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1.
Adv Exp Med Biol ; 1240: 47-58, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32060887

RESUMEN

Inflammation is recognized as representing a double-edged sword in terms of tumor growth, in some instances contributing to attenuation of growth and in others to enhanced progression and metastasis. Extracellular signals, released by cells within the tumor microenvironment (TME), including cancer cells themselves, as well as infiltrating immune cells, stromal cells, and other components of the extracellular matrix, all can contribute to reshaping the tumor microenvironment (TME) and tumor growth/survival. Most recently, attention has centered on contributions in the TME made by the pro-inflammatory interleukin 17 (IL-17) and the T cells (Th17) and non-T cells which produce this cytokine, as well as the target cells (IL-17 receptor positive, IL-17R+) signaled by IL-17. The IL-17 family itself comprises at least six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F, all of which are known to be secreted as disulfide-linked homo- or heterodimers. These in turn bind to IL-17R, a type I cell surface receptor, of which at least five variants have been described to date, IL-17RA to IL-17RE. The discussion below focuses on what we know to date about the role of IL-17/IL-17R interactions in the tumor microenvironment in regulation of tumor growth and metastasis and highlights recent ideas concerning the possible utility of this knowledge in the clinic.


Asunto(s)
Interleucina-17/inmunología , Microambiente Tumoral/inmunología , Animales , Humanos , Interleucina-27/inmunología , Receptores de Interleucina-17/inmunología , Células Th17/inmunología
2.
J Agric Food Chem ; 68(9): 2664-2672, 2020 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-32033515

RESUMEN

The immunomodulatory activity of a few Lactobacillus exopolysaccharides (EPS) has been reported. However, whether Lactobacillus EPS can promote the differentiation of CD4 T lymphocytes (CD4+T) cells into T-helper 17 cells (Th17 cells) in the Peyer's Patches (PPs) of mice has not been addressed. In this study, we found the molecular weight (Mw) of the purified EPS from L. casei ranged from 2.7 × 106 Da to 1.7 × 107 Da, and the average Mw was approximately 8.4 × 106 Da. In healthy BALB/c mice, EPS elevated the numbers of Th17 cells and levels of Th17-related cytokines. In vitro, EPS induced BMDCs to stimulate the differentiation of CD4+T cells of PPs into Th17 cells and the related cytokine secretions. Results suggest that L. casei EPS can effectively induce and promote the differentiation of CD4+T cells of PPs into Th17 cells in healthy mice and has the potential ability to improve intestinal mucosa immunity.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Factores Inmunológicos/farmacología , Lactobacillus casei/química , Ganglios Linfáticos Agregados/efectos de los fármacos , Polisacáridos Bacterianos/farmacología , Células Th17/inmunología , Animales , Citocinas/genética , Citocinas/inmunología , Femenino , Factores Inmunológicos/química , Factores Inmunológicos/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Lactobacillus casei/metabolismo , Ratones , Ratones Endogámicos BALB C , Peso Molecular , Ganglios Linfáticos Agregados/citología , Ganglios Linfáticos Agregados/inmunología , Polisacáridos Bacterianos/química , Polisacáridos Bacterianos/metabolismo , Células Th17/citología , Células Th17/efectos de los fármacos
3.
Nat Commun ; 11(1): 147, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31919342

RESUMEN

During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.


Asunto(s)
Infecciones por VIH/inmunología , VIH-1/inmunología , Células TH1/inmunología , Células Th17/inmunología , Receptor Toll-Like 8/metabolismo , Línea Celular , Infecciones por VIH/transmisión , Humanos , Inmunidad Innata/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 8/inmunología
4.
Cell Mol Life Sci ; 77(5): 781-788, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31897541

