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1.
J Surg Res ; 245: 610-618, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31522034

RESUMO

BACKGROUND: Herpes virus entry mediator (HVEM) is a coinhibitory molecule which can both stimulate and inhibit host immune responses. Altered expression of HVEM and its ligands is associated with increased nosocomial infections in septic patients. We hypothesize critically ill trauma patients will display increased lymphocyte HVEM expression and that such alteration is predictive of infectious events. MATERIALS AND METHODS: Trauma patients prospectively enrolled from the ICU were compared with healthy controls. Leukocytes were isolated from whole blood, stained for CD3 (lymphocytes) and HVEM, and evaluated by flow cytometry. Charts were reviewed for injuries sustained, APACHE II score, hospital course, and secondary infections. RESULTS: Trauma patients (n = 31) were older (46.7 ± 2.4 versus 36.8 ± 2.1 y; P = 0.03) than healthy controls (n = 10), but matched for male sex (74% versus 60%; P = 0.4). Trauma patients had higher presenting WBC (13.9 ± 1.3 versus 5.6 ± 0.5 × 106/mL; P = 0.002), lower percentage of CD3+ lymphocytes (7.5% ± 0.8 versus 22.5% ± 0.9; P < 0.001), but significantly greater expression of HVEM+/CD3+ lymphocytes (89.6% ± 1.46 versus 67.3% ± 1.7; P < 0.001). Among trauma patients, secondary infection during the hospitalization was associated with higher APACHE II scores (20.6 ± 1.6 versus 13.6 ± 1.4; P = 0.03) and markedly lower CD3+ lymphocyte HVEM expression (75% ± 2.6 versus 93% ± 0.7; P < 0.01). CONCLUSIONS: HVEM expression on CD3+ cells increases after trauma. Patients developing secondary infections have less circulating HVEM+CD3+. This implies HVEM signaling in lymphocytes plays a role in maintaining host defense to infection in after trauma. HVEM expression may represent a marker of infectious risk as well as a potential therapeutic target, modulating immune responses to trauma.


Assuntos
Tolerância Imunológica , Linfócitos/imunologia , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Ferimentos e Lesões/imunologia , APACHE , Adulto , Biomarcadores/metabolismo , Complexo CD3/metabolismo , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Humanos , /diagnóstico , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Membro 14 de Receptores do Fator de Necrose Tumoral/imunologia , Ferimentos e Lesões/sangue , Ferimentos e Lesões/complicações
2.
Nat Commun ; 10(1): 3258, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332204

RESUMO

CD160 and BTLA both bind to herpes virus entry mediator. Although a negative regulatory function of BTLA in natural killer T (NKT) cell activation has been reported, whether CD160 is also involved is unclear. By analyzing CD160-/- mice and mixed bone marrow chimeras, we show that CD160 is not essential for NKT cell development. However, CD160-/- mice exhibit severe liver injury after in vivo challenge with α-galactosylceramide (α-GalCer). Moreover, CD160-/- mice are more susceptible to Concanavalin A challenge, and display elevated serum AST and ALT levels, hyperactivation of NKT cells, and enhanced IFN-γ, TNF, and IL-4 production. Lastly, inhibition of BTLA by anti-BTLA mAb aggravates α-GalCer-induced hepatic injury in CD160-/- mice, suggesting that both CD160 and BTLA serve as non-overlapping negative regulators of NKT cells. Our data thus implicate CD160 as a co-inhibitory receptor that delivers antigen-dependent signals in NKT cells to dampen cytokine production during early innate immune activation.


Assuntos
Antígenos CD/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fígado/metabolismo , Células T Matadoras Naturais/metabolismo , Receptores Imunológicos/metabolismo , Animais , Antígenos CD/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Concanavalina A/administração & dosagem , Concanavalina A/toxicidade , Citocinas/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Galactosilceramidas/administração & dosagem , Galactosilceramidas/toxicidade , Fígado/efeitos dos fármacos , Fígado/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Receptores Imunológicos/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Análise de Sobrevida
3.
Immunity ; 51(2): 310-323.e7, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31204070

