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1.
Nat Commun ; 12(1): 481, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33473108

RESUMO

T helper type 17 (Th17) cells have important functions in the pathogenesis of inflammatory and autoimmune diseases. Retinoid-related orphan receptor-γt (RORγt) is necessary for Th17 cell differentiation and functions. However, the transcriptional regulation of RORγt expression, especially at the enhancer level, is still poorly understood. Here we identify a novel enhancer of RORγt gene in Th17 cells, RORCE2. RORCE2 deficiency suppresses RORγt expression and Th17 differentiation, leading to reduced severity of experimental autoimmune encephalomyelitis. Mechanistically, RORCE2 is looped to RORγt promoter through SRY-box transcription factor 5 (SOX-5) in Th17 cells, and the loss of SOX-5 binding site in RORCE abolishes RORCE2 function and affects the binding of signal transducer and activator of transcription 3 (STAT3) to the RORγt locus. Taken together, our data highlight a molecular mechanism for the regulation of Th17 differentiation and functions, which may represent a new intervening clue for Th17-related diseases.


Assuntos
Diferenciação Celular , Encefalomielite Autoimune Experimental/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismo , Células Th17/metabolismo , Animais , Autoimunidade , Diferenciação Celular/genética , Encefalomielite Autoimune Experimental/imunologia , Epigenômica , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células Th17/imunologia
2.
Biomed Pharmacother ; 133: 111028, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378943

RESUMO

Aspirin is one of the most commonly prescribed medications. Evidence shows that it can even treat and prevent intestinal tumors. However, it has also caused a great deal of controversy due to its intestinal side effects. We therefore explored whether aspirin was beneficial or harmful to the intestines. We used aspirin continuously interfered with C57BL/6 J mice for 48 weeks, examining their intestinal tissues at 13, 26 and 48 weeks to determine the drug's effect on the intestines. In addition, we used flow cytometry (FCM) used to detect T cells and expression of T-cell immunoreceptor with immunoglobulin (Ig)- and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) on their surfaces to determine aspirin's immunomodulatory effects. The results showed that long-term aspirin intervention could reverse damage to the intestines, an effect related to the drug's significant inhibitory effect on TIGIT. The change in TIGIT level could regulate T-cell subsets, so that counts of Cluster of Differentiation 4 (CD4)+/chemokine (C-X3-C motif) receptor 3 (CXCR3)+ T-helper 1 (Th1) cells and CD4+/interleukin-4 (IL-4)+ Th2 cells increased, while those of CD4+/C-C chemokine receptor type 6 (CCR6)+ Th17 cells and CD4+/CD25+ regulatory T cells (Tregs) decreased. In summary, we demonstrated that long-term aspirin intervention could inhibit TIGIT, regulating T cells to reverse damage to the intestines. Furthermore, aspirin is a potential therapy for diseases related to an increase in TIGIT.


Assuntos
Aspirina/toxicidade , Colo/efeitos dos fármacos , Receptores Imunológicos/metabolismo , Reto/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Animais , Colo/imunologia , Colo/metabolismo , Colo/patologia , Regulação para Baixo , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Reto/imunologia , Reto/metabolismo , Reto/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Tempo
3.
Front Immunol ; 11: 596553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324414