RESUMEN

Age-related macular degeneration (AMD) is a leading cause of visual impairment of the elderly population. Since AMD is a multifactorial age-related disease with various genetic risk factors, the understanding of its complex pathophysiology is still limited. However, animal experiments, genome-wide association data and the molecular profiling of AMD patient samples have highlighted a key role of systemic and local immune processes that contribute to this chronic eye disease. In this overview article, we concentrate on the role of lymphocytes and mononuclear phagocytes and their interplay in triggering a persistent immune response in the AMD retina. We preferentially review findings from human immune cell analyses and complement these with related findings in experimental models. We conclude that both immune cell types as their signaling network may be a rich source to identify novel molecular targets for immunomodulation in AMD.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Degeneración Macular/inmunología , Fagocitos/inmunología , Células TH1/inmunología , Células Th17/inmunología , Anciano de 80 o más Años , Proteínas del Sistema Complemento/inmunología , Humanos , Inmunomodulación/fisiología , Degeneración Macular/patología , Retina/inmunología , Retina/patología , Trastornos de la Visión/inmunología
5.
Medicine (Baltimore) ; 99(1): e18462, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31895778

RESUMEN

Proinflammatory interleukin-26 (IL-26) is involved in chronic inflammation; however, the role of IL-26 in chronic hepatitis B (CHB) remains unknown.In this study, serum IL-26 was quantified in a cohort of CHB patients at baseline and during telbivudine (LdT) treatment.Our results showed that the serum IL-26 level was significantly elevated in CHB patients compared with that in healthy controls and was time-dependently decreased during LdT treatment, accompanying hepatitis B e antigen (HBeAg) seroconversion and reduced serum levels of hepatitis B virus (HBV) DNA, aspartate transaminase, and alanine transaminase across baseline and treatment. In addition, the serum level of IL-26 exhibited a similar declining trend to that of T helper 17 (Th17) cell-secreted IL-17 during LdT treatment in CHB patients. The percentage of IL-26-expressing CD4 cells was significantly higher than that of IL-26-expressing CD4 cells isolated from the peripheral blood mononuclear cells of CHB patients, suggesting that serum IL-26 might be mainly released from CD4 T cells. Furthermore, the baseline mRNA levels of IL-26 and orphan nuclear receptor RORγt-an important transcription factor expressed by Th17 cells-were positively correlated and displayed the same declining trend across the baseline and LdT treatment in CHB patients, suggesting that Th17 cells could be a possible cellular source of the increased serum IL-26 in CHB patients.Taken together, our results suggest that serum IL-26, possibly produced by Th17 CD4 cells, is a novel and potential biomarker for CHB prognosis and treatment.


Asunto(s)
Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/inmunología , Interleucinas/sangre , Adulto , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Telbivudina/uso terapéutico , Células Th17/inmunología , Adulto Joven
6.
An Bras Dermatol ; 94(6): 677-683, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31789253

RESUMEN

BACKGROUND: Psoriasis is a skin-articular disease with unclear etiopathogenesis. It has been suggested that the disease is immune-mediated by T-lymphocytes, predominantly Th17 cells. Similar to psoriasis, geographic tongue is an inflammatory disease with participation of Th17 cells and direct correlation with psoriasis. OBJECTIVE: To investigate and compare the inflammatory responses and the Th17 pathway in psoriasis and geographic tongue. METHODS: This was a cross-sectional study with 46 participants that were categorized into three groups: (A) patients with psoriasis vulgaris; (B) patients with geographic tongue and psoriasis; (C) patients with geographic tongue without psoriasis. All patients underwent physical examination, and a skin and oral biopsy for histopathological examination and immunohistochemical analysis with anti-IL6, anti-IL17, and anti-IL23 antibodies. RESULTS: Histological analysis of all lesions showed mononuclear inflammatory infiltrate. However, moderate intensity was prevalent for the patients with geographic tongue and psoriasis and geographic tongue groups. Immunopositivity for the antibodies anti-IL6, anti-IL17, and anti-IL23 revealed cytoplasmic staining, mainly basal and parabasal, in both psoriasis and geographic tongue. Regarding IL-6, in patients with geographic tongue and psoriasis cases the staining was stronger than in patients with geographic tongue without psoriasis cases. IL-17 evidenced more pronounced and extensive staining when compared to the other analyzed interleukins. IL-23 presented similar immunopositivity for both geographic tongue and psoriasis, demonstrating that the neutrophils recruited into the epithelium were stained. STUDY LIMITATION: This study was limited by the number of cases. CONCLUSION: The inflammatory process and immunostaining of IL-6, IL-17, and IL-23 were similar in geographic tongue and psoriasis, suggesting the existence of a type of geographic tongue that represents an oral manifestation of psoriasis.


