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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 595-600, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537243

RESUMO

Objective To observe the effect of esculentoside A (EsA) on Th17 cell-related factors in psoriasis-like mouse model. Methods A total of 48 female BALB/c mice were randomly divided into blank control group, model group, Tuiyin decoction group [66.60 g/(kg.d)], low-, middle- and high-dose groups of EsA [5, 10, 20 mg/(kg.d), respectively], 8 mice in each group. Psoriasis mouse model was induced by imiquimod. Pathological changes of skin lesions in mice were assessed by psoriasis area and severity index (PASI) and HE staining. ELISA was used to detect the changes of interleukin-17 (IL-17), IL-22, IL-6 and tumor necrosis factor-α (TNF-α). Results Compared with the model group, the skin lesions, pathological changes and PASI scores were improved after the treatments with either Tuiyin decoction or EsA, among which the PASI score of Tuiyin decoction group and high-dose group of EsA decreased significantly. The expression of Th17 cell-related factors of the model group was obviously higher than that of the blank control group. Each treated group had obviously lower expression than the model group, and the expression of IL-6 of high-dose group of EsA was close to the blank control group. Conclusion EsA may improve the skin lesions of the psoriasis-like mice by down-regulating the expression of Th17 cell-related cytokines.


Assuntos
Dermatite/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Psoríase/tratamento farmacológico , Saponinas/farmacologia , Células Th17/imunologia , Animais , Citocinas/imunologia , Dermatite/imunologia , Feminino , Imiquimode , Camundongos , Camundongos Endogâmicos BALB C , Ácido Oleanólico/farmacologia , Psoríase/induzido quimicamente , Distribuição Aleatória , Pele/imunologia , Pele/patologia
2.
Expert Opin Ther Pat ; 29(9): 663-674, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31403347

RESUMO

Introduction: RORγt is critical for the differentiation of Th17 cells and the production of IL-17. Inhibition of RORγt is considered as a promising strategy to treat Th17-mediated autoimmune diseases. Quite a number of RORγt inhibitors have been progressed into clinical trials, besides much biological interests in this attractive target. Areas covered: This article reviews the progress of RORγt inhibitors (antagonists and inverse agonists) that are active in clinical development based on an analysis of the related patents published by the corresponding companies in the period of January 2016 through May 2019. Expert opinion: The development of RORγt inhibitors has gone through a boom period in the past three years. However, with a little bit frustration, some of the frontrunner clinical compounds were either discontinued or suspended for further development possibly due to some safety concerns or lack of efficacy in humans. There is a need to probe deeply into these concerns in the on-going pre-clinical and clinical studies. Given the effectiveness of a few recently FDA-approved anti-IL-17(R) antibodies on psoriasis, the discovery of RORγt inhibitors continues to be an exciting field for the development of novel treatment approaches.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Animais , Doenças Autoimunes/imunologia , Descoberta de Drogas , Humanos , Interleucina-17/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Patentes como Assunto , Células Th17/imunologia
3.
J Agric Food Chem ; 67(34): 9522-9531, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31379161

RESUMO

The imbalance of T lymphocyte subsets substantially conduces to disturbed intestinal immune system and succeeding colonic tissue damage in inflammatory bowel diseases. It is considered that regulation of phytochemicals on cytokine production potentially provides a broad prospect for the exploitation of immunomodulatory agents. Here, we reported that oral administration of feruloylated oligosaccharides (FOs) effectively alleviated mice colitis disease induced by dextran sulfate sodium (DSS). FOs decreased the percentage of T helper (Th)17 cells and downregulated the production of Th17-specific cytokines. In contrast, FOs increased the percentage of regulatory T (Treg) cells and elevated the production of Treg-specific cytokines in colons of DSS-challenged mice. These results indicated that FOs restored the immunologic equilibrium of Th17 and Treg subsets, hereby ameliorating the deterioration of colitis. Furthermore, FOs diminished the secretion of interleukin (IL)-23 and IL-6 but enhanced the transforming growth factor-ß1 (TGF-ß1) in dendritic cells in vitro and in vivo, which contributed to the restoration of Th17 and Treg cells immune balance. The mechanistic analysis showed that the regulation of FOs on IL-23 and IL-6 was associated with the nuclear factor-κ-gene binding signaling pathway and TGF-ß1 with mitogen-activated protein kinase-activator protein 1 signaling pathway. Taken together, oral administration of FOs exerted potent immunomodulatory effects against mice colitis via restoring the immune balance of Th17 and Treg cells.


