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1.
Adv Exp Med Biol ; 1172: 97-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628653

RESUMO

The IL-17 family in humans consists of six distinct cytokines (IL-17A-F) that can interact with five IL-17 receptors (IL-17RA-E). The interaction between these cytokines and their receptors are critical in mediating host defenses while also making major contributions to inflammatory and autoimmune responses as demonstrated through both in vitro and in vivo experiments as well as human clinical trials. Inhibition of the IL-17A/IL-17RA interaction by monoclonal antibodies has also displayed remarkable efficacies in clinical trials against psoriasis and other autoimmune diseases. Recently, we and others reported the identification and characterization of both small-molecule and peptide IL-17A antagonists. These non-antibody IL-17A antagonists can effectively and selectively disrupt the IL-17A/IL-17RA complex and may provide alternative modalities to treat IL-17-related autoimmune and inflammatory diseases. This chapter summarizes the reported crystal structures of the IL-17 cytokines, their complexes with IL-17RA, and their complexes with both monoclonal antibodies as well as small-molecule and peptide antagonists.


Assuntos
Interleucina-17 , Receptores de Interleucina-17 , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Doenças Autoimunes/imunologia , Cristalização , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/química , Interleucina-17/imunologia , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/química , Receptores de Interleucina-17/imunologia
2.
Expert Opin Drug Saf ; 18(11): 1031-1041, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479282

RESUMO

Introduction: Psoriasis is a chronic inflammatory disease and affects about 10% of the world's population. Psoriasis is associated with a number of comorbidities. Biologic therapies for the treatment of moderate-severe plaque psoriasis include tumor necrosis factor α inhibitors (TNFi), and newer molecules targeting IL-12 and 23, blocking p40 subunit, or targeting subunit p19 of IL-23 and other molecules blocking IL-17A, or directed against the IL-17 receptor. Areas covered: Anti-interleukin drugs show great improvement in disease control and on the other hand are not affected by important adverse reactions of older compounds. Approach to chronic disease affected patients, in particular, and to patients with multiple comorbidities is revolutionized by novel molecules that are safer and more manageable. Expert opinion: A recent work suggests that pro-fibrogenic cytokines, IL-17, might be important player of liver damage and even in regulation of obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Choosing to interfere with IL-23/Il-17 axis, definitely, is like acting against psoriatic march and in a parallel way against its comorbidities.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Produtos Biológicos/imunologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/imunologia , Humanos , Interleucina-12/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Psoríase/imunologia , Psoríase/patologia , Índice de Gravidade de Doença
3.
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
4.
Exp Parasitol ; 204: 107725, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306646

RESUMO

Characterisation of the cellular immune response to schistosomiasis is well established for Schistosoma mansoni but a comprehensive description of T cell-mediated immune responses against S. japonicum infection is lacking. Accordingly, 20 CBA mice were infected with cercariae of S. japonicum and the immune response at different time points was determined. Mouse spleen and liver lymphocytes were isolated from the mice and stimulated with schistosomal adult worm antigen preparation (SWAP) and schistosomal soluble egg antigen (SEA). There was a relatively higher Th1 immune response to SWAP compared to SEA at the early phase of infection (up to week 5 post challenge). However, a Th2 immune response directed against SEA was dominant at week 6 post-infection, a time point when the highest IgG response against both SWAP and, especially, SEA was generated. The regulatory immune response was highest at the early phase of the immune response (up to week 5 post challenge) followed by a rapid decline at week 6-post infection. Before egg-laying, S. japonicum induced a regulatory T cell immune response which may limit the early Th1-mediated immune response that is believed to be protective in murine schistosomiasis. Following egg laying, the immune response was polarized to a Th2 immune response mainly directed against the eggs and this may contribute to parasite survival.