Asunto(s)
Glositis Migratoria Benigna/patología , Psoriasis/patología , Células Th17/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/análisis , Biopsia , Estudios Transversales , Femenino , Glositis Migratoria Benigna/inmunología , Humanos , Inmunohistoquímica , Interleucina-17/inmunología , Interleucina-23/inmunología , Interleucina-6/inmunología , Queratinocitos/patología , Masculino , Persona de Mediana Edad , Psoriasis/inmunología , Índice de Severidad de la Enfermedad , Células Th17/inmunología , Adulto Joven
7.
Nat Commun ; 10(1): 5722, 2019 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-31844089

RESUMEN

IL-17-producing CD8+ (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8+ T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond.


Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Dimetilfumarato/farmacología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Adolescente , Adulto , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Dimetilfumarato/uso terapéutico , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Humanos , Inmunosupresores , Interleucina-17/inmunología , Interleucina-17/metabolismo , Estudios Longitudinales , Masculino , Ratones , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Resultado del Tratamiento , Adulto Joven
8.
Adv Exp Med Biol ; 1197: 107-117, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31732938

RESUMEN

T helper 17 (Th17) cells were first described as a T helper subset involved in the pathogenesis of experimental autoimmune inflammation. Since then, these cells have been described as orchestrators of immunopathology in several human inflammatory conditions including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. More recently, the crucial role of Th17 cells in the regulation of immunity and protection of barrier sites has been unveiled. In the present work, we review the available evidence regarding Th17 cells in health and disease with a focus on the oral mucosa and their role in periodontitis pathogenesis. Recent mechanistic studies in animal models have demonstrated that interleukin-17A (IL-17A) and Th17 cells are critical mediators for alveolar bone destruction during periodontal inflammation. Observations in a cohort of patients with naturally occurring impaired Th17 cell differentiation supported these findings. However, interventional studies are needed to conclusively implicate Th17 cells in the immunopathogenesis of human alveolar bone and tissue destruction that characterize periodontitis.


Asunto(s)
Periodontitis , Células Th17 , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Humanos , Inflamación , Interleucina-17/inmunología , Periodontitis/fisiopatología , Células Th17/citología , Células Th17/inmunología
9.
Braz Oral Res ; 33: e093, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31664358

RESUMEN

Cytokines and chemokines have a fundamental role in the maintenance of inflammation and bone response, which culminate in the development of chronic periapical lesions. Regulatory (Treg) and Th17 cytokines play a key role in regulating the immune response involved in this process. The aim of this study was to investigate the role of Treg and Th17 cells in chronic inflammatory periapical disease, by comparing the expression of the immunoregulatory mediators TGF-ß, IL-10, CCL4, and the proinflammatory IL-17 and CCL20 in the periapical tissue of teeth with pulp necrosis, with and without associated chronic lesions. Eighty-six periapical tissue samples were obtained from human teeth. The samples were divided into three groups: pulp necrosis with a periapical lesion (n=26); pulp necrosis without a periapical lesion (n=30), and control (n=30). All samples were submitted to histopathological analysis and cytokine and chemokine measurement through ELISA. Statistical analyses were done with Kruskal-Wallis and Mann-Whitney tests and Spearman correlation. The group with pulp necrosis and a periapical lesion showed a higher expression of CCL4 and TGF-ß in comparison with pulp necrosis without a lesion. CCL20 was higher in the group with a periapical lesion when compared to the control. In all groups there was a weak positive correlation between IL-17/CCL20, IL-10/CCL4, and IL-17/TGF-ß. Both types of cytokines, pro-inflammatory and immunoregulatory, occur simultaneously in periapical tissue. However, a rise in immunosuppressive cytokines and chemokines (CCL4 and TGF-ß) in periapical lesions suggests a role of these cytokines in stable periapical disease.