Assuntos
Colite/tratamento farmacológico , Oligossacarídeos/administração & dosagem , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Citocinas/genética , Citocinas/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Humanos , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligossacarídeos/química , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
4.
Nihon Yakurigaku Zasshi ; 154(2): 66-71, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31406045

RESUMO

Cytokine signal is essential for the biological function including development, maintenance of homeostasis and progression of disease. There are growing evidences that signaling via pro-inflammatory cytokines underlie a variety of immunological diseases such as psoriasis, atopic dermatitis, inflammatory bowel disease, and metabolic syndromes, in which cytokine signals are known as a potential therapeutic target of antibody drugs. In contrast, anti-inflammatory cytokines, which is represented by IL-10, largely contribute to suppression of inflammation and restoration of injured tissues. IL-19 is a member of IL-10 cytokine family, which comprises IL-20 cytokine subfamily with IL-20, IL-22, IL-24, and IL-26. IL-19 is produced by myeloid and epithelial cells with stimulation of bacterial components and cytokines. Although IL-19 has been originally recognized as a potential Th2-related cytokine, in recent researches, it has been reported that this cytokine upregulates Th17 response to reflect and promote progression of Th17-related disease including psoriasis. On the other hand, IL-19 has anti-inflammatory effects on inflammatory diseases such as infectious skin disease, inflammatory bowel disease, and cardiovascular disease. Therefore, IL-19 may exert pleiotropic effects dependent on the pathological mechanism of inflammatory diseases. In this review, we summarize recent studies about IL-19 and introduce the pathophysiological and therapeutic role of IL-19 in inflammatory diseases.


Assuntos
Interleucinas/imunologia , Psoríase/imunologia , Citocinas/imunologia , Humanos , Inflamação/imunologia , Células Th17/imunologia
5.
Environ Pollut ; 252(Pt B): 1519-1531, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31277021

RESUMO

Some basic research has shown that nanomaterials can aggravate allergic asthma. However, its potential mechanism is insufficient. Based on the research that alumina nanopowder (nAl2O3) has been reported to cause lung tissue damage, the purpose of this study was to explore the relationship between nAl2O3 and allergic asthma as well as its molecular mechanism. In this study, Balb/c mice were sensitized with ovalbumin (OVA) to construct the allergic asthma model while intratracheally administered 0.5, 5 or 50 mg kg-1·day-1 nAl2O3 for 3 weeks. It was observed that exposure to nAl2O3 exacerbated airway hyperresponsiveness (AHR), airway remodeling, and inflammation cell infiltration, leading to lung function damage in mice. Results revealed that nAl2O3 could increase ROS levels and decrease GSH levels in lung tissue, promote the increases of the T-IgE, TGF-ß, IL-1ß and IL-6 levels, stimulate the overexpression of transcription factors GATA-3 and RORγt, decrease the levels of IFN-γ and IL-10 and increase the levels of IL-4 and IL-17A, resulting in the imbalance of Th1/Th2 and Treg/Th17 immune responses. In addition, antioxidant Vitamin E (Vit E) could alleviate asthma-like symptoms through blocking oxidative stress. The study displayed that exposure of nAl2O3 deteriorated allergic asthma through promoting the imbalances of Th1/Th2 and Treg/Th17.