RESUMO

The tumor necrosis factor receptor superfamily member HVEM is one of the most frequently mutated surface proteins in germinal center (GC)-derived B cell lymphomas. We found that HVEM deficiency increased B cell competitiveness during pre-GC and GC responses. The immunoglobulin (Ig) superfamily protein BTLA regulated HVEM-expressing B cell responses independently of B-cell-intrinsic signaling via HVEM or BTLA. BTLA signaling into T cells through the phosphatase SHP1 reduced T cell receptor (TCR) signaling and preformed CD40 ligand mobilization to the immunological synapse, thus diminishing the help delivered to B cells. Moreover, T cell deficiency in BTLA cooperated with B cell Bcl-2 overexpression, leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells to influence GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Proliferação de Células , Sinapses Imunológicas , Ativação Linfocitária , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Comunicação Parácrina , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores Imunológicos/genética , Transdução de Sinais
4.
J Clin Exp Hematop ; 59(1): 1-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918139

RESUMO

The microenvironment influences the behavior of follicular lymphoma (FL) but the specific roles of the immunomodulatory BTLA and TNFRSF14 (HVEM) are unknown. Therefore, we examined their immunohistochemical expression in the intrafollicular, interfollicular and total histological compartments in 106 FL cases (57M/49F; median age 57-years), and in nine relapsed-FL with transformation to DLBCL (tFL). BTLA expression pattern was of follicular T-helper cells (TFH) in the intrafollicular and of T-cells in the interfollicular compartments. The mantle zones were BTLA+ in 35.6% of the cases with similar distribution of IgD. TNFRSF14 expression pattern was of neoplastic B lymphocytes (centroblasts) and "tingible body macrophages". At diagnosis, the averages of total BTLA and TNFRSF14-positive cells were 19.2%±12.4STD (range, 0.6%-58.2%) and 46.7 cells/HPF (1-286.5), respectively. No differences were seen between low-grade vs. high-grade FL but tFL was characterized by low BTLA and high TNFRSF14 expression. High BTLA correlated with good overall survival (OS) (total-BTLA, Hazard Risk=0.479, P=0.022) and with high PD-1 and FOXP3+Tregs. High TNFRSF14 correlated with poor OS and progression-free survival (PFS) (total-TNFRSF14, HR=3.9 and 3.2, respectively, P<0.0001), with unfavorable clinical variables and higher risk of transformation (OR=5.3). Multivariate analysis including BTLA, TNFRSF14 and FLIPI showed that TNFRSF14 and FLIPI maintained prognostic value for OS and TNFRSF14 for PFS. In the GSE16131 FL series, high TNFRSF14 gene expression correlated with worse prognosis and GSEA showed that NFkB pathway was associated with the "High-TNFRSF14/dead-phenotype".In conclusion, the BTLA-TNFRSF14 immune modulation pathway seems to play a role in the pathobiology and prognosis of FL.


Assuntos
Linfoma Folicular/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/química , Linfócitos B/patologia , Transformação Celular Neoplásica , Feminino , Humanos , Fatores Imunológicos , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Linfócitos T/química
5.
Rheumatology (Oxford) ; 58(3): 502-510, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508197

RESUMO

OBJECTIVES: This study aimed to assess the potential role of the TNF superfamily member lymphocyte T-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT) in SSc through evaluation of: skin expression of LIGHT and its receptors, herpesvirus entry mediator and lymphotoxin ß-related receptor, and serum concentration of LIGHT in SSc patients. METHODS: Expression of LIGHT and its receptors was investigated by immunohistochemistry and evaluated semi-quantitatively in skin biopsies from 19 SSc patients and 9 healthy controls. Serum levels of LIGHT were measured using ELISA in 329 patients with SSc and 50 control subjects. RESULTS: Expression of LIGHT and both receptors was higher in SSc patients compared with controls (P < 0.05 for all comparisons). Patients with early SSc (⩽ 3 years from the first non-Raynaud's phenomenon symptom) showed higher expression of LIGHT and herpesvirus entry mediator compared with patients with longer disease duration (P < 0.05 for both comparisons). The mean serum concentration of LIGHT was significantly higher in SSc patients compared with the controls (P < 0.05). High serum concentration of LIGHT was associated with male sex, presence of digital ulcers, muscle involvement (defined by elevated serum creatine kinase levels), steroid treatment and lack of ACA. However, in multivariate regression analysis only presence of digital ulcers and creatine kinase elevation were independently associated with serum concentration of LIGHT. CONCLUSION: These data provide the first evidence of overexpression of LIGHT and its receptors in SSc and suggest that the LIGHT axis might contribute to the pathogenesis of SSc. Increased serum concentrations of LIGHT seem to reflect vascular injury in SSc.