RESUMO

The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate responses and impaired adaptive immune responses mostly due to exhausted T lymphocytes and lymphopenia. In this work we have characterized the nature of the lymphopenia and demonstrate a set of factors that hinder the effective control of virus infection and the activation and arming of effector cytotoxic T CD8 cells and showing signatures defining a high-risk population. We performed immune profiling of the T helper (Th) CD4+ and T CD8+ cell compartments in peripheral blood of 144 COVID-19 patients using multiparametric flow cytometry analysis. On the one hand, there was a consistent lymphopenia with an overrepresentation of non-functional T cells, with an increased percentage of naive Th cells (CD45RA+, CXCR3-, CCR4-, CCR6-, CCR10-) and persistently low frequency of markers associated with Th1, Th17, and Th1/Th17 memory-effector T cells compared to healthy donors. On the other hand, the most profound alteration affected the Th1 subset, which may explain the poor T cells responses and the persistent blood virus load. Finally, the decrease in Th1 cells may also explain the low frequency of CD4+ and CD8+ T cells that express the HLA-DR and CD38 activation markers observed in numerous patients who showed minimal or no lymphocyte activation response. We also identified the percentage of HLA-DR+CD4+ T cells, PD-1+CD+4/CD8+ T cells in blood, and the neutrophil/lymphocyte ratio as useful factors for predicting critical illness and fatal outcome in patients with confirmed COVID-19.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , /imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Th1/imunologia , ADP-Ribosil Ciclase 1/imunologia , ADP-Ribosil Ciclase 1/metabolismo , Idoso , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Feminino , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
4.
Nat Commun ; 11(1): 5173, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057068

RESUMO

In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission.


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/transplante , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/terapia , Células Th17/imunologia , Idoso , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Intervalo Livre de Doença , Feminino , Receptor 1 de Folato/imunologia , Humanos , Imunidade Humoral , Injeções Intradérmicas , Interferon gama/metabolismo , Interleucina-17/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Células Th17/metabolismo , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos
5.
Nat Commun ; 11(1): 4368, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868758

RESUMO

Increased extracellular sodium activates Th17 cells, which provide protection from bacterial and fungal infections. Whilst high salt diets have been shown to worsen autoimmune disease, the immunological consequences of clinical salt depletion are unknown. Here, we investigate immunity in patients with inherited salt-losing tubulopathies (SLT). Forty-seven genotyped SLT patients (with Bartter, Gitelman or EAST Syndromes) are recruited. Clinical features of dysregulated immunity are recorded with a standardised questionnaire and immunological investigations of IL-17 responsiveness undertaken. The effects of altering extracellular ionic concentrations on immune responses are then assessed. Patients are hypokalaemic and hypomagnesaemic, with reduced interstitial sodium stores determined by 23Na-magnetic resonance imaging. SLT patients report increased mucosal infections and allergic disease compared to age-matched controls. Aligned with their clinical phenotype, SLT patients have an increased ratio of Th2:Th17 cells. SLT Th17 and Tc17 polarisation is reduced in vitro, yet STAT1 and STAT3 phosphorylation and calcium flux following T cell activation are unaffected. In control cells, the addition of extracellular sodium (+40 mM), potassium (+2 mM), or magnesium (+1 mM) reduces Th2:Th17 ratio and augments Th17 polarisation. Our results thus show that the ionic environment typical in SLT impairs IL-17 immunity, but the intracellular pathways that mediate salt-driven Th17 polarisation are intact and in vitro IL-17 responses can be reinvigorated by increasing extracellular sodium concentration. Whether better correction of extracellular ions can rescue the immunophenotype in vivo in SLT patients remains unknown.


Assuntos
Síndromes de Imunodeficiência/etiologia , Interleucina-17/metabolismo , Túbulos Renais Distais/patologia , Adolescente , Adulto , Idoso de 80 Anos ou mais , Animais , Pré-Escolar , Doença Crônica , Estudos de Coortes , Feminino , Doenças Genéticas Inatas , Humanos , Magnésio/metabolismo , Masculino , Pessoa de Meia-Idade , Potássio/metabolismo , Sais/metabolismo , Sais/uso terapêutico , Sódio/metabolismo , Cloreto de Sódio/metabolismo , Cloreto de Sódio na Dieta/uso terapêutico , Células Th17/metabolismo , Células Th2/metabolismo , Adulto Jovem
6.
Nat Commun ; 11(1): 4367, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868763

RESUMO

Invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT), and γδ T cells are innate T cells that acquire memory phenotype in the thymus and share similar biological characteristics. However, how their effector differentiation is developmentally regulated is still unclear. Here, we identify analogous effector subsets of these three innate T cell types in the thymus that share transcriptional profiles. Using single-cell RNA sequencing, we show that iNKT, MAIT and γδ T cells mature via shared, branched differentiation rather than linear maturation or TCR-mediated instruction. Simultaneous TCR clonotyping analysis reveals that thymic maturation of all three types is accompanied by clonal selection and expansion. Analyses of mice deficient of TBET, GATA3 or RORγt and additional in vivo experiments corroborate the predicted differentiation paths, while human innate T cells from liver samples display similar features. Collectively, our data indicate that innate T cells share effector differentiation processes in the thymus.