Assuntos
Antioxidantes/farmacologia , Asma/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Vitamina E/farmacologia , Óxido de Alumínio/toxicidade , Animais , Asma/induzido quimicamente , Asma/imunologia , Interleucina-17/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/toxicidade , Ovalbumina/imunologia , Estresse Oxidativo/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Th2/imunologia
6.
Scand J Immunol ; 90(5): e12810, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325389

RESUMO

MicroRNAs (miRNAs) play a vital role in the occurrence and development of many human diseases, including systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by the production of autoantibodies against nuclear antigens and multiorgan involvement. Study of miRNAs involved in SLE provides new insights into the pathogenesis of SLE and might lead to the identification of new therapeutic interventions. The aim of this study was to investigate the effect of miR-183 injection on the progression of SLE by using MRL/lpr mouse model. The expression levels of miR-183 and mTOR mRNA were detected by quantitative real-time PCR assay. The effect of miR-183 on the course of spontaneous disease progression in the MRL/lpr mice was examined by intraperitoneal injection of miR-183 into mice and followed by monitoring lifespan, anti-dsDNA antibody levels, urinary albumin levels, blood urea nitrogen (BUN) levels, and Tregs and Th17 cell population. We found that miR-183 injection resulted in reduction of anti-DNA antibody and immune complex component levels, restoration of Tregs and Th17 cell population and prolongation of survival. Our findings suggest that miR-183 injection may serve as an effective therapeutic treatment for delaying or easing pathologic features of SLE.


Assuntos
Nefrite Lúpica/terapia , MicroRNAs/genética , MicroRNAs/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Adulto , Albuminúria/urina , Animais , Anticorpos Antinucleares/sangue , Nitrogênio da Ureia Sanguínea , Modelos Animais de Doenças , Feminino , Humanos , Nefrite Lúpica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/genética , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo , Células Th17/imunologia
8.
APMIS ; 127(9): 642-652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274210

RESUMO

Hepatitis C virus (HCV) infection always leads to chronic hepatitis via dysregulation of host immunity. Notch signaling also modulates the response of monocytes/macrophages. Thus, we aimed to investigate the regulatory role of Notch signaling to CD14+ monocytes. Forty patients with chronic hepatitis C and twenty normal controls (NC) were enrolled. CD14+ monocytes and CD4+ T cells were purified from peripheral bloods. Notch receptors' mRNA expression in CD14+ monocytes was semi-quantified by real-time PCR. Cytokine production by CD14+ monocytes in response to γ-secretase inhibitor (GSI) was investigated by ELISA. GSI-induced CD14+ monocytes activity to HCV clearance in Huh7.5 cells and to CD4+ T cell differentiation was also assessed in direct and indirect contact co-culture system. Notch1 mRNA relative level was approximately 10-fold elevated in CD14+ monocytes from chronic hepatitis C patients when compared with NC. GSI stimulation resulted in enhanced cytokines production by CD14+ monocytes from chronic hepatitis C patients. GSI-stimulated CD14+ monocytes from chronic hepatitis C patients induced suppression of HCV RNA replication in both direct and indirect contact co-culture system of CD14+ monocytes and HCVcc-infected Huh7.5 cells, and this process was accompanied by elevation of interferon-γ production but not increased target cell death. Moreover, GSI stimulation also enhanced CD14+ monocytes-induced Th1 and Th17 cells activation, and this process required direct cell-to-cell contact. Effective antiviral therapy down-regulated Notch1 mRNA expression and promoted cytokine production by CD14+ monocytes from chronic hepatitis C. Current data revealed an important immunoregulatory property of Notch signaling to CD14+ monocytes in chronic HCV infection.


Assuntos
Hepatite C Crônica/imunologia , Monócitos/imunologia , Receptor Notch1/imunologia , Transdução de Sinais/imunologia , Adulto , Linfócitos T CD4-Positivos , Diferenciação Celular/imunologia , Técnicas de Cocultura , Regulação para Baixo/imunologia , Feminino , Hepacivirus/imunologia , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th17/imunologia , Adulto Jovem
9.
Mol Immunol ; 112: 305-311, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31229843