Assuntos
Receptor beta de Linfotoxina/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Adulto , Feminino , Humanos , Receptor beta de Linfotoxina/genética , Masculino , Pessoa de Meia-Idade , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Pele/patologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
6.
Lung Cancer ; 125: 115-120, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30429008

RESUMO

BACKGROUND: Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (B- and T-lymphocyte attenuator, BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC. METHODS: A TMA of 527 resected NSCLC samples and 56 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 28-8 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used. RESULTS: HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was 18.6% (77/415) and 48.2% (27/56) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, p = 0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, p = 0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p = 0.706) and PD-L1 expression (median 45 vs 48 months, p = 0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.274, p < 0.001) in patients with NSCLC and also a weak negative correlation in NSCLC cell lines (r=-0.162, p = 0.352). CONCLUSION: HVEM was found to be overexpressed in NSCLC patients of N2 lymph node metastasis or later stage and has a negative co-relationship with PD-L1 expression. HVEM was not prognostic for NSCLC patients.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática/imunologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Membro 14 de Receptores do Fator de Necrose Tumoral/imunologia
7.
Front Immunol ; 9: 2611, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30483269

RESUMO

CD8+ T cells are key players during infection with the malaria parasite Plasmodium berghei ANKA (PbA). While they cannot provide protection against blood-stage parasites, they can cause immunopathology, thus leading to the severe manifestation of cerebral malaria. Hence, the tight control of CD8+ T cell function is key in order to prevent fatal outcomes. One major mechanism to control CD8+ T cell activation, proliferation and effector function is the integration of co-inhibitory and co-stimulatory signals. In this study, we show that one such pathway, the HVEM-CD160 axis, significantly impacts CD8+ T cell regulation and thereby the incidence of cerebral malaria. Here, we show that the co-stimulatory molecule HVEM is indeed required to maintain CD8+ T effector populations during infection. Additionally, by generating a CD160-/- mouse line, we observe that the HVEM ligand CD160 counterbalances stimulatory signals in highly activated and cytotoxic CD8+ T effector cells, thereby restricting immunopathology. Importantly, CD160 is also induced on cytotoxic CD8+ T cells during acute Plasmodium falciparum malaria in humans. In conclusion, CD160 is specifically expressed on highly activated CD8+ T effector cells that are harmful during the blood-stage of malaria.


Assuntos
Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Malária Cerebral/metabolismo , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Animais , Proliferação de Células/fisiologia , Células Cultivadas , Proteínas Ligadas por GPI/metabolismo , Humanos , Ativação Linfocitária/fisiologia , Malária Cerebral/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Plasmodium berghei/metabolismo , Plasmodium falciparum/metabolismo
8.
Cell Host Microbe ; 24(2): 249-260.e4, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-30092201

RESUMO

Innate lymphoid cells (ILCs) are important regulators of early infection at mucosal barriers. ILCs are divided into three groups based on expression profiles, and are activated by cytokines and neuropeptides. Yet, it remains unknown if ILCs integrate other signals in providing protection. We show that signaling through herpes virus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor superfamily, in ILC3 is important for host defense against oral infection with the bacterial pathogen Yersinia enterocolitica. HVEM stimulates protective interferon-γ (IFN-γ) secretion from ILCs, and mice with HVEM-deficient ILC3 exhibit reduced IFN-γ production, higher bacterial burdens and increased mortality. In addition, IFN-γ production is critical as adoptive transfer of wild-type but not IFN-γ-deficient ILC3 can restore protection to mice lacking ILCs. We identify the TNF superfamily member, LIGHT, as the ligand inducing HVEM signals in ILCs. Thus HVEM signaling mediated by LIGHT plays a critical role in regulating ILC3-derived IFN-γ production for protection following infection. VIDEO ABSTRACT.


