes, making CD56 a potential co-activating receptor in NK cells. Interestingly, this effect was only observed in cytokine pre-activated and not in freshly isolated human NK cells, demonstrating that NK cell reactivity upon CD56 engagement was dependent on cytokine stimulation. Inhibition of Syk, PI3K, Erk, and src-family-kinases impaired CD56-mediated NK cell stimulation. Finally, we used CRISPR/Cas9 to delete CD56 from primary human NK cells. While this abolished the stimulatory effect of CD56 on pre-activated NK cells, the cytotoxic activity of NK cells against several tumor target cells was not affected by the absence of CD56. This demonstrates that the stimulating effect of CD56 on pre-activated NK cells does not have a major impact on their cytotoxic activity, but it may contribute to the function of CD56 as a fungal recognition receptor and in the NK cell developmental synapse.


Assuntos
Antígeno CD56 , Citocinas , Células Matadoras Naturais , Antígeno CD56/imunologia , Citocinas/imunologia , Humanos , Células Matadoras Naturais/imunologia , Ativação Linfocitária
11.
Sci Rep ; 12(1): 11821, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35821240

RESUMO

T cell exhaustion refers to a dysfunctional state in which effector T cells present a decreased ability to proliferate and to produce cytokines, while the co-expression of inhibitory receptors increases. We investigated global and donor-specific T cell responses in a cohort of stable, living-donor kidney transplant patients that received similar immunosuppression. After transplantation, an increase in the ratio of TIGIT + /CD226 + in mCD4 + T cells (r = 0.47, p = 0.01), and a decrease of CD226 + TIGIT-mCD4 + T cells was observed (r = - 0.55, p = 0.001). This leads to an increase of dysfunctional T cells in patients far from transplantation. In mCD8 + T cells, a decrease of IL-2 production after mitogenic stimulation was observed far from transplantation. Phenotypic analyses revealed an increase of mCD8 + T cells co-expressing PD-1 and TIGIT over time (r = 0.51, p = 0.02). After donor-specific stimulation, the ability of CD4 + T cells to proliferate was decreased compared with third parties. CD4 + T cells expressing CD226 and TIGIT were correlated with allospecific CD4 + proliferation (r = 0.68, p = 0.04). Our study suggests that after kidney transplantation a T cell hyporesponsiveness appears over time, driven by a dysregulation of CD226/TIGIT axis in mCD4 + T cells, associated with an increase of PD1 + TIGIT + in mCD8 + T cells.


Assuntos
Antígenos de Diferenciação de Linfócitos T , Linfócitos T CD4-Positivos , Transplante de Rim , Receptores Imunológicos , Antígenos de Diferenciação de Linfócitos T/imunologia , Citocinas/imunologia , Humanos , Receptores Imunológicos/imunologia , Imunologia de Transplantes
12.
Int J Mol Sci ; 23(13)2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35806450

RESUMO

P2X7R-NLRP3 and AIM2 inflammasomes activate caspase-1 and the release of cytokines involved in viral-related liver disease. Little is known about their role in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH). We characterized the role of inflammasomes in NAFLD, NASH, and HCV. Gene expression and subcellular localization of P2X7R/P2X4R-NLRP3 and AIM2 inflammasome components were examined in histopathological preparations of 46 patients with biopsy-proven viral and metabolic liver disease using real-time PCR and immunofluorescence. P2X7R, P2X4R, and Caspase-1 are two- to five-fold more expressed in patients with NAFLD/NASH associated with chronic HCV infection than those with metabolic damage only (p ≤ 0.01 for all comparisons). The AIM2 inflammasome is 4.4 times more expressed in patients with chronic HCV infection, regardless of coexistent metabolic abnormalities (p = 0.0006). IL-2, a cytokine playing a pivotal role during chronic HCV infection, showed a similar expression in HCV and NASH patients (p = 0.77) but was virtually absent in NAFLD. The P2X7R-NLRP3 complex prevailed in infiltrating macrophages, while AIM2 was localized in Kupffer cells. Caspase-1 expression correlated with elastography-based liver fibrosis (r = 0.35, p = 0.02), whereas P2X7R, P2X4R, NRLP3, Caspase-1, and IL-2 expression correlated with circulating markers of disease severity. P2X7R and P2X4R play a major role in liver inflammation accompanying chronic HCV infection, especially when combined with metabolic damage, while AIM2 is specifically expressed in chronic viral hepatitis. We describe for the first time the hepatic expression of IL-2 in NASH, so far considered a peculiarity of HCV-related liver damage.