RESUMO

The pathophysiology of type II diabetes (T2D) in patients with normal body-mass index (BMI) remains unclear. In this study, we investigated the circulating CD4+CXCR5+ T cells in lean T2D patients. Compared with age-, gender-, and BMI-matched healthy controls, the lean T2D patients presented similar frequency and number of CD4+CXCR5+ T cells; however, the composition of CD4+CXCR5+ T subsets was altered. The CD4+CXCR5+ T cells in lean T2D patients were enriched with a Th17-like subset, characterized by an increase in the frequency of IL-17-secreting cells, and an increase in the frequency of CCR6+ cells. Compared to CCR6- CD4+CXCR5+ T cells, CCR6+ CD4+CXCR5+ T cells secreted significantly higher IL-17. Neither the frequency of IL-17-secreting CD4+CXCR5+ T cells, nor the frequency of CCR6+ CD4+CXCR5+ T cells, was associated with the BMI of the T2D patients. Interestingly, 10 out of 30 lean T2D patients in our cohort presented islet-reactive autoantibodies. Compared to the autoantibody-negative T2D patients, the autoantibody-positive T2D patients had significantly higher levels of IL-17-secreting CD4+CXCR5+ T cells and CCR6+ CD4+CXCR5+ T cells. In addition, compared to the CCR6- CD4+CXCR5+ T cells, the CCR6+ CD4+CXCR5+ T cells were more effective at promoting Ig secretion from autologous B cells. Together, this study demonstrated that an upregulation of Th17-like CD4+CXCR5+ T cells was present in lean T2D patients and was associated with autoantibody positivity.


Assuntos
Autoanticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 2/imunologia , Receptores CXCR5/imunologia , Células Th17/imunologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-17/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Zhonghua Nei Ke Za Zhi ; 58(6): 419-422, 2019 Jun 01.
Artigo em Chinês | MEDLINE | ID: mdl-31159519

RESUMO

Objective: To study the significance of Th17 cells in patients with myelodysplastic syndrome (MDS) and iron overload. Methods: A total of 77 patients with MDS admitted to Guangzhou First People's Hospital were enrolled from January 2017 to December 2018,who were divided into iron overload group (37 cases) with serum ferritin (SF) over 1000 µg/L and non-ferrous overload group(40 cases). CD(4)(+)T cells in peripheral blood (PB) and bone marrow (BM) were sorted by flow cytometry. The ratio of Th17 cells and cells with abnormal karyotype were compared. IL-17 and IL-6 protein and RNA expression were detected by ELISA and quantitative real-time PCR(qRT-PCR). Results: The proportions of Th17 cells in PB and BM in iron overload group were significantly higher than those in non-iron overload group [(41.06±0.96)% vs. (26.80±1.21)%; (47.39±1.60)% vs. (34.29±1.03)%; P<0.01]. The Th17 positive cells with abnormal karyotype in iron overload group were more than those in non-iron overload group[(4.96±0.53)% vs. (3.67±0.12)% in PB; (10.06±1.67)% vs. (4.36±0.43)% in BM; P<0.01]. Similarly,the protein levels as well as mRNA expression of IL-6 and IL-17 in patients with iron overload were significantly higher than those in non-iron overload group (P<0.01 both in PB and BM). Conclusions: As hematopoietic regulators secreted by Th17 cells, the expression of IL-6 and IL-17 in MDS patients with iron overload are elevated. This may predict the influence of these factors to the differentiation of Th17 cells.


Assuntos
Interleucina-17/imunologia , Interleucina-6/imunologia , Interleucinas/imunologia , Sobrecarga de Ferro , Síndromes Mielodisplásicas/sangue , Células Th17/imunologia , Medula Óssea , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Ferritinas/sangue , Citometria de Fluxo , Humanos , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Interleucinas/metabolismo , Ferro/sangue , Síndromes Mielodisplásicas/imunologia , RNA , Reação em Cadeia da Polimerase em Tempo Real
11.
J Agric Food Chem ; 67(24): 6773-6784, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31154759