Assuntos
Infecções por Enterobacteriaceae/prevenção & controle , Interferon gama/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/imunologia , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Transferência Adotiva , Adulto , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/metabolismo , Transporte Proteico , Receptores CCR6/genética , Receptores CCR6/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Baço/microbiologia , Baço/patologia , Yersinia enterocolitica/patogenicidade
9.
Mol Med Rep ; 18(3): 3403-3410, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30066919

RESUMO

Despite advances in management, bladder cancer remains a principal cause of cancer­associated complications. Tumor necrosis factor receptor superfamily member 14 (TNFRSF14) is dysregulated in certain types of cancer; however, limited data are available on the expression and function of TNFRSF14 in bladder cancer. In the present study, the aim was to evaluate the expression and biological functions of TNFRSF14 in bladder cancer. Firstly, the expression levels of TNFRSF14 in bladder cancer tissue were examined using The Cancer Genome Atlas (TCGA) database. Secondly, reverse transcription­quantitative polymerase chain reaction was utilized to investigate the expression levels of TNFRSF14 in the T24, SW780 and EJ­M3 bladder cancer cell lines. Transfection and Cell Counting kit­8 (CCK­8) assay was used to evaluate whether TNFRSF14 overexpression or silencing would have an effect on cell proliferation of T24 and EJ­M3 cells. In addition, TNFRSF14­induced apoptotic cells were identified using Annexin V­fluorescein isothiocyanate and propidium iodide staining. Western blot analysis was used to detect proteins associated with the phosphatidylinositol 3­kinase pathway. According to the TCGA dataset, the expression levels TNFRSF14 were decreased in bladder cancer tissue compared with in normal control samples. Patients with bladder cancer exhibiting low expression levels of TNFRSF14 had a worse prognosis compared to those with high expression levels of TNFRSF14. Overexpression of TNFRSF14 in T24 cells led to increased apoptosis and inhibited cell proliferation in vitro. Western blotting demonstrated that TNFRSF14 overexpression increased the expression levels of caspase3­p17 in T24 cells, but significantly decreased the expression levels of phosphorylated (p)­protein kinase B (AKT) and P70 S6 kinase (P70). TNFRSF14 silencing in EJ­M3 cells enhanced cell growth, inhibited cell apoptosis, increased the expression levels of p­AKT and P70, and decreased the expression levels of caspase3­p17. In conclusion, TNFRSF14 may serve a tumor suppressive role in bladder cancer by inducing apoptosis and suppressing proliferation, and act as a novel prognostic biomarker for bladder cancer.


Assuntos
Apoptose/genética , Regulação Neoplásica da Expressão Gênica , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Humanos , Estimativa de Kaplan-Meier , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
10.
Cytokine ; 110: 126-130, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29730385

RESUMO

Melanin synthesis in melanocytes is affected by various cytokines. Here, we reported for the first time that tumor necrosis factor superfamily member 14 (TNFSF14) inhibits melanogenesis in the primary culture of human epidermal melanocytes. TNFSF14 is known to bind to its receptors herpes virus entry mediator (HVEM) and lymphotoxin ß receptor (LTßR) for signal transduction, but TNFSF14-induced hypopigmentation was independent of HVEM and LTßR in melanocytes. To explore signaling in melanocytes treated with TNFSF14, we performed RNA-seq and found that nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling is activated by TNFSF14. Further, we observed that inhibition of NF-kB effectively blocks the hypopigmentation induced by TNFSF14. We conclude that TNFSF14 inhibits melanogenesis in melanocytes via NF-κB signaling and could be applied in the treatment of cutaneous pigment disorders.


Assuntos
Melanócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Linhagem Celular , Humanos , Ativação Linfocitária/fisiologia , Receptor beta de Linfotoxina/metabolismo , Melaninas/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo
11.
J Exp Med ; 215(2): 415-422, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29339444

RESUMO

Dermatitis is often associated with an allergic reaction characterized by excessive type 2 responses leading to epidermal acanthosis, hyperkeratosis, and dermal inflammation. Although factors like IL-4, IL-13, and thymic stromal lymphopoietin (TSLP) are thought to be instrumental for the development of this type of skin disorder, other cytokines may be critical. Here, we show that the tumor necrosis factor (TNF) superfamily protein LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes) is required for experimental atopic dermatitis, and LIGHT directly controls keratinocyte hyperplasia, and production of periostin, a matricellular protein that contributes to the clinical features of atopic dermatitis as well as other skin diseases such as scleroderma. Mice with a conditional deletion of the LIGHT receptor HVEM (herpesvirus entry mediator) in keratinocytes phenocopied LIGHT-deficient mice in exhibiting reduced epidermal thickening and dermal collagen deposition in a model of atopic dermatitis driven by house dust mite allergen. LIGHT signaling through HVEM in human epidermal keratinocytes directly induced proliferation and periostin expression, and both keratinocyte-specific deletion of HVEM or antibody blocking of LIGHT-HVEM interactions after disease onset prevented expression of periostin and limited atopic dermatitis symptoms. Developing reagents that neutralize LIGHT-HVEM signaling might be useful for therapeutic intervention in skin diseases where periostin is a central feature.


