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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 56-62, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027253

RESUMO

OBJECTIVE: To investigate the expression and significance of B and T lymphocyte weakening factor (BTLA) in patients with chronic myelomonocytic leukemia (CMML). METHODS: Real-time PCR was used to detect the expression of BTLA and its ligand HVEM mRNA in 11 patients with chronic myelomonocytic leukemia and 11 normal donors. Flow cytometry was used to detect expression of BTLA and its HVEM on the cell surface of peripheral blood T lymphocytes and γδ T cells. RESULTS: The median values of BTLA and its ligand HVEM mRNA expression in peripheral blood of patients with CMML were 0.009% and 559.4%, respectively, which were significantly lower than those of normal controls (0.053% and 1031%)(P<0.001). The expression level of BTLA and HVEM on cell surface of peripheral lymphocytes was not significantly different from that in normal controls (P=0.3031 and 0.2576), however, the proportion of peripheral blood T lymphocytes in patients with CMML (median: 37.73%) was significantly lower than that in controls (median 69.23%)(P=0.0005). The expression of BTLA on the surface of γδ T cells in peripheral blood of patients with CMML (median: 23.26%) was significantly lower than that of the controls (median: 52.64%) (P<0.05), and there was no significant abnormality in HVEM expression (P=0.2791). CONCLUSION: The expression of BTLA and its ligand HVEM, the proportion of T lymphocytes and the expression of BTLA on the surface of γδ T cells in patients with CMML are reduced. The effects of these abnormalities on T cell function and prognosis and efficacy of patients need to be further observed.


Assuntos
Leucemia Mielomonocítica Crônica , Receptores Imunológicos/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Humanos , Leucemia Mielomonocítica Crônica/genética , Ligantes , Linfócitos T
2.
EBioMedicine ; 43: 159-170, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30987862

RESUMO

BACKGROUND: Dysregulation of immune checkpoint molecules leads to immune evasion in human tumours but has become a viable target for tumour therapy. Here, we examined expression of Herpes virus entry mediator (HVEM), an immune checkpoint molecule, in human glioblastoma (GBM) to assess its potential as a molecular target for treatment. METHODS: Molecular and clinical data from publicly available genomic databases containing WHO grade II-IV human glioma cases (n = 1866) were analyzed. Immunohistochemistry was applied to assess HVEM protein levels in primary tumour sections. Statistical analysis was performed using Matlab and R language. FINDINGS: HVEM was found to be elevated in aggressive gliomas, particularly in the mesenchymal and isocitrate dehydrogenase (IDH) wild-type molecular subtypes of GBM. HVEMhigh tumours tended to be associated with amplification of EGFR and loss of PTEN, while HVEMlow tumours harbored mutations in IDH1 (93%). HVEM exhibited potential as a prognostic marker based on Cox regression and nomogram models. HVEM displayed intra-tumour heterogeneity and was more highly expressed in peri-necrotic and microvascular regions. Gene ontology and pathway analysis revealed enrichment of HVEM in multiple immune regulatory processes, such as suppression of T cell mediated immunity in GBM. Finally, in cell lineage analysis, HVEM was found to be tightly associated with several infiltrating immune and stromal cell types which localized to the tumour microenvironment. INTERPRETATION: Our data highlights the importance of HVEM in the development of GBM and as a potential molecular target in combination with current immune checkpoint blockades for treatment of GBM.


Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/mortalidade , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Progressão da Doença , Heterogeneidade Genética , Variação Genética , Genômica/métodos , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Imunomodulação/genética , Estimativa de Kaplan-Meier , Gradação de Tumores , Prognóstico , Células Estromais/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
3.
mSphere ; 4(2)2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30918059