Asunto(s)
Quimiocinas CC/análisis , Interleucinas/análisis , Periodontitis Periapical/patología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta/análisis , Adulto , Estudios de Casos y Controles , Quimiocinas CC/inmunología , Enfermedad Crónica , Necrosis de la Pulpa Dental/inmunología , Necrosis de la Pulpa Dental/patología , Humanos , Interleucinas/inmunología , Persona de Mediana Edad , Periodontitis Periapical/inmunología , Valores de Referencia , Estadísticas no Paramétricas , Factor de Crecimiento Transformador beta/inmunología , Adulto Joven
10.
Infect Immun ; 88(1)2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-31611273

RESUMEN

Infection of the host with Mycobacterium avium subsp. paratuberculosis results in chronic and progressive enteritis that traverses both subclinical and clinical stages. The mechanism(s) for the shift from an asymptomatic subclinical disease state to advanced clinical disease is not fully understood. In the present study, naturally infected dairy cattle were divided into subclinical and clinical infection groups, along with noninfected control cows of similar parity, to study host immune responses in different stages of infection. Both infection groups had higher levels of secretion of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) than control cows, whereas only clinical cows had increased secretion of IL-10, IL-12, and IL-18 upon stimulation of peripheral blood mononuclear cells (PBMCs) with antigen. Conversely, secretion of IL-17Α was decreased for clinical cows compared to subclinical and control cows. Proinflammatory cytokine genes were upregulated only for subclinical cows, whereas increased IL-10 and IL-17 gene expression levels were observed for both infection groups. Increased CD4+, CD8+, and γδ T cell receptor-positive (TCR+) T cells were observed for subclinical cows compared to clinical cows. Although clinical cows expressed antigen-specific immune responses, the profile for subclinical cows was one of a dominant proinflammatory response to infection. We reason that a complex coordination of immune responses occurs during M. avium subsp. paratuberculosis infection, with these responses shifting as the host transitions through the different stages of infection and disease (subclinical to clinical). A further understanding of the series of events characterized by Th1/Th2/Th17 responses will provide mechanisms for disease progression and may direct insightful intervention strategies.


Asunto(s)
Antígenos Bacterianos/inmunología , Enfermedades de los Bovinos/inmunología , Enfermedades de los Bovinos/patología , Inmunidad Celular , Mycobacterium avium subsp. paratuberculosis/inmunología , Paratuberculosis/inmunología , Paratuberculosis/patología , Animales , Bovinos , Citocinas/metabolismo , Factores Inmunológicos/metabolismo , Mycobacterium avium subsp. paratuberculosis/crecimiento & desarrollo , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología
11.
Immunology ; 158(4): 287-295, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31566706

RESUMEN

Mature T helper (Th) effector cells originate following antigen recognition by naive T precursors. The maturation process is accompanied by the acquisition of specific effector functions that distinguish at least three different T helper subsets: Th1, Th2 and Th17. In general, maturation of somatic cells is accompanied by terminal differentiation. However, accumulating evidence shows that effector T cells retain a certain degree of plasticity. This is especially true for Th17 cells, which have been shown to converge towards other phenotypes in response to specific microenvironmental pressure. In this review we will discuss the experimental evidence that supports the hypothesis of Th17 plasticity, with particular emphasis on the generation of Th17-derived 'non-classic' Th1 cells, and the molecular networks that control it. Moreover, we will consider why Th17 plasticity is important for host protection, but also why it can have pathogenic functions during chronic inflammation. Regarding the last point, we will discuss a possible role for biological drugs in the control of Th17 plasticity and disease course.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Inmunoterapia/tendencias , Inflamación/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Enfermedades Autoinmunes/terapia , Diferenciación Celular , Microambiente Celular , Humanos , Inmunidad Celular
12.
Infect Immun ; 87(12)2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31570560