Assuntos
Diferenciação Celular , Imunidade Inata , Linfócitos T/metabolismo , Timo/imunologia , Animais , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Humanos , Fígado/citologia , Fígado/imunologia , Ativação Linfocitária , Camundongos , Células T Invariáveis Associadas à Mucosa/metabolismo , Células T Matadoras Naturais/metabolismo , Análise de Sequência de RNA , Análise de Célula Única , Células Th17/metabolismo , Timo/citologia
7.
Proc Natl Acad Sci U S A ; 117(33): 20088-20099, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32732436

RESUMO

T lymphocyte motility and interaction dynamics with other immune cells are vital determinants of immune responses. Regulatory T (Treg) cells prevent autoimmune disorders by suppressing excessive lymphocyte activity, but how interstitial motility patterns of Treg cells limit neuroinflammation is not well understood. We used two-photon microscopy to elucidate the spatial organization, motility characteristics, and interactions of endogenous Treg and Th17 cells together with antigen-presenting cells (APCs) within the spinal cord leptomeninges in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Th17 cells arrive before the onset of clinical symptoms, distribute uniformly during the peak, and decline in numbers during later stages of EAE. In contrast, Treg cells arrive after Th17 cells and persist during the chronic phase. Th17 cells meander widely, interact with APCs, and exhibit cytosolic Ca2+ transients and elevated basal Ca2+ levels before the arrival of Treg cells. In contrast, Treg cells adopt a confined, repetitive-scanning motility while contacting APCs. These locally confined but highly motile Treg cells limit Th17 cells from accessing APCs and suppress Th17 cell Ca2+ signaling by a mechanism that is upstream of store-operated Ca2+ entry. Finally, Treg cell depletion increases APC numbers in the spinal cord and exaggerates ongoing neuroinflammation. Our results point to fundamental differences in motility characteristics between Th17 and Treg cells in the inflamed spinal cord and reveal three potential cellular mechanisms by which Treg cells regulate Th17 cell effector functions: reduction of APC density, limiting access of Th17 cells to APCs, and suppression of Th17 Ca2+ signaling.


Assuntos
Sinalização do Cálcio/fisiologia , Medula Espinal/metabolismo , Células Th17/metabolismo , Animais , Autoantígenos , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Fluorescência Verde , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina , Linfócitos T Reguladores
8.
Medicine (Baltimore) ; 99(31): e21491, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756180

RESUMO

BACKGROUND: To investigate the effect of high-volume hemofiltration (HVHF) on Th17/Treg imbalance in patients with severe acute pancreatitis (SAP). METHODS: Forty-two patients with SAP were randomly received 24 hours of continuous HVHF (n = 21) or without HVHF (n = 21). At day 28, all 42 patients were divided into survival group (n = 32) and non-survival group (n = 10). Venous blood samples collected at 0, 6, 12, and 24 hours during HVHF treatment (or equivalent time in non-HVHF group) were assessed by flow cytometry to detect Th17 and Treg cells. Concentrations of IL-6, IL-17, IL-10, and TGF-ß1 were detected by enzyme-linked immunosorbent assay. RESULTS: Th17%, Treg%, Th17/Treg, and levels of related cytokines were significantly higher in SAP patients than healthy controls (P < .05), and these changes were more pronounced in SAP patients with multiple organ failure than those with single organ failure (P < .05). After HVHF treatment, Th17%, Treg%, Th17/Treg, IL-6, IL-17, and IL-10 significantly reduced (P < .05), while there were no significant changes in non-HVHF group (P > .05). In addition, acute physiology and chronic health evaluation II and sequential organ failure assessment scores decreased markedly after HVHF treatment. Baselines of Th17%, Treg%, Th17/Treg, and related cytokines were significantly higher in non-survival group than survival group. Both acute physiology and chronic health evaluation I score and IL-6 level were positively correlated with Th17% before and after HVHF treatment (P < .01). CONCLUSIONS: Th17/Treg imbalance is present in SAP and may be correlated with its severity and prognosis. HVHF effectively attenuates the Th17/Treg imbalance in SAP patients. The beneficial effect of HVHF on Th17/Treg imbalance is possibly associated with removing excess inflammatory mediators.