RESUMO

Sex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050-1059, 2012, https://doi.org/10.1002/bies.201200099). Herpes simplex virus 1 (HSV-1) causes chronic inflammatory disease in the cornea, an immune-privileged tissue, resulting in irreversible damage and blindness in affected individuals (A. Rowe, A. St Leger, S. Jeon, D. K. Dhaliwal, et al., Prog Retin Eye Res 32:88-101, 2013, https://doi.org/10.1016/j.preteyeres.2012.08.002). Our research focuses on the role of herpesvirus entry mediator (HVEM) as an immune regulator during ocular HSV-1 infection. Mice lacking HVEM (HVEM knockout [KO] mice) exhibit lower levels of immune cell infiltrates and less severe ocular disease in the cornea than wild-type (WT) mice. As sex differences contribute to pathogenesis in many inflammatory diseases, we tested whether sex acts as a biological variable in the immune response to HSV-1 infection and herpes stromal keratitis (HSK) pathogenesis. Adult male and female WT and HVEM KO mice were inoculated with HSV-1 via corneal scarification and monitored daily for disease course. Viral titers were determined, and immune cell infiltrates were collected and analyzed. Our results indicated no significant differences in viral titers in tear film or affected tissues, in immune cell infiltration, or in clinical symptoms between males and females of either genotype. These results suggest that sex is not a significant biological variable in this experimental model and that male and female mice of the C57BL/6 background can be used similarly in studies of ocular HSV-1 pathogenesis.IMPORTANCE Sex hormones have come to be considered an important factor for the development of certain diseases only recently and as such should continue to be considered a biological variable. Ocular HSV-1, and the resulting HSK, is the leading cause of infectious blindness worldwide. We compared levels of ocular HSV-1 infection and pathogenesis in the two sexes and found no significance differences between male and female WT mice or HVEM KO mice.


Assuntos
Olho/virologia , Herpesvirus Humano 1/imunologia , Ceratite Herpética/imunologia , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Fatores Sexuais , Animais , Olho/patologia , Feminino , Técnicas de Inativação de Genes , Inflamação , Ceratite Herpética/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Carga Viral
4.
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
5.
J Virol ; 92(24)2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30282707

RESUMO

Recently, we reported that the herpesvirus entry mediator (HVEM; also called TNFRSF14 or CD270) is upregulated by the latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1) and that the absence of HVEM affects latency reactivation but not primary infection in ocularly infected mice. gD has been shown to bind to HVEM. LIGHT (TNFSF14), CD160, and BTLA (B- and T-lymphocyte attenuator) also interact with HVEM and can interfere with HSV gD binding. It was not known if LIGHT, CD160, or BTLA affected the level of latency reactivation in the trigeminal ganglia (TG) of latently infected mice. To address this issue, we ocularly infected LIGHT-/-, CD160-/-, and BTLA-/- mice with LAT(+) and LAT(-) viruses, using similarly infected wild-type (WT) and HVEM-/- mice as controls. The amount of latency, as determined by the levels of gB DNA in the TG of the LIGHT-/-, CD160-/-, and BTLA-/- mice infected with either LAT(+) or LAT(-) viruses, was lower than that in WT mice infected with LAT(+) virus and was similar in WT mice infected with LAT(-) virus. The levels of LAT RNA in HVEM-/-, LIGHT-/-, CD160-/-, and BTLA-/- mice infected with LAT(+) virus were similar and were lower than the levels of LAT RNA in WT mice. However, LIGHT-/-, CD160-/-, and BTLA-/- mice, independent of the presence of LAT, had levels of reactivation similar to those of WT mice infected with LAT(+) virus. Faster reactivation correlated with the upregulation of HVEM transcript. The LIGHT-/-, CD160-/-, and BTLA-/- mice had higher levels of HVEM expression, and this, along with the absence of BTLA, LIGHT, or CD160, may contribute to faster reactivation, while the absence of each molecule, independent of LAT, may have contributed to lower latency. This study suggests that, in the absence of competition with gD for binding to HVEM, LAT RNA is important for WT levels of latency but not for WT levels of reactivation.IMPORTANCE The effects of BTLA, LIGHT, and CD160 on latency reactivation are not known. We show here that in BTLA, LIGHT, or CD160 null mice, latency is reduced; however, HVEM expression is upregulated compared to that of WT mice, and this upregulation is associated with higher reactivation that is independent of LAT but dependent on gD expression. Thus, one of the mechanisms by which BTLA, LIGHT, and CD160 null mice enhance reactivation appears to be the increased expression of HVEM in the presence of gD. Thus, our results suggest that blockade of HVEM-LIGHT-BTLA-CD160 contributes to reduced HSV-1 latency and reactivation.