Assuntos
Dermatite Atópica/metabolismo , Queratinócitos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Antígenos de Dermatophagoides/efeitos adversos , Moléculas de Adesão Celular/metabolismo , Proliferação de Células , Dermatite Atópica/etiologia , Dermatite Atópica/imunologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Queratinócitos/imunologia , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Interferente Pequeno/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Membro 14 de Receptores do Fator de Necrose Tumoral/deficiência , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Transdução de Sinais , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/deficiência , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
12.
J Mol Endocrinol ; 60(3): 171-183, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29330151

RESUMO

Interleukin (IL)-22 has recently been suggested as an anti-inflammatory cytokine that could protect the islet cells from inflammation- and glucose-induced toxicity. We have previously shown that the tumor necrosis factor family member, LIGHT, can impair human islet function at least partly via pro-apoptotic effects. Herein, we aimed to investigate the protective role of IL-22 on human islets exposed to the combination of hyperglycemia and LIGHT. First, we found upregulation of LIGHT receptors (LTßR and HVEM) in engrafted human islets exposed to hyperglycemia (>11 mM) for 17 days post transplantation by using a double islet transplantation mouse model as well as in human islets cultured with high glucose (HG) (20 mM glucose) + LIGHT in vitro, and this latter effect was attenuated by IL-22. The effect of HG + LIGHT impairing glucose-stimulated insulin secretion was reversed by IL-22. The harmful effect of HG + LIGHT on human islet function seemed to involve enhanced endoplasmic reticulum stress evidenced by upregulation of p-IRE1α and BiP, elevated secretion of pro-inflammatory cytokines (IL-6, IL-8, IP-10 and MCP-1) and the pro-coagulant mediator tissue factor (TF) release and apoptosis in human islets, whereas all these effects were at least partly reversed by IL-22. Our findings suggest that IL-22 could counteract the harmful effects of LIGHT/hyperglycemia on human islet cells and potentially support the strong protective effect of IL-22 on impaired islet function and survival.


Assuntos
Apoptose/efeitos dos fármacos , Hiperglicemia/patologia , Interleucinas/farmacologia , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/fisiopatologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/toxicidade , Adulto , Idoso , Animais , Citocinas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Transplante das Ilhotas Pancreáticas , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Receptores de Interleucina/metabolismo , Receptores do LH/genética , Receptores do LH/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
13.
Med Sci Monit ; 24: 387-396, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29352109

RESUMO

BACKGROUND Acute rejection is a common predisposing cause of allograft dysfunction in kidney transplantation. Recently, the B and T lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/lymphotoxin (LIGHT)/CD160 pathway was found to be potentially involved in the regulation of T cell activation. This could mean that this pathway is involved in graft rejection in kidney transplantation; the present study aimed to explore this possibility. MATERIAL AND METHODS The expression of BTLA, HVEM, LIGHT and CD160 on peripheral CD4+, CD8+ and CD19+ lymphocytes were analyzed by flow cytometry in recipients with biopsy-proven acute rejection (BPAR) or stable allograft function, as well as in healthy volunteers. Moreover, we performed HE staining and immunohistochemical staining to assess the expression of BTLA and HVEM in kidney samples from recipients with BPAR and patients who underwent the surgery of radical nephrectomy. RESULTS We observed the significantly lower expression of BTLA on CD4+ T cells in recipients from the BPAR group than in recipients from the stable group. The expression of BTLA on CD8+ T cells among recipients both from the BPAR and stable group was statistically increased than that in the healthy volunteers. A significant difference in the expression of CD160 in the stable group was found when compared with the BPAR group or control group. Moreover, there was no significance in the expression of HVEM, LIGHT or CD160 on other subtypes of T cells between the 3 groups or in the expression of BTLA on CD4+ T cells between the BPAR and control group. CONCLUSIONS The findings indicate that the BTLA/HVEM pathway does be involved in pathogenesis of acute rejection following kidney transplantation, as well as the induction of transplant tolerance. This pathway may therefore be a useful target for therapy against acute rejection after kidney transplantation.