RESUMEN

Chronic helminth infections are known to be associated with the modulation of antigen-specific T-cell responses. Strongyloides stercoralis infection is characterized by the downmodulation of antigen-specific Th1 and Th17 responses and the upregulation of Th2 and Th9 responses. Immune homeostasis is partially maintained by negative regulators of T-cell activation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), which dampen effector responses during chronic infections. However, their roles in S. stercoralis infection are yet to be defined. Therefore, we sought to determine the role of CTLA-4 and PD-1 in regulating CD4+ and CD8+ T-cell responses and examined the frequencies of monofunctional and dual functional Th1/T cytotoxic type 1 (Tc1), Th17/Tc17, Th2/Tc2, and Th9/Tc9 cells in S. stercoralis infection in 15 infected individuals stimulated with parasite antigen following CTLA-4 or PD-1 blockade. Our data reveal that CTLA-4 or PD-1 blockade results in significantly enhanced frequencies of monofunctional and dual functional Th1/Tc1 and Th17/Tc17 cells and, in contrast, diminishes the frequencies of monofunctional and dual functional Th2/Tc2 and Th9/Tc9 cells with parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that CTLA-4 and PD-1 limit the induction of particular T-cell subsets in S. stercoralis infection, which suggests the importance of CTLA-4 and PD-1 in immune modulation in a chronic helminth infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Strongyloides stercoralis/inmunología , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología , Adulto , Animales , Humanos , India , Activación de Linfocitos/inmunología , Persona de Mediana Edad , Estrongiloidiasis/inmunología , Estrongiloidiasis/parasitología , Subgrupos de Linfocitos T/inmunología , Adulto Joven
13.
Medicine (Baltimore) ; 98(43): e17608, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31651870

RESUMEN

This study aims to investigate the changes of cytokines and the effect of programmed death ligand 1 (PD-L1) signaling pathway on T cell function in patients with immune thrombocytopenic purpura (ITP).Totally, 40 untreated ITP patients were recruited and 30 healthy people were recruited as the healthy control. Then whole blood of ITP patients and healthy control was collected, respectively. The sPD-L1/anti-PD-1 was used to activate or block the programmed death (PD-1)/PD-L1 signaling pathway. The expression of PD-1 and PD-L1 on peripheral blood mononuclear cells (PBMCs) were detected by flow cytometry. PBMCs were treated with cluster of differentiation (CD3), cluster of differentiation 28 (CD28), and phytohaemagglutinin (PHA) for 48 hours. Serum levels of sPD-1, sPD-L1, and cytokines were measured by enzyme-linked immunosorbent assay (ELISA).Compared with the healthy control group, the percentages of PD-1+CD3+CD4+ T cells and PD-L1+HLA-DR+CD11c+ DC cells were increased in ITP patients. The levels of interferon-gamma (IFN-γ), interleukin-17 (IL-17), and sPD-1 in the serum of ITP patients were increased, while IL-4 and transforming growth factor-ß (TGF-ß) were decreased. Additionally, the level of sPD-1 was negatively correlated with the platelet count. Consistently, after treatment with CD3, CD28, and PHA, IFN-γ and IL-17 levels in culture supernatant of PBMCs from ITP patients were significantly higher than those from healthy controls whereas IL-4 and TGF-ß levels were significantly lower. Furthermore, IFN-γ and IL-17 levels secreted by PBMCs from ITP patients decreased after sPD-L1 administration, however, IL-4 and TGF-ß levels were increased. The level of IFN-γ in ITP group remained higher after anti-PD-1 blockage, but the levels of IL-4, TGF-ß, and IL-17 were not significantly influenced.sPD-1 may cause the dysfunction of PD-1/PD-L1 signaling pathway, and its level is related to the severity of ITP patients. Activation of PD-1/PD-L1 with sPD-L1 may restore the imbalance of Th1/Th2 and Treg/Th17 cell subtypes in ITP patients but anti-PD-1 may exacerbate disease by enhancing IFN-γ production.