Assuntos
Antígenos CD/genética , Oftalmopatias/virologia , Herpes Simples/genética , Herpesvirus Humano 1/fisiologia , MicroRNAs/genética , Receptores Imunológicos/genética , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Animais , Oftalmopatias/genética , Feminino , Proteínas Ligadas por GPI/genética , Técnicas de Inativação de Genes , Herpes Simples/virologia , Cinética , Masculino , Camundongos , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Proteínas do Envelope Viral/genética , Internalização do Vírus , Latência Viral , Replicação Viral
6.
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
7.
Virchows Arch ; 473(4): 453-462, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29858685

RESUMO

Primary cutaneous follicle center lymphoma (PCFCL) is an indolent variant of follicular lymphoma (FL) with limited information available on the genetic background of the disease. The genetic hallmark of nodal FL, the t(14;18) translocation, affecting the BCL2 gene, is rare in PCFCL. Loss of 1p36, the most common secondary chromosomal abnormality in nodal FL, has been recently reported in 16.7% of PCFCL cases. In order to further characterize PCFCL, 21 cases were analyzed using interphase fluorescence in situ hybridization with BCL2 break apart and 1p36/1q25 dual color probes. Sanger sequencing was used to investigate TNFRSF14 and EZH2 mutations and immunohistochemistry to assess BCL2, EZH2 protein expressions.1p36 deletion occurred in 22% (5/21), BCL2 gene break in 10% (2/20) of the PCFCL cases. Mutations of the candidate tumor suppressor gene of the 1p36 region, TNFRSF14 mutations were detected in 4/17 (23.5%) cases with 2 cases presenting with concurrent 1p36 deletion. EZH2 hotspot mutations at Y641, A682, and A692 were not found. High EZH2 protein expression associated with a BCL2 negative phenotype was observed in 43% (9/21) of the cases. BCL2 gene break or 1p36 deletion did not impact the prognosis; however, they showed association with advanced stages at diagnosis (p = 0.016) and a tendency with shorter event free survival (p = 0.052).In conclusion, 1p36 deletion co-occurs with acquired TNFRSF14 mutations, suggesting a role of this tumor suppressor gene in the development of a subgroup of PCFCL. High EZH2 protein expression associated with BCL2 negative phenotype is common and might represent an ideal therapeutic target.


Assuntos
Biomarcadores Tumorais/genética , Deleção Cromossômica , Cromossomos Humanos Par 1 , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma Folicular/genética , Mutação , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Análise Mutacional de DNA , Intervalo Livre de Doença , Proteína Potenciadora do Homólogo 2 de Zeste/análise , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Folicular/química , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Estudos Retrospectivos , Neoplasias Cutâneas/química , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
8.
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
9.
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
10.
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 Fármacos , 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
11.
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
12.
Autoimmunity ; 50(7): 403-408, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28925718