Assuntos
Hemofiltração/métodos , Pancreatite/sangue , Pancreatite/terapia , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Doença Aguda , Adulto , Idoso , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/terapia , Pancreatite/mortalidade , Resultado do Tratamento , Adulto Jovem
9.
Am J Psychiatry ; 177(10): 974-990, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32731813

RESUMO

OBJECTIVE: Microbiota dysbiosis has been linked to major depressive disorder, but the mechanisms whereby the microbiota modulates mood remain poorly understood. The authors tested whether specific changes in the microbiome modulate depressive-like behaviors. METHODS: Stools from learned helpless, non-learned helpless, and non-shocked mice were analyzed by V4 16S RNA sequencing to identify gut bacteria associated with learned helplessness and to quantify the level of the quorum-sensing molecule autoinducer-2 (AI-2). T cells were analyzed by flow cytometry, and serum amyloid proteins (SAA) were analyzed by quantitative real-time polymerase chain reaction. Fecal transfer approach and administration of oleic acid and AI-2 were used to determine the effects of the microbiome and quorum-sensing molecules on depressive-like behaviors. RESULTS: Mice deficient in segmented filamentous bacteria (SFB) were resilient to the induction of depressive-like behavior, and were resensitized when SFB was reintroduced in the gut. SFB produces the quorum-sensing AI-2 and promotes the production of SAA1 and SAA2 by the host, which increases T helper 17 (Th17) cell production. Th17 cells were required to promote depressive-like behaviors by AI-2, as AI-2 administration did not promote susceptibility to depressive-like behaviors or SAA1 and SAA2 production in Th17-deficient mice after stress. Oleic acid, an AI-2 inhibitor, exhibited antidepressant properties, reducing depressive-like behavior, intestinal SAA1 and SAA2 production, and hippocampal Th17 cell accumulation. Stool samples from 10 people with current depressive symptoms and 10 matched healthy control subjects were analyzed as well. Patients with current major depressive disorder exhibited increased fecal interleukin 17A, SAA, and SFB levels. CONCLUSIONS: The study results reveal a novel mechanism by which bacteria alter mood.


Assuntos
Depressão/metabolismo , Microbioma Gastrointestinal/fisiologia , Células Th17/fisiologia , Adulto , Animais , Transtorno Depressivo Maior/metabolismo , Modelos Animais de Doenças , Fezes/química , Feminino , Citometria de Fluxo , Microbioma Gastrointestinal/genética , Desamparo Aprendido , Humanos , Interleucina-17/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Percepção de Quorum , RNA Ribossômico 16S/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteína Amiloide A Sérica/análise , Células Th17/metabolismo
10.
Nat Commun ; 11(1): 3434, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632085

RESUMO

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1+CD57+ exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4+ T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Senescência Celular , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Memória Imunológica , Itália/epidemiologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia
11.
Nat Commun ; 11(1): 3334, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620760

RESUMO

TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-ß signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.