Asunto(s)
Antígeno B7-H1/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Linfocitos T Reguladores/inmunología , Balance Th1 - Th2/fisiología , Células Th17/inmunología , Adulto , Antígenos CD28/inmunología , Complejo CD3/inmunología , Estudios de Casos y Controles , Citocinas/inmunología , Femenino , Humanos , Interferón gamma/metabolismo , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Fitohemaglutininas/inmunología , Receptor de Muerte Celular Programada 1/fisiología , Púrpura Trombocitopénica Idiopática/sangre , Transducción de Señal/inmunología , Linfocitos T/inmunología , Balance Th1 - Th2/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo
14.
Ecotoxicol Environ Saf ; 186: 109772, 2019 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-31614297

RESUMEN

Trichloroethylene (TCE) is a common organic solvent which can cause TCE hypersensitivity syndrome (THS) in exposure workers. THS is an adverse skin disorder with severe inflammatory kidney damage. Complement C3a receptor (C3aR) acts as a specific receptor for the key complement cleavage product C3a and involves multiple inflammatory responses, but the role of C3aR in TCE induced kidney inflammatory injury remains unknown. In this study, BALB/c mouse model of skin sensitization induced by TCE was set up in the presence or absence of C3aR antagonist (C3aRA). Kidney pathology and renal function, expression of inflammatory mediators and C3aR, changes in Th17 cell numbers, and activation of signal transducer and activator of transcription 3 (STAT3) in the kidney were examined. TCE sensitization produced histopathological and functional damage to the kidney, accompanied by increased levels of interleukin (IL-) 1ß, IL-6, and IL-23. Local accumulation of Th17 cells and enhanced phosphorylation of STAT3 were also seen in the impaired kidney in TCE sensitization-positive mice. C3aR was mainly located in the impaired glomerulus and upregulated in TCE sensitization-positive mice. C3aRA pretreatment alleviated the structural and functional kidney damage and the inflammatory cytokine and Th17 responses by TCE sensitization, and specifically reduced the phosphorylation of STAT3. Together, our results demonstrate that C3aR signaling promotes the inflammatory responses and regulates the accumulation of Th17 phenotype via phosphorylation of STAT3 in TCE sensitization induced inflammatory kidney damage. C3aR may serve as a potential therapeutic target in TCE sensitization mediated kidney injury.


Asunto(s)
Dermatitis Alérgica por Contacto/etiología , Riñón/efectos de los fármacos , Receptores de Complemento/metabolismo , Células Th17/inmunología , Tricloroetileno/toxicidad , Animales , Citocinas/sangre , Dermatitis Alérgica por Contacto/inmunología , Dermatitis Alérgica por Contacto/patología , Riñón/inmunología , Riñón/patología , Pruebas de Función Renal , Ratones , Ratones Endogámicos BALB C , Fenotipo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Células Th17/patología
15.
Trans Am Clin Climatol Assoc ; 130: 88-99, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31516171

RESUMEN

We have found that calcium calmodulin kinase IV is increased in T cells, podocytes, and mesangial cells from patients with systemic lupus erythematosus, as well as in lupus-prone mice, podocytes of patients with focal segmental glomerulosclerosis, and in mice injected with doxorubicin. We showed that this accounts for aberrant T cell function and glomerular damage. Using nanoparticles (nlg) loaded with a small drug inhibitor of calcium calmodulin kinase IV and tagged with antibodies directed to CD4 we have been able to show inhibition of autoimmunity and lupus nephritis. Also, using nlg tagged with antibodies to nephrin, we showed suppression of nephritis in lupus-prone mice and of glomerular damage in mice exposed to doxorubicin. We propose the development of approaches to deliver drugs to cells in a targeted and precise manner.


Asunto(s)
Bencilaminas/administración & dosificación , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Nefritis Lúpica/tratamiento farmacológico , Nanopartículas , Inhibidores de Proteínas Quinasas/administración & dosificación , Sulfonamidas/administración & dosificación , Linfocitos T/inmunología , Animales , Antibióticos Antineoplásicos/toxicidad , Bencilaminas/uso terapéutico , Antígenos CD4 , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/inmunología , Metilación de ADN , Modelos Animales de Enfermedad , Doxorrubicina/toxicidad , Sistemas de Liberación de Medicamentos , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Glomeruloesclerosis Focal y Segmentaria/inmunología , Humanos , Lupus Eritematoso Sistémico , Nefritis Lúpica/inmunología , Proteínas de la Membrana , Ratones , Ratones Endogámicos MRL lpr , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Sulfonamidas/uso terapéutico , Linfocitos T Reguladores/inmunología , Células Th17/inmunología
16.
Life Sci ; 235: 116838, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31493482