Assuntos
Imunidade Celular , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Helmintos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Fígado/citologia , Fígado/imunologia , Fígado/parasitologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos CBA , Óvulo/imunologia , Contagem de Ovos de Parasitas , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Caramujos/parasitologia , Baço/citologia , Baço/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia
6.
Georgian Med News ; (290): 73-77, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31322519

RESUMO

The problem of HBV and HCV infections in addition to the HIV-infection in sub-Saharan African countries remains important due to the high prevalence and mortality after fast progressing fibrogenesis and development of hepatocellular carcinoma. Despite of the large number of investigations on diagnostics and prediction of the disease course, the exact role of the proinflammatory influence of IP-10 and IL-17A on the fibrogenesis during HIV/HBV-co-infection is still unknown. The aim of the study was to investigate IP-10 and IL-17A concentration in blood serum among HIV/HBV patients to consider their potential role in improvement of diagnostics of liver fibrosis progression. 53 HIV/HBV patients of Lewanika General Hospital (West Zambia) and 21 healthy blood donors were checked for serological markers, liver biopsy and IP-10, IL-17A in blood serum. The obtained results were analyzed by statistical package SPSS 12.0. Mean IP-10 was 753,6 pg/ml among HIV/HBV co-infected patients with F3-4 and it was reliably higher than in F1-2 patients and healthy responders (р=0,005). This group had also higher level of IL-17A (37,54 pg/ml) than comparison groups (р=0,032). We found out strong correlation between increasing IP-10 (r=0,6), IL-17A (r=0,52) and fibrotic severity (р<0,05). High IP-10, IL-17A amount increases the risk of F3-4 formation in HIV/HBV patients.


Assuntos
Quimiocina CXCL10/sangue , Coinfecção/epidemiologia , Infecções por HIV/complicações , HIV-1/isolamento & purificação , Hepatite B/complicações , Interleucina-17/sangue , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Fígado/virologia , Soro/virologia , Adulto , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Quimiocina CXCL10/imunologia , Progressão da Doença , Feminino , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Hepatite B/sangue , Hepatite B/epidemiologia , Vírus da Hepatite B , Humanos , Interleucina-17/imunologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Zâmbia/epidemiologia
7.
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
8.
Korean J Parasitol ; 57(3): 225-232, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31284344

RESUMO

Innate lymphoid cells (ILCs) are key players during an immune response at the mucosal surfaces, such as lung, skin, and gastrointestinal tract. Giardia lamblia is an extracellular protozoan pathogen that inhabits the human small intestine. In this study, ILCs prepared from the lamina propria of mouse small intestine were incubated with G. lamblia trophozoites. Transcriptional changes in G. lamblia-exposed ILCs resulted in identification of activation of several immune pathways. Secretion of interleukin (IL)-17A, IL-17F, IL-1ß, and interferon-γ was increased, whereas levels of IL-13, IL-5, and IL22, was maintained or reduced upon exposure to G. lamblia. Goup 3 ILC (ILC3) was found to be dominant amongst the ILCs, and increased significantly upon co-cultivation with G. lamblia trophozoites. Oral inoculation of G. lamblia trophozoites into mice resulted in their presence in the small intestine, of which, the highest number of parasites was detected at the 5 days-post infection. Increased ILC3 was observed amongst the ILC population at the 5 days-post infection. These findings indicate that ILC3 from the lamina propria secretes IL-17 in response to G. lamblia, leading to the intestinal pathology observed in giardiasis.


Assuntos
Giardia lamblia/fisiologia , Giardíase/imunologia , Interleucina-17/imunologia , Linfócitos/imunologia , Membrana Mucosa/parasitologia , Animais , Células Cultivadas , Giardíase/genética , Giardíase/parasitologia , Humanos , Imunidade Inata , Interleucina-17/genética , Linfócitos/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/imunologia
9.
J Dermatol ; 46(9): 794-797, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31294481

RESUMO

We report a case of kerion celsi due to Trichophyton tonsurans. An 18-year-old male student judo practitioner had alopecic patches, black dots and subcutaneous abscesses on the right temporal region. The damaged hair represented endothrix infection with T. tonsurans, as assessed by mycological examinations. He was treated with oral itraconazole without any therapeutic effect, followed by terbinafine with good effect. A skin biopsy showed neutrophil, lymphocyte and histiocyte infiltration into the dermis and subcutaneous tissue with abscesses around a number of dilated hair follicles. Immunostaining showed that the expression level of human ß-defensin 2 (HBD-2) was decreased in the epidermis of the alopecic and adjacent skin. Because interleukin (IL)-17A generally induces HBD-2 production by epidermal keratinocytes, we also immunohistochemically investigated IL-17A expression. Unexpectedly, many IL-17A-bearing cells were found around destructed hair follicles, indicating that IL-17A expression was not attenuated, but rather increased in the skin lesion. Our case suggests that IL-17A-upregulated antimicrobial peptide expression is disordered in kerion celsi, and severe inflammation with IL-17A may cause tissue damage and resultant scar.