RESUMO

The aim of this study was to evaluate the immunomodulatory effects of atractylodin, a polyethylene alkyne, on the maturation of bone marrow-derived dendritic cells (BM-DC) as well as its antirheumatic effect on collagen-induced arthritis (CIA) in DBA/1 mice. Our results indicate that atractylodin effectively suppressed the secretion of pro-inflammatory cytokines, expression of costimulatory molecules, and p38 MAPK, ERK, and NF-κBp65 signaling pathways in LPS-incubated dendritic cells (DCs). Additionally, the proliferation and cytokine secretion (IFN-γ and IL-17A) of CD8+ and CD4+ T cells were reduced. In a murine CIA model, intraperitoneal injection of atractylodin significantly alleviated the severity of the disease progression, as indicated by reduced paw swelling, clinical arthritis scores, and pathological changes of joint tissues. In addition, the overall proliferation of T cells stimulated by type II collagen and the abundance of Th1 and Th17 in the spleens were also significantly decreased with atractylodin treatments. Furthermore, atractylodin significantly downregulated the expression levels of CD40, CD80, and CD86 of DCs in the spleens. In conclusion, this study shows for the first time that atractylodin has potential to manipulate the maturation of BM-DCs and should be further explored as a therapeutic agent in the treatment of rheumatoid arthritis (RA).


Assuntos
Artrite Reumatoide/tratamento farmacológico , Atractylodes/química , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo II/efeitos adversos , Células Dendríticas/citologia , Furanos/administração & dosagem , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Células Th17/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia
12.
Scand J Immunol ; 90(3): e12799, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31211854

RESUMO

Pemphigus vulgaris (PV) is an autoimmune disease characterized by the production of IgG autoantibodies owing to an imbalance in the Th1/Th2 and Th17/Tregs cell pathways. The role of gut microbiota in the development of immune system and autoimmune diseases has been unraveled in the last two decades. However, data pertaining to gut microbiota of PV patients is largely lacking. We aimed to compare the gut microbiota of PV patients and healthy controls and assessed potential correlation with circulating cytokines of Th1/Th2/Th17 cell. Faecal bacterial diversity was analysed in 18 PV patients and 14 age- and gender-matched healthy individuals using hypervariable tag sequencing of the V3-V4 region of the 16S rRNA gene. Plasma levels of 20 inflammatory cytokines were assessed using the Luminex screening system. As a result, we identified 10 differentially abundant taxa between patients and controls. At the genera level, Lachnospiracea_incertae_sedis and Coprococcus decreased, while Granulicatella, Flavonifractor enriched in PV. Plasma levels of C5a, interleukin (IL)-2R, IL-6, IL-8, IL-7, IL-1ß, IL17A, IL-5 and IL-21 were significantly increased in PV Flavonifractor exhibited a positive correlation with C5a, IL-6, IL-8, IL-7, IL-1ß, IL17A and IL-21. Lachnospiracea_incertae_sedis and Coprococcus showed a negative correlation with IL-17A. Our results are consistent with the hypothesis that PV patients have gut microbial dysbiosis which might contribute to the immune disorder and the development of PV.


Assuntos
Doenças Autoimunes/imunologia , Citocinas/imunologia , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Pênfigo/imunologia , Plasma/imunologia , Adulto , Autoanticorpos/imunologia , Doenças Autoimunes/microbiologia , Fezes/microbiologia , Feminino , Humanos , Inflamação/microbiologia , Masculino , Pessoa de Meia-Idade , Pênfigo/microbiologia , Plasma/microbiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , Células Th1/imunologia , Células Th1/microbiologia , Células Th17/imunologia , Células Th17/microbiologia , Células Th2/imunologia , Células Th2/microbiologia
13.
PLoS Negl Trop Dis ; 13(5): e0007247, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107882