Assuntos
Hepatite C , Hepatite , Hepatopatia Gordurosa não Alcoólica , Caspase 1/genética , Caspase 1/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hepatite/imunologia , Hepatite/metabolismo , Hepatite C/imunologia , Hepatite C/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Interleucina-2 , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/virologia , Receptores Purinérgicos P2X7
13.
F S Sci ; 3(3): 279-287, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35697654

RESUMO

OBJECTIVE: To identify immune cells, cytokines, and immune cell transcriptome in the menstrual effluent (ME) of women with endometriosis compared with that of healthy donors. DESIGN: Live immune cells were isolated from human ME samples and were analyzed by flow cytometry to identify various immune cell populations. Selected cytokines from the same patients were evaluated using multiplex cytokine analyses. The transcriptome of the immune cell population was subsequently profiled using NanoString nCounter's PanCancer Immune panel. SETTING: Academic institution. PATIENT(S): Surgically confirmed endometriosis patients (n = 14) and healthy fertile donors (n = 19). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): In-depth immune cell profiling of ME obtained from women with endometriosis compared with that of healthy donors. RESULT(S): ME analysis revealed that the number of T helper 17 (TH17) cells was significantly lower in patients with endometriosis compared with that of healthy donors; the number of macrophages was also lower (P=.06) in the former. Multiplex cytokine analysis revealed significantly lower transforming growth factor α in the ME "serum" of patients with endometriosis. Transcriptomic analysis of CD45+ cells revealed 47 differentially expressed genes, mainly associated with the TH17 axis (IL10, IL23A, and IL6), as well as genes associated with macrophage signaling/activation (CD74, CD83, CXCL16, and CCL3). CONCLUSION(S): We demonstrate for the first time that the levels of TH17 axis, macrophages, and transforming growth factor α were altered in the ME of women with endometriosis compared with that of healthy donors. These findings shed light on the potential immune pathways that could partly explain the pathogenesis and progression of endometriosis. Future large-scale studies on ME samples are warranted to exploit the use of these markers to study the pathogenesis of endometriosis.


Assuntos
Endometriose , Macrófagos , Células Th17 , Citocinas/imunologia , Endometriose/patologia , Endométrio , Feminino , Humanos , Macrófagos/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador alfa/imunologia
14.
J Virol ; 96(13): e0050922, 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35699447

RESUMO

Cell-mediated immunity is critical for long-term protection against most viral infections, including coronaviruses. We studied 23 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected survivors over a 1-year post-symptom onset (PSO) interval by ex vivo cytokine enzyme-linked immunosorbent spot assay (ELISpot) assay. All subjects demonstrated SARS-CoV-2-specific gamma interferon (IFN-γ), interleukin 2 (IL-2), and granzyme B (GzmB) T cell responses at presentation, with greater frequencies in severe disease. Cytokines, mainly produced by CD4+ T cells, targeted all structural proteins (nucleocapsid, membrane, and spike) except envelope, with GzmB and IL-2 greater than IFN-γ. Mathematical modeling predicted that (i) cytokine responses peaked at 6 days for IFN-γ, 36 days for IL-2, and 7 days for GzmB, (ii) severe illness was associated with reduced IFN-γ and GzmB but increased IL-2 production rates, and (iii) males displayed greater production of IFN-γ, whereas females produced more GzmB. Ex vivo responses declined over time, with persistence of IL-2 in 86% and of IFN-γ and GzmB in 70% of subjects at a median of 336 days PSO. The average half-life of SARS-CoV-2-specific cytokine-producing cells was modeled to be 139 days (~4.6 months). Potent T cell proliferative responses persisted throughout observation, were CD4 dominant, and were capable of producing all 3 cytokines. Several immunodominant CD4 and CD8 epitopes identified in this study were shared by seasonal coronaviruses or SARS-CoV-1 in the nucleocapsid and membrane regions. Both SARS-CoV-2-specific CD4+ and CD8+ T cell clones were able to kill target cells, though CD8 tended to be more potent. IMPORTANCE Our findings highlight the relative importance of SARS-CoV-2-specific GzmB-producing T cell responses in SARS-CoV-2 control and shared CD4 and CD8 immunodominant epitopes in seasonal coronaviruses or SARS-CoV-1, and they indicate robust persistence of T cell memory at least 1 year after infection. Our findings should inform future strategies to induce T cell vaccines against SARS-CoV-2 and other coronaviruses.