RESUMO

Two pairwise genetic interactions (B cell lymphocyte kinase (BLK) rs13277113,B cell scaffold protein with ankyrin repeats 1 (BANK1) rs3733197and BLK rs13277113 membrane metalloendopeptidase like 1 (MMEL1)/ tumor necrosis factor receptor superfamily member 14 (TNFRSF14) rs3890745) have been demonstrated in determining susceptibility to rheumatoid arthritis (RA) without replication, thus this study was performed to examine whether abovementioned genetic polymorphisms were associated with RA and further tests were performed to see whether aforementioned genetic interactions existed in RA among Chinese population. A total of 328 patients with RA and 449 healthy control subjects were included in the current study. The polymorphisms were genotyped using the ligase detection reaction-polymerase chain reaction (LDR-PCR) technology. The association of RA with each polymorphism was analyzed by multivariate logistic regression model. Interaction analysis was done by multiple methods. Significant difference in genotype distribution of BLK rs13277113 polymorphism between RA patients and healthy controls was found (p = 1.01 × 10-2). The major allele A of BLK rs13277113 polymorphism was significantly increased in RA patients compared with controls (OR = 1.36, 95% CI = 1.08-1.71, p = 9.27 × 10-3). Significant association of RA with the major allele A of BLK rs13277113 polymorphism under dominant model was also detected (OR = 2.74, 95% CI = 1.42-5.29, p = 2.73 × 10-3). However, we did not find significant association between neither BANK1 rs3733197 polymorphism nor MMEL1/TNFRSF14 rs3890745 polymorphism and RA. Non-significant evidence was found for neither additive nor multiplicative interaction for these two pairwise genetic polymorphisms (BLK rs13277113-BANK1 rs3733197; BLK rs13277113-MMEL1/TNFRSF14 rs3890745). Significant association of RA with G allele of BANK1 rs3733197 polymorphism was only found among individuals carrying A/A genotype of the BLK rs13277113 polymorphism (OR = 1.49, 95% CI = 1.01-2.18, p = .04). In summary, our results indicated that the BLK rs13277113 polymorphism was involved in the genetic background of RA in Chinese population and the association of BANK1 rs3733197 polymorphism with RA was dependent on the genotype of BLK rs13277113 polymorphism, highlighting B-cell response implicated in the pathogenesis of RA.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Artrite Reumatoide/genética , Epistasia Genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Neprilisina/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Quinases da Família src/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
13.
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
14.
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
15.
Blood ; 130(3): 323-327, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28533310

RESUMO

Pediatric-type follicular lymphoma (PTFL) is a B-cell lymphoma with distinctive clinicopathological features. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (TNFRSF14, IRF8), immune escape (TNFRSF14), and anti-apoptosis (MAP2K1) have been described. In an attempt to shed more light onto the pathogenesis of PTFL, an integrative analysis of these mutations was undertaken in a large cohort of 43 cases previously characterized by targeted next-generation sequencing and copy number array. Mutations in MAP2K1 were found in 49% (20/41) of the cases, second in frequency to TNFRSF14 alterations (22/41; 54%), and all together were present in 81% of the cases. Immunohistochemical analysis of the MAP2K1 downstream target extracellular signal-regulated kinase demonstrated its phosphorylation in the evaluable cases and revealed a good correlation with the allelic frequency of the MAP2K1 mutation. The IRF8 p.K66R mutation was present in 15% (6/39) of the cases and was concomitant with TNFRSF14 mutations in 4 cases. This hot spot seems to be highly characteristic for PTFL. In conclusion, TNFRSF14 and MAP2K1 mutations are the most frequent genetic alterations found in PTFL and occur independently in most cases, suggesting that both mutations might play an important role in PTFL lymphomagenesis.


Assuntos
Regulação Neoplásica da Expressão Gênica , Fatores Reguladores de Interferon/genética , Linfoma Folicular/genética , MAP Quinase Quinase 1/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Alelos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Criança , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fatores Reguladores de Interferon/metabolismo , Linfoma Folicular/diagnóstico , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , MAP Quinase Quinase 1/metabolismo , Masculino , Análise em Microsséries , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mutação , Fosforilação , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo
16.
Res Vet Sci ; 112: 185-191, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28500993