Assuntos
Rejeição de Enxerto/imunologia , Receptores Imunológicos/metabolismo , Receptores Imunológicos/fisiologia , Adulto , Antígenos CD/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biópsia , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/metabolismo , Rejeição de Enxerto/metabolismo , Humanos , Rim/metabolismo , Transplante de Rim/efeitos adversos , Ativação Linfocitária/fisiologia , Linfotoxina-alfa/metabolismo , Masculino , Pessoa de Meia-Idade , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/fisiologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplantados
14.
J Cell Physiol ; 233(2): 1095-1103, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28422285

RESUMO

The cytokine LT-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT) is a member of the tumor necrosis factor (TNF) superfamily. It is expressed primarily on activated T lymphocytes, and detectable on monocytes, granulocytes, and immune dendritic cells. It mainly plays a role in immune regulation including T cell activation and dendritic cell maturation. We recently reported its role as an inducer in embryonic stem cell differentiation, but its role in regulation of adult stem cell has not been defined. In the present study, we examined the expression of LIGHT receptor in Lin- c-kit+ Sca-1+ hematopoietic stem/progenitor cells (HSC/HPCs). We found that HSC express HVEM, a LIGHT receptor, on its surface. We further identified the role of LIGHT in promoting myeloid differentiation of HSCs driven by granulocyte-monocyte colony stimulating factor (GM-CSF). Further studies showed that LIGHT enhances both GM-CSF and GM-CSF receptor (GM-CSFR) expression in HSCs. LIGHT stimulation increases PU.1 expression in HSC/HPCs. In vivo administration of LIGHT increases the colony-forming unit-granulocyte/monocyte (CFU-GM) colony formation and plasma GM-CSF level. Altogether, the data suggest LIGHT promote myeloid differentiation of HSC/HPCs.


Assuntos
Diferenciação Celular , Linhagem da Célula , Células-Tronco Hematopoéticas/metabolismo , Células Mieloides/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Antígenos Ly/metabolismo , Proliferação de Células , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Fenótipo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transativadores/metabolismo
15.
Exp Lung Res ; 43(8): 301-310, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29140131

RESUMO

BACKGROUND: The tumor necrosis factor superfamily member LIGHT (the official gene symbol approved by NCBI Gene Database), an inflammatory factor secreted by T cells after allergen exposure, recently discovered to play crucial roles in asthmatic airway remodeling. However, it is unclear whether LIGHT could be controlled by inhaled corticosteroids, a key component of asthma management. This study was to investigate the effects and potential mechanisms of inhaled budesonide on the expressions of LIGHT and its receptors (LTßR and HVEM) of lung tissues in ovalbumin-sensitized mice. MATERIALS AND METHODS: Thirty-three BALB/c mice were randomly divided into the control, asthma model, and budesonide treatment groups (11 in each group). Mice were sensitized and challenged by OVA to develop mouse model of chronic asthma, and treated with aerosolized budesonide before OVA challenge. Bronchoalveolar lavage fluid (BALF) and lungs were obtained after the final OVA challenge. Protein and mRNA Levels of LIGHT, LTßR, and HVEM in the lungs were investigated by immunohistochemistry, image analysis, and real-time PCR. Expressions of IL-6 and IFN-γ in BALF were measured by ELISA. RESULTS: Inhaled budesonide significantly reduced protein and mRNA levels of lung LIGHT, LTßR, and HVEM in asthmatic mice. Correspondingly, the number of eosinophils and neutrophils and IL-6 levels in BALF after budesonide treatment were found to be decreased, whereas the IFN-γ levels in BALF were increased. Moreover, the expressions of LIGHT and HVEM mRNA showed positive correlation with IL-6 levels in the treatment group. CONCLUSIONS: Inhaled budesonide can down-regulate the expressions of LIGHT, LTßR, and HVEM in the lungs of asthmatic mice, and LIGHT/LTßR/HVEM interactions may be a potentially key target for asthma treatment.