Assuntos
Interleucina-17/metabolismo , Tinha do Couro Cabeludo/imunologia , Trichophyton/imunologia , beta-Defensinas/metabolismo , Adolescente , Biópsia , Folículo Piloso/imunologia , Folículo Piloso/metabolismo , Folículo Piloso/patologia , Humanos , Interleucina-17/imunologia , Masculino , Tinha do Couro Cabeludo/microbiologia , Tinha do Couro Cabeludo/patologia , Trichophyton/isolamento & purificação , beta-Defensinas/imunologia
10.
Egypt J Immunol ; 26(1): 43-54, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31332995

RESUMO

Different cytokines play roles in the pathogenesis and tissue damage of Rheumatoid Arthritis (RA) including, Tumor necrosis factor superfamily (TNFSF) and their receptors particularly TNF-like ligand 1A (TL1A), and its decoy receptor DcR3. This study included 150 subjects, of them 50 patients having Rheumatoid Arthritis (RA), 50 patients with Osteoarthritis (OA), and 50 normal controls. Clinical examination was done and data was collected from patient's sheets, routine laboratory investigations included, rheumatoid factor (RF) antibody, anti-cyclic citrullinated peptide (anti-CCP) antibody, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Disease activity score 28 was calculated and used to measure the activity of RA. Serum and synovial fluid (SF) TL1A and DcR3 levels were measured by (ELISA), while IL-17 was measured in supernatant fluid of PBMC culture after stimulation with recombinant human (rh) TL1A. Results showed significantly higher levels of TL1A and its decoy receptor DcR3 in RA patients than the other two groups. It was also found that TL1A is significantly related to the disease activity and enhances IL-17 production after stimulation of PBMC. These results can guide scientists to the future substitutions in the way of treatment of various inflammatory and autoimmune diseases.


Assuntos
Artrite Reumatoide/fisiopatologia , Autoanticorpos/imunologia , Membro 6b de Receptores do Fator de Necrose Tumoral/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Células Cultivadas , Humanos , Interleucina-17/imunologia , Leucócitos Mononucleares
11.
Virol J ; 16(1): 79, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196204

RESUMO

BACKGROUND: The increased levels of blood cytokines is the main immunopathological process that were attributed to severe clinical outcomes in cases of influenza A, influenza B and people with influenza-like illness (ILI). Functional genetic polymorphisms caused by single nucleotide polymorphisms (SNPs) in inflammatory cytokines genes can influence their functions either qualitatively or quantitatively, which is associated with the possibility of severe influenza infections. The aim of the present case-control study was to investigate the association of polymorphisms in inflammatory cytokines genes with influenza patients and ILI group in an Iranian population. METHODS: Total number of 30 influenza B, 50 influenza A (H1N1) and 96 ILI inpatient individuals were confirmed by Real-time RT-PCR and HI assays. The genotype determination was assessed for defined SNPs in IL-1ß, IL-17, IL-10 and IL-28 genes. RESULTS: The frequencies of the IL-1ß rs16944 (P = 0.007) and IL-17 rs2275913 (P = 0.006) genotypes were associated with severe influenza disease, while the frequencies of IL-10 rs1800872 and IL-28 rs8099917 were not associated with the disease (P > 0.05). Also, the absence of A allele in IL-17 rs2275913 SNP increased the risk of influenza A (H1N1) infection (P = 0.008). CONCLUSIONS: This study demonstrated that influenza A- (H1N1) and B-infected patients and also ILI controls have different profiles of immune parameters, and individuals carrying the specific cytokine-derived polymorphisms may show different immune responses towards severe outcome.