RESUMEN

AIMS: This work aimed to evaluate the regulatory function of IL-10-producing B cells in viral myocarditis (VMC). MAIN METHODS: We adoptively transferred purified IL-10-producing B cells to VMC mice via the tail vein. We observed the inflammatory responses and cardiac lesions by histological analysis, examined the proportions of spleen Th1 and T17 cells by flow cytometry and expression levels of related transcription factors (T-bet and RORγt) by reverse transcription polymerase chain reaction (RT-PCR), and calculated the cardiac pathological scores and the mean survival times. KEY FINDINGS: IL-10-producing B cells were found to be T cell-dependent in the pathogenesis of VMC. They mainly downregulated T-bet and RORγt mRNA levels to decrease the proportions of Th1 and Th17 cells, thereby restraining the inflammation and damage in the myocardium in B cell-deficient VMC mice. Adoptive transfer of IL-10-producing B cells before VMC induction also normalized the inflammatory responses and prolonged the survival time in wild-type (WT) VMC mice. While the transfer of IL-10-producing B cells on day 3 of VMC alleviated the severity of disease, it did not extend the mean survival time of VMC mice. By contrast, IL-10-producing B cells showed no effect on day 7 of VMC. In conclusion, IL-10-producing B cells downregulate the proportion of Th1 and Th17 cells to alleviate inflammatory damage in the myocardium during VMC before the induction or the early phase of disease. SIGNIFICANCE: These findings suggest that IL-10-producing B cells may be a new therapeutic target for modulating the immune response in VMC.


Asunto(s)
Linfocitos B/metabolismo , Enterovirus Humano B/inmunología , Inflamación/fisiopatología , Interleucina-10/fisiología , Miocarditis/fisiopatología , Células TH1/inmunología , Células Th17/inmunología , Traslado Adoptivo , Animales , Infecciones por Coxsackievirus/inmunología , Infecciones por Coxsackievirus/virología , Regulación hacia Abajo , Interleucina-10/biosíntesis , Masculino , Ratones , Miocarditis/metabolismo , Miocarditis/patología , Miocarditis/virología , Miocardio/patología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/biosíntesis , Tasa de Supervivencia , Proteínas de Dominio T Box/biosíntesis
17.
Arch Med Res ; 50(3): 113-121, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-31495388

RESUMEN

BACKGROUND: Peptic ulcer disease (PUD) is a common disease worldwide moreover known as stomach ulcer or peptic ulcer. Increased the number of T CD4+ helper cells in response to gastric infection by Helicobacter pylori (H. pylori) play an important role in the development of PUD. The aim of this study was to determine the frequency of T-bet+ cells in H. pylori-infection, its interaction with Th17/Treg cells and its association with the clinical consequences of the infection. METHODS: A total of 63 patients with PUD, 89 patients with gastritis and 48 H. pylori-negative subjects were enrolled in this study. The number of T-bet+ cells were determined by immunohistochemistry. RESULTS: The numbers of T-bet+ cells and INF-γ expression in infected patients were significantly higher than uninfected. Moreover, the number of T-bet+ cells and INF-γ expression in infected patients with PUD were significantly higher than infected patients with gastritis. Additionally, the number of T-bet+ cells and INF-γ expression were found to be inversely correlated with degree of H. pylori density and chronic inflammation score (CIS) in infected patients with gastritis disease, but this correlation was positive in the infected patients with PUD. The number of T-bet+ cells was found to be positively correlated with the number of Th17 cells and inversely correlated with the number of Treg cells in infected patients with gastritis and PUD. CONCLUSION: Abnormal hyper-activation of T-bet+ cells during H. pylori-infection may lead to tissue damage caused by immunopathologic reactions.