Assuntos
Corticosteroides/farmacologia , Asma/tratamento farmacológico , Fatores de Necrose Tumoral/metabolismo , Corticosteroides/administração & dosagem , Animais , Asma/metabolismo , Budesonida/administração & dosagem , Budesonida/farmacologia , Receptor beta de Linfotoxina/efeitos dos fármacos , Receptor beta de Linfotoxina/metabolismo , Camundongos , Membro 14 de Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/efeitos dos fármacos , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
16.
J Biol Chem ; 292(51): 21060-21070, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29061848

RESUMO

The human cytomegalovirus opening reading frame UL144 is an ortholog of the TNF receptor superfamily member, herpesvirus entry mediator (HVEM; TNFRSF14). HVEM binds the TNF ligands, LIGHT and LTa; the immunoglobulin inhibitory receptor, B and T lymphocyte attenuator (BTLA); and the natural killer cell-activating receptor CD160. However, UL144 selectively binds BTLA, avoiding activation of inflammatory signaling initiated by CD160 in natural killer cells. BTLA and CD160 cross-compete for binding HVEM, but the structural basis for the ligand selectivity by UL144 and how it acts as an anti-inflammatory agonist remains unclear. Here, we modeled the UL144 structure and characterized its binding with BTLA. The UL144 structure was predicted to closely mimic the surface of HVEM, and we also found that both HVEM and UL144 bind a common epitope of BTLA, whether engaged in trans or in cis, that is shared with a BTLA antibody agonist. On the basis of the UL144 selectivity, we engineered a BTLA-selective HVEM protein to understand the basis for ligand selectivity and BTLA agonism to develop novel anti-inflammatory agonists. This HVEM mutein did not bind CD160 or TNF ligands but did bind BTLA with 10-fold stronger affinity than wild-type HVEM and retained potent inhibitory activity that reduced T-cell receptor, B-cell receptor, and interferon signaling in B cells. In conclusion, using a viral immune evasion strategy that shows broad immune-ablating activity, we have identified a novel anti-inflammatory BTLA-selective agonist.


Assuntos
Linfócitos B/metabolismo , Células Matadoras Naturais/metabolismo , Glicoproteínas de Membrana/metabolismo , Modelos Moleculares , Receptores Imunológicos/agonistas , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Linfócitos T/metabolismo , Proteínas Virais/metabolismo , Substituição de Aminoácidos , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Antígenos CD/química , Antígenos CD/genética , Antígenos CD/metabolismo , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Sítios de Ligação , Linhagem Celular Tumoral , Desenho de Drogas , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Células HEK293 , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Cinética , Ligantes , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Mutação , Conformação Proteica , Engenharia de Proteínas , Domínios e Motivos de Interação entre Proteínas , Receptores Imunológicos/química , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/química , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteínas Virais/química , Proteínas Virais/genética
17.
J Immunol ; 199(8): 2968-2975, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28864473

RESUMO

Mucosal immunity to reinfection with a highly virulent virus requires the accumulation and persistence of memory CD8 T cells at the site of primary infection. These cells may derive from memory precursor effector cells (MPECs), which are distinct from short-lived effector cells that provide acute protection but are often destined to die. Using respiratory virus infection, we show that herpes virus entry mediator (HVEM; TNFRSF14), a member of the TNF receptor superfamily, provides key signals for MPEC persistence. HVEM-deficient CD8 T cells expanded normally but were skewed away from MPECs with resultant poor development of circulating and lung-resident memory cells. HVEM was selectively expressed on MPECs whereas MPECs deficient in HVEM failed to survive in adoptive transfer recipients. As a consequence, HVEM-deficient recipients failed to afford protection against respiratory reinfection with influenza virus. HVEM therefore represents a critical signal for MPECs and development of protective mucosal CD8 T cell memory.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Células Precursoras de Linfócitos T/imunologia , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/virologia , Autorrenovação Celular , Células Cultivadas , Modelos Animais de Doenças , Feminino , Imunidade nas Mucosas , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Precursoras de Linfócitos T/virologia , Membro 14 de Receptores do Fator de Necrose Tumoral/genética
18.
J Gen Virol ; 98(9): 2351-2361, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28809154

RESUMO

Herpes simplex virus type 2 (HSV-2) increases human immunodeficiency virus type 1 (HIV-1) acquisition and transmission via unclear mechanisms. Herpesvirus entry mediator (HVEM), an HSV-2 entry receptor, is highly expressed on HIV-1 target cells (CD4+ T cells) and may be incorporated into HIV-1 virions, while HSV-2 glycoproteins can be present on the infected cell surface. Since HVEM-gD interaction together with gB/gH/gL is essential for HSV-2 entry, HVEM-bearing HIV-1 (HIV-1/HVEM) may enter HSV-2-infected cells through such interactions. To test this hypothesis, we first confirmed the presence of HVEM on HIV-1 virions and glycoproteins on the HSV-2-infected cell surface. Additional studies showed that HIV-1/HVEM bound to the HSV-2-infected cell surface in an HSV-2 infection-time-dependent manner via HVEM-gD interaction. HIV-1/HVEM entry of HSV-2-infected cells was dependent on HVEM-gD interaction and the presence of gB/gH/gL, and was inhibited by azidothymidine. Furthermore, peripheral blood mononuclear cell-derived HIV-1 infected HSV-2-infected primary foreskin epithelial cells and the infection was inhibited by anti-HVEM/gD antibodies. Together, our results indicate that HIV-1 produced from CD4+ T cells bears HSV-2 receptor HVEM and can bind to and enter HSV-2-infected epithelial cells depending on HVEM-gD interaction and the presence of gB/gH/gL. Our findings provide a potential new mechanism underlying HSV-2 infection-enhanced HIV-1 mucosal transmission and may shed light on HIV-1 prevention.