Assuntos
COVID-19 , Citocinas , Imunidade , SARS-CoV-2 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , COVID-19/imunologia , Vacinas contra COVID-19 , Citocinas/imunologia , Feminino , Humanos , Memória Imunológica , Interferon gama/metabolismo , Interleucina-2/imunologia , Masculino , Índice de Gravidade de Doença , Fatores de Tempo
15.
Aging Cell ; 21(6): e13646, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35645319

RESUMO

Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID-19 infection. The pathogenesis of COVID-19-related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS-CoV-2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF-α + IFN-γ or a cocktail of TNF-α + IFN-γ + IL-6, increased expression of ACE2/DPP4, accentuated the pro-inflammatory senescence-associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence-like state. IL-6 by itself failed to induce substantial effects on viral entry receptors or SASP-related genes, while synergy between TNF-α and IFN-γ initiated a positive feedback loop via hyper-activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper-inflammation, normalized SARS-CoV-2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine-mediated viral entry receptor activation and links with senescence and hyper-inflammation.


Assuntos
COVID-19 , Interferon gama , SARS-CoV-2 , Fator de Necrose Tumoral alfa , COVID-19/tratamento farmacológico , COVID-19/virologia , Citocinas/imunologia , Sinergismo Farmacológico , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/virologia , Interferon gama/farmacologia , Interleucina-6/metabolismo , Receptores Virais/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Fator de Transcrição STAT1/biossíntese , Fator de Transcrição STAT1/imunologia , Fator de Necrose Tumoral alfa/farmacologia
16.
J Med Life ; 15(4): 479-482, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35646178

RESUMO

Cytokine response to Ancylostoma duodenale (A. duodenale) infection was measured after starting treatments with piperazine. This study aims to determine the impact of cytokine production after infection with A. duodenale before and after treatment with piperazine. Blood and stool samples of 50 patients with A. duodenale infection and 28 healthy individuals (control) were collected. In this study, IFNγ, IL-5, IL-12, and IL-13 in serum (using ELISA-based methods) were measured. Stool samples were examined using the Kato-Katz technique to detect A. duodenale parasites. Blood and stool samples were analyzed 14 days after starting piperazine treatment for A. duodenale infection. The medium concentration of IFNγ, IL-5, IL-12, and IL-13 in the serum samples with A. duodenale infection is higher than that of the control group. IFNγ, IL-5, IL-12, and IL-13 levels were significantly higher in the infected individuals (10.5±7.4 pg/ml, 14.6±5.1 pg/ml, 8.5±3.2 pg/ml and 13.6±7.5 pg/ml respectively) than the control group (4.7±2.4 pg/ml, 7.8±4.06 pg/ml, 6.3±3.4 pg/ml and 3.5±2.7 pg/ml respectively). Also, piperazine treatment can significantly reduce cytokines levels (IFN-γ: P=0.043, IL-5: P=0.02, and IL-12, p=0.001). This study shows that piperazine treatment can reduce cytokines profiles in patients with A. duodenale infection.


Assuntos
Ancilostomíase , Citocinas , Ancilostomíase/tratamento farmacológico , Ancilostomíase/imunologia , Citocinas/imunologia , Humanos , Interleucina-12 , Interleucina-13 , Interleucina-5 , Piperazinas/uso terapêutico
17.
Front Cell Infect Microbiol ; 12: 862656, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35656028

RESUMO

Objectives: To assess humoral and cellular immune responses against SARS-CoV-2 variants in COVID-19 convalescent and confirmed patients, to explore the correlation between disease severity, humoral immunity, and cytokines/chemokines in confirmed patients, and to evaluate the ADE risk of SARS-CoV-2. Methods: Anti-RBD IgG were quantified using an ELISA. Neutralization potency was measured using pseudovirus and real virus. Cellular immunity was measured using ELISpot. Cytokine/chemokine levels were detected using multiplex immunoassays. In vitro ADE assays were performed using Raji cells. Results: One-month alpha convalescents exhibited spike-specific antibodies and T cells for alpha and delta variants. Notably, the RBD-specific IgG towards the delta variant decreased by 2.5-fold compared to the alpha variant. Besides, serum from individuals recently experienced COVID-19 showed suboptimal neutralizing activity against the delta and omicron variants. Humoral immune response, IL-6, IP-10 and MCP-1 levels were greater in patients with severe disease. Moreover, neither SARS-CoV-1 nor SARS-CoV-2 convalescent sera significantly enhanced SARS-CoV-2 pseudovirus infection. Conclusions: Significant resistance of the delta and omicron variants to the humoral immune response generated by individuals who recently experienced COVID-19. Furthermore, there was a significant correlation among disease severity, humoral immune response, and specific cytokines/chemokine levels. No evident ADE was observed for SARS-CoV-2.