Assuntos
Homeostase/imunologia , Inflamação/imunologia , Interleucina-10/imunologia , Intestinos/imunologia , Células Th17/imunologia , Animais , Plasticidade Celular/imunologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Células HEK293 , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/fisiologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
12.
BMC Womens Health ; 20(1): 126, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32552719

RESUMO

BACKGROUND: Nearly all uterine cervical cancer (UCC) cases result from human papillomavirus (HPV) infection. After high-risk HPV infection, most HPV infections are naturally cleared by humoral and cell-mediated immune responses. Thus, cervical lesions of only few patients progress into cervical cancer via cervical intraepithelial neoplasia (CIN) and lead to persistent oncogenic HPV infection. This suggests that immunoregulation plays an instrumental role in the carcinogenesis. However, there was a few studies on the relation between the immunologic dissonance and clinical characteristics of UCC patients. METHOD: We examined the related immune cells (Th1, Th2, Th17, and Treg cells) by flow cytometric analysis and analyzed their relations with UCC stages, tumor size, differentiation, histology type, lymph node metastases, and vasoinvasion. Next, we quantified the Th1, Th2, Th17, and Treg cells before and after the operation both in UCC and CIN patients. RESULTS: When compared with stage I patients, decreased levels of circulating Th1 cells and elevated levels of Th2, Th17, and Treg cells were detected in stage II patients. In addition, the imbalance of Th1/Th2 and Th17/Treg cells was related to the tumor size, lymph node metastases, and vasoinvasion. We found that immunological cell levels normalized after the operations. In general, immunological cell levels in CIN patients normalized sooner than in UCC patients. CONCLUSIONS: Our findings suggested that peripheral immunological cell levels reflect the patient's condition.


Assuntos
Neoplasia Intraepitelial Cervical/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Neoplasias do Colo do Útero/imunologia , Adulto , Neoplasia Intraepitelial Cervical/sangue , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Carga Tumoral , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/metabolismo
13.
J Neuroimmunol ; 345: 577286, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32559555

RESUMO

We investigated the effects of matairesinol (MAT) in the experimental autoimmune uveitis (EAU), a classical animal model of uveitis. We found that treatment with MAT could alleviate intraocular inflammation of EAU. Notably, Th17 cells in eyes of EAU mice could be predominantly restrained by MAT. Furthermore, MAT could inhibit Th17 differentiation in vitro. In addition, MAT inhibited the signaling of MAPK and ROR-γt, a pivotal transcription factor for Th17 cell differentiation in vitro and in vivo. Taken together, these results suggested that MAT had immune-suppressive effects on autoimmune inflammation through Th17 cells.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Proteínas do Olho/antagonistas & inibidores , Furanos/uso terapêutico , Lignanas/uso terapêutico , Proteínas de Ligação ao Retinol/antagonistas & inibidores , Células Th17/efeitos dos fármacos , Uveíte/tratamento farmacológico , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Proteínas do Olho/imunologia , Proteínas do Olho/metabolismo , Feminino , Adjuvante de Freund/toxicidade , Furanos/farmacologia , Lignanas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Ligação ao Retinol/imunologia , Proteínas de Ligação ao Retinol/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Uveíte/imunologia , Uveíte/metabolismo
14.
J Neuroimmunol ; 344: 577263, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32416557

RESUMO

The Th17 profile immune response is influenced by the presence of cytokines such as IL-1, IL-6, TGF-ß, IL-17, and IL-23. We sought to characterize the Th17 profile in CNS samples from human rabies cases transmitted by dogs and examine its possible influence on disease pathogenesis. We observed a high expression of TGF-ß, followed by IL-23, IL-17 and IL-6, and a low expression of IL-1ß and IFN-γ. Those results suggest the participation of Th17 in rabies virus neuroinfection transmitted by dogs. IL-23 probably plays a role in maintaining the Th17 profile, but it can also interfere with the establishment of the Th1 profile and viral clearance.


Assuntos
Encéfalo/imunologia , Citocinas/imunologia , Imunidade Celular/imunologia , Raiva/imunologia , Raiva/transmissão , Células Th17/imunologia , Adolescente , Adulto , Animais , Encéfalo/metabolismo , Citocinas/metabolismo , Cães , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Raiva/metabolismo , Células Th17/metabolismo , Adulto Jovem
15.
Proc Natl Acad Sci U S A ; 117(22): 12269-12280, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32409602

RESUMO

In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A-induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.