Asunto(s)
Gastritis/patología , Úlcera Péptica/epidemiología , Úlcera Péptica/microbiología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adulto , Femenino , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/fisiología , Gastritis/inmunología , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/inmunología , Humanos , Inmunohistoquímica , Interferón gamma/biosíntesis , Masculino , Persona de Mediana Edad
18.
BMC Immunol ; 20(1): 32, 2019 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-31484501

RESUMEN

BACKGROUND: The development of Systemic lupus erythematosus (SLE) has been associated with the balance of Th17 and Treg cells. IL-2 and rapamycin can influence the populations of both Th17 and Treg cells. However, it is unclear whether low dose of IL-2 and rapamycin can relieve the symptoms of SLE patients and what is the mechanisms. In this study, we aim to analyze the effect of low dose of IL-2 plus rapamycin on the number of Tregs, Th17 cells and the ratio of Th17/Treg cells, as well as to evaluate its therapeutic efficacy in refractory SLE patients. RESULT: Fifty refractory SLE patients and 70 healthy controls were enrolled and followed up for 24 weeks. We found that compared with HC, the refractory SLE patients had a lower number of Tregs, a similar number of Th17 cells, but an increased ratio of Th17/Treg. After the treatment, the number of Tregs of the patients at 12th and 24th week was significantly increased. While the number of Th17 cells was unchanged, the ratio of Th17/Treg was significantly decreased at both 6 weeks and 24 weeks. After 6, 12 and 24 weeks of treatment, the SLEDAI score was significantly reduced. The prednison dosage at 6th,12th and 24th week post treatment was significantly decreased. CONCLUSION: Our results support that the reduction of Tregs and the imbalance of Th17/Treg cells were correlated with the occurrence and development of refractory SLE. Low dose of IL-2 combined with rapamycin was able to restore the number of Tregs and the balance of Th17/Treg cells. As a result, this approach was able to induce immune tolerance and promote disease remission, allowing for the reduction in prednisone dosage. TRIAL REGISTRATION: ChiCTR-IPR-16009451 Registration date: 2016/10/16.


Asunto(s)
Interleucina-2/farmacología , Lupus Eritematoso Sistémico/inmunología , Sirolimus/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Adulto , Biomarcadores , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Interleucina-2/administración & dosificación , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/metabolismo , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sirolimus/administración & dosificación , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Resultado del Tratamiento
19.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 595-600, 2019 Jul.
Artículo en Chino | MEDLINE | ID: mdl-31537243

RESUMEN

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.


Asunto(s)
Dermatitis/tratamiento farmacológico , Ácido Oleanólico/análogos & derivados , Psoriasis/tratamiento farmacológico , Saponinas/farmacología , Células Th17/inmunología , Animales , Citocinas/inmunología , Dermatitis/inmunología , Femenino , Imiquimod , Ratones , Ratones Endogámicos BALB C , Ácido Oleanólico/farmacología , Psoriasis/inducido químicamente , Distribución Aleatoria , Piel/inmunología , Piel/patología
20.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-31514450

RESUMEN

An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim of this study was to investigate BTLA expression on regulatory and effector CD4+ T-cells in SLE patients with and without lupus nephritis (LN) during active and inactive disease. Therefore, peripheral blood of forty-one SLE patients and twenty-one healthy controls (HC) was phenotypically analyzed. Next, ex vivo stimulated T-cells were analyzed for the expression of BTLA on Th1-, Th2-, and Th17-effector cells by flow cytometry. Renal involvement was defined as biopsy-proven LN. Disease activity was assessed by SLE disease activity index (SLEDAI). Percentages of peripheral unstimulated BTLA+ CD4+ T-cells were significantly decreased in SLE patients with active disease. However, ex vivo stimulated Th1, Th2, and Th17 effector T-cells, expressed increased percentages of BTLA expression in active disease. In contrast, the BTLA expression on CD4+CD25++CD127- regulatory T-cells was not significantly different. BTLA seems to be an important co-inhibitory molecule in the T-cell homeostasis of patients with systemic lupus erythematosus and crucial for disease activity.


Asunto(s)
Lupus Eritematoso Sistémico/inmunología , Receptores Inmunológicos/metabolismo , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología , Adulto , Femenino , Humanos , Nefritis Lúpica/inmunología , Activación de Linfocitos/inmunología , Masculino , Modelos Inmunológicos , Linfocitos T Reguladores/inmunología
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