RESUMO

Cutaneous leishmaniasis (CL) is a parasitic disease causing chronic, ulcerating skin lesions. Most humans infected with the causative Leishmania protozoa are asymptomatic. Leishmania spp. are usually introduced by sand flies into the dermis of mammalian hosts in the presence of bacteria from either the host skin, sand fly gut or both. We hypothesized that bacteria at the dermal inoculation site of Leishmania major will influence the severity of infection that ensues. A C57BL/6 mouse ear model of single or coinfection with Leishmania major, Staphylococcus aureus, or both showed that single pathogen infections caused localized lesions that peaked after 2-3 days for S. aureus and 3 weeks for L. major infection, but that coinfection produced lesions that were two-fold larger than single infection throughout 4 weeks after coinfection. Coinfection increased S. aureus burdens over 7 days, whereas L. major burdens (3, 7, 28 days) were the same in singly and coinfected ears. Inflammatory lesions throughout the first 4 weeks of coinfection had more neutrophils than did singly infected lesions, and the recruited neutrophils from early (day 1) lesions had similar phagocytic and NADPH oxidase capacities. However, most neutrophils were apoptotic, and transcription of immunomodulatory genes that promote efferocytosis was not upregulated, suggesting that the increased numbers of neutrophils may, in part, reflect defective clearance and resolution of the inflammatory response. In addition, the presence of more IL-17A-producing γδ and non-γδ T cells in early lesions (1-7 days), and L. major antigen-responsive Th17 cells after 28 days of coinfection, with a corresponding increase in IL-1ß, may recruit more naïve neutrophils into the inflammatory site. Neutralization studies suggest that IL-17A contributed to an enhanced inflammatory response, whereas IL-1ß has an important role in controlling bacterial replication. Taken together, these data suggest that coinfection of L. major infection with S. aureus exacerbates disease, both by promoting more inflammation and neutrophil recruitment and by increasing neutrophil apoptosis and delaying resolution of the inflammatory response. These data illustrate the profound impact that coinfecting microorganisms can exert on inflammatory lesion pathology and host adaptive immune responses.


Assuntos
Coinfecção/imunologia , Interleucina-17/imunologia , Leishmania major/fisiologia , Leishmaniose Cutânea/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Animais , Coinfecção/microbiologia , Coinfecção/parasitologia , Coinfecção/patologia , Feminino , Humanos , Interleucina-17/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leishmania major/genética , Leishmania major/isolamento & purificação , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Células Th17/imunologia
14.
Scand J Immunol ; 90(4): e12793, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31141182

RESUMO

Evidence indicates that reprogramming of metabolism is critically important for the differentiation of CD4 + T lymphocytes, and the manipulation of metabolic pathways in these cells may shape their fate and function. Distinct subgroups from T lymphocytes, such as Th17, adopt specific metabolic programmes to support their needs. Some important metabolic reactions, such as glycolysis, oxidative phosphorylation, are considered important for the differentiation of these lymphocytes. Since their discovery nearly a decade ago, Th17 lymphocytes have received significant attention because of their role in the pathology of several immune-mediated inflammatory diseases such as multiple sclerosis. In this review, it will be discussed as the involvement of T cell metabolism and as metabolic reprogramming in activated T cells dictates fate decisions to Th17. The involvement of nuclear receptors such as RORyt e PPARs in the induction of Th17 cells was also discussed. Understanding the metabolic pathways involved in the differentiation of the distinct subgroups of T lymphocytes helps in the design of promising therapeutic proposals.


Assuntos
Esclerose Múltipla/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Células Th17/metabolismo , Animais , Autoimunidade , Diferenciação Celular , Reprogramação Celular , Glicólise , Humanos , Ativação Linfocitária , Fosforilação Oxidativa , Células Th17/imunologia
15.
Immunity ; 50(5): 1289-1304.e6, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31079916

RESUMO

Pathogenic lymphocytes initiate the development of chronic inflammatory diseases. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) (encoded by Csf2) is a key communicator between pathogenic lymphocytes and tissue-invading inflammatory phagocytes. However, the molecular properties of GM-CSF-producing cells and the mode of Csf2 regulation in vivo remain unclear. To systematically study and manipulate GM-CSF+ cells and their progeny in vivo, we generated a fate-map and reporter of GM-CSF expression mouse strain (FROG). We mapped the phenotypic and functional profile of auto-aggressive T helper (Th) cells during neuroinflammation and identified the signature and pathogenic memory of a discrete encephalitogenic Th subset. These cells required interleukin-23 receptor (IL-23R) and IL-1R but not IL-6R signaling for their maintenance and pathogenicity. Specific ablation of this subset interrupted the inflammatory cascade, despite the unperturbed tissue accumulation of other Th subsets (e.g., Th1 and Th17), highlighting that GM-CSF expression not only marks pathogenic Th cells, but that this subset mediates immunopathology and tissue destruction.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-1beta/imunologia , Subunidade p19 da Interleucina-23/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Inflamação/genética , Inflamação/patologia , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CXCR6/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/imunologia , Fator de Necrose Tumoral alfa/metabolismo
16.
J Dermatol ; 46(7): 584-589, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087594