RESUMO

Equine lentivirus receptor-1 (ELR1) has been characterized as the specific functional receptor that mediates equine infectious anemia virus (EIAV) entrance to horse macrophages. This receptor is tumor necrosis factor receptor superfamily member 14 (TNFRSF14). The aim of this study was to investigate the occurrence of allelic variants in the coding sequence of equine TNFRSF14 gene by screening for single-nucleotide polymorphisms (SNPs) in different equine populations. Forty seven horse samples were randomly selected from a reservoir of EIAV-seropositive and seronegative samples collected from different outbreaks and regions of Argentina. DNA samples were scanned via PCR and direct sequencing of exon 3 and exon 5 of TNFRSF14 gene. A total of 21 SNPs were identified, of which 11 were located in coding sequences. Within exon 5, four SNPs caused nonsynonymous substitutions, while two other SNPs caused synonymous substitutions in crucial residues (Ser112 and Thr114) implicated in the interaction with EIAV. Despite some of exon 5 variants occurred exclusively in EIAV-positive or EIAV-negative horses, critical residues for the function of the mature protein were conserved, accounting for selective pressures in favor of preserving the specific function of TNFRSF members and the host immune response. To our knowledge, this is the first report of the existence of allelic variations involving some crucial amino acid residues in horse ELR1. Further, it could be an initial step to test the possible functional relevance and relationship of these variants with EIAV infection and disease progression as well as to develop preventive strategies.


Assuntos
Anemia Infecciosa Equina/virologia , Regulação da Expressão Gênica/imunologia , Vírus da Anemia Infecciosa Equina , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Sequência de Aminoácidos , Animais , Argentina/epidemiologia , Anemia Infecciosa Equina/epidemiologia , Cavalos/genética , Reação em Cadeia da Polimerase , Membro 14 de Receptores do Fator de Necrose Tumoral/genética
17.
PLoS Pathog ; 13(4): e1006352, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28423057

RESUMO

Herpes simplex virus (HSV) entry into the cells requires glycoproteins gD, gH/gL and gB, activated in a cascade fashion by conformational modifications induced by cognate receptors and intermolecular signaling. The receptors are nectin1 and HVEM (Herpes virus entry mediator) for gD, and αvß6 or αvß8 integrin for gH. In earlier work, insertion of a single chain antibody (scFv) to the cancer receptor HER2 (human epidermal growth factor receptor 2) in gD, or in gH, resulted in HSVs specifically retargeted to the HER2-positive cancer cells, hence in highly specific non-attenuated oncolytic agents. Here, the scFv to HER2 was inserted in gB (gBHER2). The insertion re-targeted the virus tropism to the HER2-positive cancer cells. This was unexpected since gB is known to be a fusogenic glycoprotein, not a tropism determinant. The gB-retargeted recombinant offered the possibility to investigate how HER2 mediated entry. In contrast to wt-gB, the activation of the chimeric gBHER2 did not require the activation of the gD and of gH/gL by their respective receptors. Furthermore, a soluble form of HER2 could replace the membrane-bound HER2 in mediating virus entry, hinting that HER2 acted by inducing conformational changes to the chimeric gB. This study shows that (i) gB can be modified and become the major determinant of HSV tropism; (ii) the chimeric gBHER2 bypasses the requirement for receptor-mediated activation of other essential entry glycoproteins.


Assuntos
Glicoproteínas/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Receptor ErbB-2/metabolismo , Anticorpos de Cadeia Única/genética , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Glicoproteínas/genética , Herpes Simples/patologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Humanos , Integrinas/genética , Integrinas/metabolismo , Ligantes , Macrolídeos/farmacologia , Nectinas , Receptor ErbB-2/genética , 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 Recombinantes de Fusão , Anticorpos de Cadeia Única/metabolismo , Tropismo Viral , Internalização do Vírus
18.
Histopathology ; 70(2): 174-184, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27297871