Assuntos
Células Epiteliais/metabolismo , Infecções por HIV/metabolismo , HIV-1/fisiologia , Herpes Simples/metabolismo , Herpesvirus Humano 2/fisiologia , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Receptores Virais/metabolismo , Proteínas do Envelope Viral/metabolismo , Animais , Linfócitos T CD4-Positivos/virologia , Células CHO , Cricetulus , Células Epiteliais/virologia , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Herpes Simples/genética , Herpesvirus Humano 2/genética , Humanos , Camundongos , Ligação Proteica , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Receptores Virais/genética , Proteínas do Envelope Viral/genética , Internalização do Vírus
19.
J Gen Virol ; 98(7): 1815-1822, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28671524

RESUMO

Herpesvirus entry mediator A (HVEM), nectin-1 and nectin-2 are cellular receptors of glycoprotein D (gD) of herpes simplex virus type-2 (HSV-2). It has been shown that soluble forms of HSV gD receptors have the antiviral potential in cultured cells and transgenic mice. Here, to compare antiviral potential of soluble forms of HVEM, nectin-1 and nectin-2 against HSV-2 infections in vivo, transgenic mice expressing fusion proteins consisting of the entire ectodomain of HVEM, nectin-1 or nectin-2 and the Fc portion of human IgG (HVEMIg, nectin-1Ig and nectin-2Ig, respectively) were intraperitoneally infected with HSV-2. In the infection with 3 MLD50 (50 % mouse lethal dose), effective resistance was not observed in transgenic mice expressing nectin-2Ig. In a transgenic mouse line with high expression of nectin-1Ig, significant protection from the infection with 30 and 300 MLD50 was observed (survival rate of 100 and 71 %, respectively). On the other hand, transgenic mice expressing HVEMIg showed a complete resistance to the lethal infection even with 300 MLD50 (survival rate of 100 %). These results demonstrated that HVEMIg could exert effective antiviral activities against HSV-2 infections in vivo as compared with other soluble forms of HSV gD receptors.


Assuntos
Moléculas de Adesão Celular/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 2/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/imunologia , Receptores Virais/imunologia , Proteínas do Envelope Viral/metabolismo , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Herpes Simples/genética , Herpes Simples/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nectinas , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo , Proteínas do Envelope Viral/genética
20.
Ann Surg Oncol ; 24(13): 4042-4050, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28612127

RESUMO

BACKGROUND: Immune checkpoint blockades are currently actively investigated in invasive breast cancers. Given the complexity of immune regulation, multiple inhibitory molecules within the immune checkpoint framework would be involved in tumor immune escape. Evaluation of the components within the framework is a prerequisite for not only identification of additional treatment targets and optimization of immunotherapeutic strategies but also understanding the prognostic value of these molecules. METHODS AND RESULTS: We examined a recently described component, herpes virus entry mediator (HVEM), in a large cohort of invasive breast cancers using immunohistochemistry, and evaluated its clinical relevance. HVEM expression was associated with aggressive tumor features, namely high grade (p < 0.001), high pT (p = 0.001) and pN stage (p = 0.008), and was most prevalently found in human epidermal growth factor receptor 2-overexpressed subtype (67%). Interestingly, a negative association with programmed death-ligand 1 (p = 0.021) has been observed. The prognostic impact of HVEM depended on the level of tumor-infiltrating lymphocytes (TILs), with the worst outcome occurring in patients with low TIL, HVEM-positive tumors. CONCLUSION: HVEM plays significant oncogenic roles in breast carcinogenesis, and may also be a tumor-specific target.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Receptor ErbB-2/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
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