Assuntos
Citocinas/genética , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza B , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Life Sci ; 231: 116536, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176785

RESUMO

AIMS: TL1A was reported to contribute to the susceptibility to ulcerative colitis (UC). However, the molecular mechanisms of TL1A in UC development are poorly understood. We aimed to investigate the role of TL1A in colitis, and reveal the regulatory mechanism of TL1A in chronic colitis development. MAIN METHODS: Wild-type mice and transgenic mice with overexpressing TL1A in lymphocytes were used to construct chronic DSS colitis models. To investigate the molecular mechanism in vitro, CD4+ T cells were sorted from spleens and mesenteric lymph node cells to induce Th9 cells. Biopsy specimens from ulcerative colitis patients were collected for in vivo validation. KEY FINDINGS: The elevated TL1A expression in chronic DSS colitis models exacerbated intestinal inflammation. The differentiation of Th9 cells, IL-9 secretion and production of TGF-ß, IL-4 and PU.1 was significantly enhanced in transgenic mice with TL1A overexpression. In vitro results showed that TL1A enhanced the Th9 cells, IL-9 and PU.1 production, while TL1A antibodies inhibited their production. In human translational studies, patients with ulcerative colitis with elevated TL1A expression also exhibited more serious inflammation with higher levels of Th9 cells, IL-9 and PU.1 expression. SIGNIFICANCE: We presented a possible mechanism of TL1A in UC development that TL1A may promote the differentiation of Th9 cells and enhanced IL-9 secretion by up-regulating the expression of TGF-ß, IL-4 and PU.1, which provided a novel perspective to study the UC pathogenesis, and indicated that targeting of TL1A signal pathway may by a likely strategy for the treatment of chronic colitis.


Assuntos
Colite/imunologia , Interleucina-9/imunologia , Linfócitos T/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Colite/induzido quimicamente , Colite/patologia , Citocinas/imunologia , Citocinas/metabolismo , Glutationa/metabolismo , Interleucina-17/imunologia , Interleucina-1beta/metabolismo , Interleucina-9/metabolismo , Mucosa Intestinal/imunologia , Intestinos/imunologia , Intestinos/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Fator de Crescimento Transformador beta/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/metabolismo
13.
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
14.
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
15.
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
16.
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
17.
Infect Immun ; 87(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061145

RESUMO

Tissue-resident memory T cells (TRM cells) are a novel population of tissue-restricted antigen-specific T cells. TRM cells are induced by pathogens and promote host defense against secondary infections. Although TRM cells cannot be detected in circulation, they are the major memory CD4+ and CD8+ T-cell population in tissues in mice and humans. Murine models of CD8+ TRM cells have shown that CD8+ TRM cells maintain tissue residency via CD69 and though tumor growth factor ß-dependent induction of CD103. In contrast to CD8+ TRM cells, there are few models of CD4+ TRM cells. Thus, much less is known about the factors regulating the induction, maintenance, and host defense functions of CD4+ TRM cells. Citrobacter rodentium is known to induce IL-17+ and IL-22+ CD4+ T cells (Th17 and Th22 cells, respectively). Moreover, data from IL-22 reporter mice show that most IL-22+ cells in the colon 3 months after C. rodentium infection are CD4+ T cells. This collectively suggests that C. rodentium may induce CD4+ TRM cells. Here, we demonstrate that C. rodentium induces a population of IL-17A+ CD4+ T cells that are tissue restricted and antigen specific, thus meeting the criteria of CD4+ TRM cells. These cells expand and are a major source of IL-22 during secondary C. rodentium infection, even before the T-cell phase of the host response in primary infection. Finally, using FTY 720, which depletes circulating naive and effector T cells but not tissue-restricted T cells, we show that these CD4+ TRM cells can promote host defense.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Animais , Citrobacter rodentium/genética , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/microbiologia , Humanos , Memória Imunológica , Interleucina-17/genética , Interleucina-17/imunologia , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th17/imunologia
18.
J Dermatol ; 46(6): 482-497, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31062408