RESUMO

CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells, as well as an antiangiogenic factor by preventing the migration of endothelial cells. CXCL14 also exerts an inhibitory effect on the CXCL12/CXCR4 signaling pathway, which is involved in the maintenance of T-helper (Th)2 bias, and promotes Th1 immune response under the physiological and pathological conditions. Because CXCL14-mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), which is characterized by Th2/Th17-skewed immune polarization and impaired neovascularization, we investigated the clinical correlation of serum CXCL14 levels in patients with this disease. Serum CXCL14 levels were significantly decreased in SSc patients compared with healthy individuals and in diffuse cutaneous SSc patients relative to limited cutaneous SSc patients. SSc patients with digital ulcers had serum CXCL14 levels significantly lower than those without. Furthermore, i.v. cyclophosphamide pulse significantly increased serum CXCL14 levels as compared with the baseline in SSc patients with interstitial lung disease successfully treated with this therapy. These results indicate that decreased CXCL14 expression may contribute to the maintenance of Th2-skewed immune polarization and dysregulated neovascularization, both of which underlie the developmental process of SSc.


Assuntos
Quimiocinas CXC/sangue , Neovascularização Fisiológica/imunologia , Escleroderma Sistêmico/imunologia , Úlcera Cutânea/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Quimiocinas CXC/imunologia , Feminino , Dedos , Voluntários Saudáveis , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologia , Pele/irrigação sanguínea , Pele/imunologia , Pele/patologia , Úlcera Cutânea/sangue , Úlcera Cutânea/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
17.
Nat Commun ; 10(1): 2162, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089134

RESUMO

Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1ß, IL-23 and TGF-ß. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents.


Assuntos
Plasticidade Celular/imunologia , Fibrose Cística/imunologia , Inflamação/imunologia , Pólipos Nasais/imunologia , Células Th17/imunologia , Adulto , Animais , Linhagem Celular , Fibrose Cística/sangue , Fibrose Cística/patologia , Feminino , Humanos , Imunidade Inata , Inflamação/sangue , Inflamação/patologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Pólipos Nasais/sangue , Pólipos Nasais/patologia , Neutrófilos/imunologia , Adulto Jovem
18.
J Agric Food Chem ; 67(22): 6313-6323, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31070910

RESUMO

Gliadins are major allergens responsible for wheat allergies. Food processing is an effective strategy to reduce the allergenicity of gluten. In the present study, we determined the secondary and tertiary structures of gluten and gliadins treated by chemical, physical, and enzymatic means through FTIR, surface hydrophobicity, intrinsic fluorescence spectra, and UV absorption spectra. The results showed that the three treatments of phosphorylation and alcalase and papain hydrolyses significantly changed the conformational structures of gliadins, especially the secondary structure. Then, the potential allergenicity of the phosphorylated and alcalase and papain hydrolyzed gliadins were further characterized, and we observed a significant decrease in the allergenicity through the results of the index of spleen, serum total IgE, gliadin-specific IgE, histamine, and serum cytokine concentrations. An elevation of Th17 cells, the absence of Treg cells, and an imbalance in Treg/Th17 are associated with allergy. On the basis of the expression levels of related cytokines and key transcription factors, we also confirmed that phosphorylation and alcalase and papain hydrolysis could effectively reduce the allergenicity of gliadins by improving the imbalance of both Th1/Th2 and Treg/Th17 in the spleens of sensitized mice. This study suggested that the changes in conformational structure contribute to gliadin hyposensitization and that phosphorylation and alcalase and papain hydrolysis may be promising strategies for the production of wheat products with low allergenicity.