Assuntos
5'-Nucleotidase/metabolismo , Ativinas/farmacologia , Antígenos CD/metabolismo , Apirase/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/prevenção & controle , Esclerose Múltipla/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Células Th17/metabolismo
16.
J Virol ; 94(14)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32350073

RESUMO

Antiretroviral therapy (ART) cannot eradicate human immunodeficiency virus (HIV) and a rapid rebound of virus replication follows analytical treatment interruption (ATI) in the vast majority of HIV-infected individuals. Sustained control of HIV replication without ART has been documented in a subset of individuals, defined as posttreatment controllers (PTCs). The key determinants of post-ART viral control remain largely unclear. Here, we identified 7 SIVmac239-infected rhesus macaques (RMs), defined as PTCs, who started ART 8 weeks postinfection, continued ART for >7 months, and controlled plasma viremia at <104 copies/ml for up to 8 months after ATI and <200 copies/ml at the latest time point. We characterized immunologic and virologic features associated with post-ART SIV control in blood, lymph node (LN), and colorectal (RB) biopsy samples compared to 15 noncontroller (NC) RMs. Before ART initiation, PTCs had higher CD4 T cell counts, lower plasma viremia, and SIV-DNA content in blood and LN compared to NCs, but had similar CD8 T cell function. While levels of intestinal CD4 T cells were similar, PTCs had higher frequencies of Th17 cells. On ART, PTCs had significantly lower levels of residual plasma viremia and SIV-DNA content in blood and tissues. After ATI, SIV-DNA content rapidly increased in NCs, while it remained stable or even decreased in PTCs. Finally, PTCs showed immunologic benefits of viral control after ATI, including higher CD4 T cell levels and reduced immune activation. Overall, lower plasma viremia, reduced cell-associated SIV-DNA, and preserved Th17 homeostasis, including at pre-ART, are the main features associated with sustained viral control after ATI in SIV-infected RMs.IMPORTANCE While effective, antiretroviral therapy is not a cure for HIV infection. Therefore, there is great interest in achieving viral remission in the absence of antiretroviral therapy. Posttreatment controllers represent a small subset of individuals who are able to control HIV after cessation of antiretroviral therapy, but characteristics associated with these individuals have been largely limited to peripheral blood analysis. Here, we identified 7 SIV-infected rhesus macaques that mirrored the human posttreatment controller phenotype and performed immunologic and virologic analysis of blood, lymph node, and colorectal biopsy samples to further understand the characteristics that distinguish them from noncontrollers. Lower viral burden and preservation of immune homeostasis, including intestinal Th17 cells, both before and after ART, were shown to be two major factors associated with the ability to achieve posttreatment control. Overall, these results move the field further toward understanding of important characteristics of viral control in the absence of antiretroviral therapy.


Assuntos
Antirretrovirais/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Células Th17 , Animais , Relação CD4-CD8 , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , DNA Viral/sangue , DNA Viral/imunologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Tempo
17.
Rev. esp. cardiol. (Ed. impr.) ; 73(5): 393-402, mayo 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-194547