Assuntos
COVID-19 , Citocinas , Imunidade Celular , Imunidade Humoral , SARS-CoV-2 , COVID-19/imunologia , Citocinas/imunologia , Humanos , Imunoglobulina G , Índice de Gravidade de Doença
18.
Int. j. cardiovasc. sci. (Impr.) ; 35(3): 410-418, May-June 2022. graf
Artigo em Inglês | LILACS | ID: biblio-1375650

RESUMO

Abstract An acute respiratory syndrome caused by SARS-CoV2 was declared a pandemic by the World Health Organization. Current data in the world and in Brazil show that approximately 40% of patients who died have some type of cardiac comorbidity. There are also robust reports showing an increase in IL-6 / IL-1B / TNF-alpha and the presence of lymphopenia in patients with COVID-19. Our team and others have shown that increased cytokines are the link between arrhythmias/Left ventricular dysfunction and the immune system in different diseases. In addition, it has been well demonstrated that lymphopenia can not only be a good marker, but also a factor that causes heart failure. Thus, the present review focused on the role of the immune system upon the cardiac alterations observed in the SARS-CoV2 infection. Additionally, it was well described that SARS-CoV-2 is able to infect cardiac cells. Therefore, here it will be reviewed in deep.


Assuntos
Arritmias Cardíacas/complicações , SARS-CoV-2/patogenicidade , COVID-19/complicações , Insuficiência Cardíaca/etiologia , Miocárdio/imunologia , Arritmias Cardíacas/fisiopatologia , Citocinas , Citocinas/imunologia , Coronavirus/patogenicidade , Disfunção Ventricular Esquerda/fisiopatologia , Miócitos Cardíacos/patologia , Síndrome Respiratória Aguda Grave , Insuficiência Cardíaca/complicações , Linfopenia/complicações
19.
Front Immunol ; 13: 843247, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693824

RESUMO

Background: Tic disorder is a neurodevelopmental disorder characterized by motor and phonic tic symptoms. Tourette syndrome (TS) is a subtype of tic disorder that shows more persistent tic symptoms. The etiological mechanism of TS concerning immune dysfunction remains unclear due to limited evidence, especially for pediatric TS patients. Method: In the present study, a meta-analysis was performed to confirm the identified changes in proinflammatory cytokines and T cells of pediatric TS patients. A total of five databases, including PubMed, Web of Science, PsycINFO, Google Scholar and the China National Knowledge Infrastructure (CNKI), were used for the literature search. The standardized mean difference (SMD) and mean difference (MD) with a 95% confidence interval (CI) were used to present the effect size of each type of proinflammatory cytokine and T cell. Sensitivity analysis, subgroup analysis and meta-regression analysis were used to explore the heterogeneity of the meta-analysis. This meta-analysis was registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (number: INPLASY2021110079). Results: In the 25 studies included in this meta-analysis, thirteen studies focused on the levels of T cells, and twelve studies focused on the levels of proinflammatory cytokines. Based on the random-effects model, the pooled MDs are -1.45 (95% CI: -3.44, 0.54) for CD3 cells, -4.44 (95% CI: -6.80, -2.08) for CD4 cells, and 1.94 (95% CI: -0.08, 3.97) for CD8 cells. The pooled SMDs are1.36 for IL-6 (95% CI: 0.00, 2.72) and 2.39 for tumor necrosis factor alpha (TNF-α) (95% CI: 0.93, 3.84). Conclusion: We provided evidence of immune dysfunction in pediatric TS patients, with elevated levels of particular proinflammatory cytokines and disproportionate changes in T-cell subpopulations. Small to large effect sizes were identified for increased IL-6 levels as well as a reduced number of T helper cells, while a large effect size was identified for increased TNF-α levels. These results indicate a close association between peripheral immune activation and TS. However, the most direct and meaningful interaction between peripheral immune status and microglial activation in the central nervous system in TS patients requires further exploration.


Assuntos
Citocinas , Linfócitos T , Síndrome de Tourette , Criança , Citocinas/imunologia , Humanos , Interleucina-6 , Linfócitos T/imunologia , Síndrome de Tourette/imunologia , Fator de Necrose Tumoral alfa
20.
Cell Rep ; 39(13): 110989, 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35767946

RESUMO

The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon ß (IFNß) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNß as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNß-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNß in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.


Assuntos
Interferon beta , Interleucina-12 , Receptor 4 Toll-Like , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Interferon beta/imunologia , Interferon beta/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Lipopolissacarídeos/farmacologia , Proteômica , SARS-CoV-2/imunologia
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