Assuntos
Gliadina/química , Gliadina/imunologia , Papaína/química , Subtilisinas/química , Hipersensibilidade a Trigo/imunologia , Alérgenos/química , Alérgenos/imunologia , Animais , Biocatálise , Histamina/imunologia , Humanos , Hidrólise , Imunoglobulina E/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Baço/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Triticum/química , Triticum/imunologia
19.
Cancer Sci ; 110(7): 2100-2109, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100180

RESUMO

The presence of interleukin (IL)-17-producing T cells has recently been reported in non-small cell lung cancer (NSCLC) patients. However, the long-term prognostic significance of these populations in NSCLC patients remains unknown. In the present study, we collected peripheral blood from 82 NSCLC patients and 22 normal healthy donors (NC). Percentages of IL-17-producing CD4+ T (Th17), CD8+ T (Tc17) and γδT cells (γδT17) were measured to determine their association with clinical outcomes and overall survival (OS) in NSCLC. All NSCLC patients were followed up until July 2018. Median follow-up time was 13.5 months (range 1-87 months). The 3- and 5-year survival rate was 27% and 19.6%, respectively. We found that Th17 cells and γδT17 cells were significantly increased, whereas Tc17 cells were markedly decreased in patients with NSCLC compared with those in NC. In addition, Th17 cells were significantly positively associated with T helper type 1 cells (Th1), whereas γδT17 cells were significantly negatively associated with γδT + interferon (IFN)-γ+ cells. High percentages of peripheral Tc17 cells were significantly associated with favorable 5-year OS (P = .025), especially in patients with early TNM stage (P = .016). Furthermore, high percentages of peripheral Th17 cells were positively associated with favorable 5-year OS in patients with late TNM stage (P = .002). However, no significant association was observed between γδT17 cells and OS, regardless of the TNM stage. In conclusion, our findings suggest that enhanced Th17 and reduced Tc17 cells in the peripheral blood could be a significant predictor of a favorable prognosis for NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Interleucina-17/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos T/citologia , Células Th17/citologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Interferon gama/metabolismo , Linfócitos Intraepiteliais/citologia , Linfócitos Intraepiteliais/imunologia , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Linfócitos T/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th17/imunologia
20.
Mol Immunol ; 111: 152-161, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31054409

RESUMO

Despite successful anti-viral (DAAs) treatment of Hepatitis C virus (HCV) infection, recent data indicated the need for an effective vaccine. Preexisting anti-vector immunity is an obstacle for application of live vectors for antigen delivery and development of effective T-cell based HCV vaccines. Herein, we report construction of recombinant Leishmania tarentolae, a lizard (non-human) parasite, expressing an HCV polytope DNA, PT-NT(gp96), encoding for several immunogenic HCV epitopes and evaluation of its immunogenicity in three different prime/boost immunization groups (G) of BALB/c mice. Homologous prime/boost immunization by L.tarentolae-PT-NT(gp96) either with or without CpG (G1 and G2 respectively) and heterologous immunization with a PT-NT(gp96) encoding-pCDNA plasmid followed by L.tarentolae-PT-NT (G3) was undertaken. Immune responses were measured three and nine weeks (W) post immunization. Splenocytes (cultured with antigen-stimulant) of mice in G1 showed the highest percentage of specific CTL-cytolytic activity compared to G2 and G3 at both short (W3:70.98% versus 41.29% and 13.12%) and long (W9: 50% versus 24.5% and 20%) term periods, accompanied with high levels of secreted IFN-γ. Comparison of IFN-γ, IL-4, IL-17 and TNF-α cytokines levels obtained from the supernatant of antigen-stimulated splenocytes as well as antibodies level (as IgG1/IgG2a ratio; obtained from sera of immunized mice) indicated higher Th1 oriented responses for G1, G2 groups and balanced Th1-Th17 for G3. Results indicated the potential of L.tarentolae (+CpG), as a non-pathogenic live vaccine vector, for delivery and enhancement of immune responses against HCV-polytope antigens.


Assuntos
Hepacivirus/imunologia , Hepatite C/imunologia , Leishmania/imunologia , Células Th1/imunologia , Vacinas de DNA/imunologia , Animais , Citocinas/imunologia , DNA/imunologia , Imunização/métodos , Camundongos , Camundongos Endogâmicos BALB C , Células Th17/imunologia , Vacinação/métodos
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