RESUMO

INTRODUCCIÓN Y OBJETIVOS: La interleucina 5 (IL-5) es una citocina antiinflamatoria que se ha involucrado en las enfermedades cardiovasculares, incluidos los aneurismas aórticos y la insuficiencia cardiaca. El objetivo de este estudio es investigar el papel de la IL-5 en la enfermedad coronaria (EC) y sus posibles mecanismos. MÉTODOS: Se analizó la expresión de la IL-5 en muestras de arterias coronarias humanas de 17 pacientes con EC y donantes fallecidos. Además, se determinaron las concentraciones plasmáticas de IL-5, IL-17 e interferón gamma en pacientes con EC usando kits ELISA con muestras de pacientes con dolor torácico (sin EC) como controles. Se separaron las células murinas CD4+T helper (Th), y el efecto de la IL-5 en la diferenciación de Th1, célula T reguladora y Th17 y la cantidad de ARNm de sus citocinas características se determinaron mediante citometría de flujo y reacción en cadena de la polimerasa tras transcripción inversa respectivamente. RESULTADOS: La IL-5 disminuyó significativamente en las placas coronarias de los pacientes con EC comparados con el grupo de donantes fallecidos, y la IL-5 derivó fundamentalmente de los macrófagos de las placas de las arterias coronarias. Además, comparados con el grupo sin EC, las concentraciones plasmáticas de IL-5 en el grupo de EC fueron significativamente menores, y la secuencia de mayor a menor fue angina estable, angina inestable e infarto de miocardio. El análisis de regresión linear binaria mostró que la IL-5 se correlacionó independientemente con la aparición de la EC. Además, el tratamiento con IL-5 recombinante de ratón disminuyó los valores de Th1 y Th17 y la expresión del ARNm de sus citocinas características en lipoproteínas oxidadas de baja densidad tratadas con CD4+Th. CONCLUSIONES: Los valores de IL-5 disminuyeron en los pacientes con EC e inhiben la diferenciación in vitro de Th1 y Th17 inducida por lipoproteínas oxidadas de baja densidad


INTRODUCTION AND OBJECTIVES: Interleukin (IL)-5 is an anti-inflammatory cytokine that has been demonstrated to be involved in cardiovascular diseases, including aortic aneurysm and heart failure. This study aimed to investigate the involvement of IL-5 in coronary artery disease (CAD) and the possible mechanisms. METHODS: We analyzed IL-5 expression in human coronary artery specimens collected from CAD patients and deceased donors. Plasma IL-5, IL-17, and interferon-γ levels in CAD patients were detected using ELISA kits, with samples from chest pain patients (non-CAD) as controls. Mouse CD4+T helper (Th) cells were separated, and the effect of IL-5 on Th1, regulatory T cell and Th17 differentiation and mRNA levels of their characteristic cytokines were detected using flow cytometry and reverse transcription-quantitative polymerase chain reaction, respectively. RESULTS: IL-5 was significantly decreased in the coronary plaque of CAD patients compared with the deceased donors group, and IL-5 was mainly derived from macrophages in the coronary artery plaque. Compared with the non-CAD group, plasma IL-5 levels in the CAD groups were significantly lower, and the sequence from high to low was stable angina pectoris, unstable angina pectoris, and acute myocardial infarction. Binary linear regression analysis showed that IL-5 was independently correlated with the occurrence of CAD. Recombinant mouse IL-5 treatment decreased Th1 and Th17 levels and mRNA expression of their characteristic cytokines in oxidized low-density lipoprotein-treated CD4+Th cells. CONCLUSION: IL-5 levels were decreased in CAD patients and inhibited oxidized low-density lipoprotein Th1 and Th17 differentiation in vitro


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Interleucina-5/sangue , Interleucina-5/metabolismo , Doença das Coronárias/sangue , Células Th1/metabolismo , Células Th17/metabolismo , Estudos Prospectivos , Western Blotting , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Am J Physiol Regul Integr Comp Physiol ; 318(6): R1036-R1046, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320265