RESUMO

AIMS: To investigate the spectrum of mutations in 20 genes involved in B-cell receptor and/or Toll-like receptor signalling resulting in activation of nuclear factor-κB (NF-κB) in 20 nodal marginal zone lymphomas (NMZLs), 20 follicular lymphomas (FLs), and 11 cases of B-cell lymphoma, unclassifiable (BCL-u). METHODS AND RESULTS: Nodal marginal zone lymphomas were diagnosed according to strict criteria, including the expression of at least one putative marginal zone marker (MNDA and/or IRTA1). Cases that showed features of NMZL but did not fulfil all criteria were included as BCL-u. All FLs were required to have a BCL2 rearrangement. Mutations were found in: nine NMZLs, with recurrent mutations in TNFAIP3 and CD79B; 12 FLs, with recurrent mutations in TNFRSF14, TNFAIP3, and CARD11; and five cases of BCL-u, with recurrent mutations in TNFRSF14. TNFRSF14 mutations were present in FL and BCL-u, but not in any of the NMZLs. In the BCL-u group, TNFRSF14 mutations clustered with a FL immunophenotype. CONCLUSIONS: These results suggest that TNFRSF14 mutations point towards a diagnosis of FL, and can be used in the sometimes difficult distinction between NMZL and FL, but to apply this in diagnostics would require confirmation in an independent cohort. In addition, the presence or absence of specific mutations in pathways converging on NF-κB could be important for decisions regarding targeted treatment.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Zona Marginal Tipo Células B/genética , NF-kappa B/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Idoso , Diagnóstico Diferencial , Intervalo Livre de Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Mutação , Transdução de Sinais/genética
19.
J Neurovirol ; 23(3): 376-384, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27981441

RESUMO

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus linked to a range of acute and chronic neurological disorders affecting distinct regions of the brain. Unusually, HSV-1 entry into cells requires the interaction of viral proteins glycoprotein D (gD) and glycoprotein B (gB) with distinct cellular receptor proteins. Several different gD and gB receptors have been identified, including TNFRSF14/HVEM and PVRL1/nectin 1 as gD receptors and PILRA, MAG, and MYH9 as gB receptors. We investigated the expression of these receptor molecules in different areas of the adult and developing human brain using online transcriptome databases. Whereas all HSV-1 receptors showed distinct expression patterns in different brain areas, the Allan Brain Atlas (ABA) reported increased expression of both gD and gB receptors in the hippocampus. Specifically, for PVRL1, TNFRFS14, and MYH9, the differential z scores for hippocampal expression, a measure of relative levels of increased expression, rose to 2.9, 2.9, and 2.5, respectively, comparable to the z score for the archetypical hippocampus-enriched mineralocorticoid receptor (NR3C2, z = 3.1). These data were confirmed at the Human Brain Transcriptome (HBT) database, but HBT data indicate that MAG expression is also enriched in hippocampus. The HBT database allowed the developmental pattern of expression to be investigated; we report that all HSV1 receptors markedly increase in expression levels between gestation and the postnatal/adult periods. These results suggest that differential receptor expression levels of several HSV-1 gD and gB receptors in the adult hippocampus are likely to underlie the susceptibility of this brain region to HSV-1 infection.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Viral da Expressão Gênica , Herpesvirus Humano 1/genética , Interações Hospedeiro-Patógeno/genética , Receptores Virais/genética , Receptores Virais/metabolismo , Adulto , Idoso de 80 Anos ou mais , Encéfalo/virologia , Mapeamento Encefálico , Pré-Escolar , Bases de Dados Genéticas , Feminino , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/metabolismo , Humanos , Lactente , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas Motores Moleculares/genética , Proteínas Motores Moleculares/metabolismo , Glicoproteína Associada a Mielina/genética , Glicoproteína Associada a Mielina/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Nectinas/genética , Nectinas/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Transcriptoma , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
20.
Nat Commun ; 7: 13696, 2016 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-27982078

RESUMO

Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support TH2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG1 and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology.


Assuntos
Asma/induzido quimicamente , Asma/metabolismo , Mastócitos/fisiologia , Receptores de IgE/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Remodelação das Vias Aéreas , Animais , Anticorpos , Antígenos de Dermatophagoides/imunologia , Antígenos de Dermatophagoides/toxicidade , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Imunoglobulina E , Imunoglobulina G , Camundongos , Camundongos Knockout , Ovalbumina/imunologia , Ovalbumina/toxicidade , Receptores de IgE/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética
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