RESUMO

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of psoriasis and is elevated in lesional psoriatic skin. Different murine models have been developed to mimic this pathophysiology each carrying specific merits and limitations. In an attempt to address some of these limitations, B10.RIII mice received a single hydrodynamic injection of IL-23 minicircles (MC) to induce hepatic transcription and the endogenous production of IL-23. Plasma and ear IL-23 levels were dose-dependently (0.3-3 µg) increased in MC injected mice and were sustained over the 14-day study duration. Beginning on day 7 post-injection, mice developed dose-related ear inflammation, histologically confirmed increases in epidermal and dermal area, as well as enhanced neutrophil and macrophage content. Flow cytometry demonstrated increased levels of granulocytes, T cells and monocytes/macrophages in the ear skin, with T cells identified as the main cellular source of IL-17A. Evaluation of mRNA and protein showed time-dependent, increased levels of the IL-23/IL-17 pathway and inflammatory/microbial cytokines/chemokines in the ear which differed kinetically from circulating levels. An anti-IL-23p40 antibody was assessed following both prophylactic administration and administration once the disease was established. Prophylactic dosing completely prevented the development of the ear phenotype across endpoints. Treatment administration showed a dose-related response, with a maximum inhibition of 64-94%, depending on endpoint. These data demonstrate that the IL-23 MC model is a useful approach to study IL-23/IL-17-driven skin inflammation and may facilitate preclinical assessment of novel therapies.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Interleucina-17/imunologia , Interleucina-23/imunologia , Psoríase/imunologia , Animais , DNA Circular/administração & dosagem , DNA Circular/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Técnicas de Transferência de Genes , Humanos , Interleucina-17/metabolismo , Interleucina-23/antagonistas & inibidores , Interleucina-23/genética , Masculino , Camundongos , Psoríase/sangue , Psoríase/tratamento farmacológico , Psoríase/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Pele/imunologia , Pele/patologia , Resultado do Tratamento
19.
MBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088921

RESUMO

Staphylococcus aureus is a major cause of skin and soft tissue infections and aggravator of the inflammatory skin disease atopic dermatitis (AD [eczema]). Epicutaneous exposure to S. aureus induces Th17 responses through skin Langerhans cells (LCs), which paradoxically contribute to host defense but also to AD pathogenesis. The molecular mechanisms underlying the interaction between S. aureus and LCs are poorly understood. Here we demonstrate that human LCs directly interact with S. aureus through the pattern recognition receptor langerin (CD207). Human, but not mouse, langerin interacts with S. aureus through the conserved ß-N-acetylglucosamine (GlcNAc) modifications on wall teichoic acid (WTA), thereby discriminating S. aureus from other staphylococcal species. Importantly, the specific S. aureus WTA glycoprofile strongly influences the level of proinflammatory cytokines that are produced by in vitro-generated LCs. Finally, in a murine epicutaneous infection model, S. aureus strongly upregulated transcripts of Cxcl1, Il6, and Il17, which required the presence of both human langerin and WTA ß-GlcNAc. Our findings provide molecular insight into the unique proinflammatory capacities of S. aureus in relation to skin inflammation.IMPORTANCE The bacterium Staphylococcus aureus is an important cause of skin infections and is also associated with the occurrence and severity of eczema. Langerhans cells (LCs), a specific subset of skin immune cells, participate in the immune response to S. aureus, but it is yet unclear how LCs recognize S. aureus Therefore, we investigated the molecular mechanism underlying the interaction between LCs and S. aureus We identified that wall teichoic acid, an abundant polymer on the S. aureus surface, is recognized by langerin, a receptor unique to LCs. This interaction allows LCs to discriminate S. aureus from other related staphylococcal species and initiates a proinflammatory response similar to that observed in patients with eczema. Our data therefore provide important new insights into the relationship between S. aureus, LCs, and eczema.


Assuntos
Antígenos CD/genética , Antígenos de Superfície/genética , Células de Langerhans/imunologia , Lectinas Tipo C/genética , Lectinas de Ligação a Manose/genética , Infecções Estafilocócicas/imunologia , Ácidos Teicoicos/imunologia , Acetilglucosamina , Animais , Antígenos CD/imunologia , Antígenos de Superfície/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Humanos , Inflamação , Interleucina-17/genética , Interleucina-17/imunologia , Lectinas Tipo C/imunologia , Lectinas de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pele/imunologia , Pele/microbiologia , Staphylococcus aureus
20.
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
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