RESUMO

T-helper (TH)17s, IL-17, and cytolytic natural killer cells (cNKs) are increased in preeclampsia and contribute to the hypertension, inflammation, and fetal growth restriction that occurs in response to placental ischemia in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. As IL-17 stimulates NK cytotoxicity in vitro, we tested the hypothesis that IL-17 inhibition in RUPP rats would decrease cNK activation as a mechanism to improve maternal and fetal outcomes. On gestation day (GD) 14, rats undergoing RUPP received a miniosmotic pump infusing IL-17RC (100 pg/day), a soluble IL-17 receptor (RUPP + IL-17RC). On GD19, mean arterial pressure (MAP) was measured in normal pregnant (NP), RUPP, and RUPP + IL-17RC rats (n = 10-12/group), animals were euthanized, and blood and tissues were collected for analysis. MAP was 30% higher in RUPP compared with NP (P < 0.0001) and was 12% lower in RUPP + IL-17RC (P = 0.0007 vs. RUPP). Placental cytolytic NK cells were 132% higher in RUPP than in NP (P = 0.04 vs. NP) and were normalized in RUPP + IL-17RC (P = 0.03 vs. RUPP). Placental levels of TNF-α, a cNK-secreted cytokine, and macrophage inflammatory protein-3α (MIP-3α), a cNK chemokine, were higher in RUPP vs. NP and lower after IL-17 blockade. Placental VEGF was lower in RUPP vs. NP and was normalized in RUPP + IL-17RC. In vitro cytolytic activity of RUPP placental NKs was higher compared with NP and was blunted in RUPP + IL-17RC NKs. Finally, both fetal weight and placental weight were lower in RUPP compared with NP, and were improved in RUPP + IL-17RC. These data identify IL-17 as a mediator of cNK activation in response to placental ischemia during pregnancy.


Assuntos
Interleucina-17/metabolismo , Isquemia/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Placenta/irrigação sanguínea , Receptores de Interleucina-17/administração & dosagem , Animais , Pressão Arterial/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Isquemia/metabolismo , Placenta/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
19.
Arch Immunol Ther Exp (Warsz) ; 68(2): 12, 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32248339

RESUMO

The effect of TNF-blockers on T-lymphocyte subsets is largely unknown in inflammatory bowel diseases (IBDs). The aim of the present study was to analyze the prevalence of T-cell subtypes and their correlation to therapeutic response. Sixty-eight patients with Crohn's disease (CD), 46 with ulcerative colitis (UC) were enrolled. (1) The clinical course was followed after the initiation of TNF-blockers (prospective study). (2) The immunophenotype was also compared between long-term anti-TNF treated-responders and non-responders (cross-sectional study). The results were compared with those of therapy-naïve patients with active disease and those in remission with non-biological immunosuppressive therapy, and with healthy controls. Fourteen subtypes of peripheral blood T cells were measured with flow cytometry. The prevalence of Th2 and Th17 cells, of HLA-DR- and CD69-positive CD4 and CD8 cells, was higher, whereas the percentage of CD45RA-positive CD4 and CD8 cells was lower in both IBDs than in controls. CD8CD69 cell frequency was lower in remission, and decreased during anti-TNF therapy in CD responders. CD8CD45RO memory cells had higher prevalence in UC non-responders than in those starting anti-TNF. CD4CD45RO percentage < 49.05 at the initiation of TNF-blockers was predictive of a subsequent therapeutic response in CD, and Th2 and Th17 prevalence correlated with the duration of remission on TNF-blockers in UC. This study provided a detailed description of the T-cell composition in IBDs. CD8CD69 prevalence may be an activity marker in CD, and CD4CD45RO, Th2 and Th17 levels could be predictive for a therapeutic response to anti-TNF.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Subpopulações de Linfócitos T/citologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Subpopulações de Linfócitos T/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Células Th2/citologia , Células Th2/metabolismo , Resultado do Tratamento , Adulto Jovem
20.
Nat Commun ; 11(1): 1913, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312989

RESUMO

The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity.


Assuntos
Antifúngicos/imunologia , Candidíase/imunologia , Diferenciação Celular , Proteínas Ativadoras de GTPase/química , Proteínas Ativadoras de GTPase/metabolismo , Receptor EphB2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Th17/metabolismo , Animais , Antifúngicos/farmacologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/microbiologia , Feminino , Proteínas Ativadoras de GTPase/genética , Humanos , Lectinas Tipo C/metabolismo , Masculino , Camundongos Knockout , Esclerose Múltipla/complicações , Esclerose Múltipla/imunologia , Fosforilação , Receptor EphB2/imunologia , Receptores Imunológicos , Receptores de Reconhecimento de Padrão/metabolismo , Células Th17/imunologia
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