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1.
Bull Cancer ; 107(3): 346-351, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31955867

RESUMO

Desmoid tumors (TDs) are derived from mesenchymal stem cells and their pathogenesis is strongly linked to the Wingless/Wnt cascade where the deregulation of ß-catenin plays a major role. A mutation of the CTNNB1 encoding ß-catenin is found in the majority of sporadic TD cases and constitutional mutations of APC have been described in heritable forms in patients with familial adenomatous polyposis (FAP). Estrogens could also play a role in pathogenesis and this is the basis for the use of hormone therapy. Other signaling pathways have been involved in the development of TDs such as Notch, Hedgehog, JAK/STAT, PI3 Kinase/AKT and mTOR. Metalloproteases are expressed in TDs and play a role in invasiveness. TGF-ß, as a growth factor, stimulates the transcriptional activity of ß-catenin. Future studies will need to focus on better describing and understanding the immune environment of TDs. One of the major difficulties for the experimental study of TDs is the virtual absence of a preclinical model, either in vitro or in vivo. This is partly why the interactions between the different signaling pathways presented here and their consequences for the development of TDs are still poorly understood.


Assuntos
Fibromatose Agressiva/etiologia , Transdução de Sinais/fisiologia , Polipose Adenomatosa do Colo/genética , Carcinogênese , Elafina/metabolismo , Estrogênios/metabolismo , Fibromatose Agressiva/genética , Fibromatose Agressiva/metabolismo , Fibromatose Agressiva/patologia , Genes APC , Proteínas Hedgehog/metabolismo , Humanos , Janus Quinases/metabolismo , Linfotoxina-alfa/metabolismo , Metaloproteases/metabolismo , Mutação , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Notch/metabolismo , Fatores de Transcrição STAT/metabolismo , Serina-Treonina Quinases TOR/metabolismo , beta Catenina/genética
2.
Cells ; 8(6)2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167379

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). T helper (Th) 17 lymphocytes play a role in the pathogenesis of MS. Indeed, Th17 cells are abundant in the cerebrospinal fluid and peripheral blood of MS patients and promote pathogenesis in the mouse model of MS. To gain insight into the function of Th17 cells in MS, we tested whether Th17 cells polarized from naïve CD4 T cells of healthy donors and MS patients display different features. To this end, we analysed several parameters that typify the Th17 profile during the differentiation process of naïve CD4 T cells obtained from relapsing-remitting (RR)-MS patients (n = 31) and healthy donors (HD) (n = 28). Analysis of an array of cytokines produced by Th17 cells revealed that expression of interleukin (IL)-21, tumour necrosis factor (TNF)-ß, IL-2 and IL-1R1 is significantly increased in Th17 cells derived from MS patients compared to healthy donor-derived cells. Interestingly, IL-1R1 expression is also increased in Th17 cells circulating in the blood of MS patients compared to healthy donors. Since IL-2, IL-21, TNF-ß, and IL-1R1 play a crucial role in the activation of immune cells, our data indicate that high expression of these molecules in Th17 cells from MS patients could be related to their high inflammatory status.


Assuntos
Esclerose Múltipla Recidivante-Remitente/patologia , Células Th17/metabolismo , Adulto , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interleucinas/metabolismo , Linfotoxina-alfa/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Células Th17/citologia
3.
Int J Cancer ; 145(5): 1358-1370, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30785217

RESUMO

Tumor angiogenesis is critical for tumor progression as the new blood vessels supply nutrients and facilitate metastasis. Previous studies indicate tumor associated lymphocytes, including B cells and T cells, contribute to tumor angiogenesis and tumor progression. The present study aims to identify the function of Lymphotoxin-α (LT-α), which is secreted by the activated lymphocytes, in the tumor angiogenesis of head and neck squamous cell carcinoma (HNSCC). The coculture system between HNSCC cell line Cal27 and primary lymphocytes revealed that tumor cells promoted the LT-α secretion in the cocultured lymphocytes. In vitro data further demonstrated that LT-α promoted the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) by enhancing the PFKFB3-mediated glycolytic flux. Genetic and pharmacological inhibition of PFKFB3 suppressed the enhanced proliferation and migration of HUVECs. We further identified that LT-α induced PFKFB3 expression was dependent on the TNFR/NF-κB signaling pathway. In addition, we proved that PFKFB3 blockade decreased the density of CD31 positive blood vessels in HNSCC xenografts. Finally, the results from the human HNSCC tissue array revealed that the expression of LT-α in HNSCC samples positively correlated with microvessel density, lymphocytes infiltration and endothelial PFKFB3 expression. In conclusion, infiltrated lymphocyte secreted LT-α enhances the glycolysis of ECs in a PFKFB3-dependent manner through the classical NF-κB pathway and promotes the proliferation and migration of ECs, which may contribute to the aberrant angiogenesis in HNSCCs. Our study suggests that PFKFB3 blockade is a promising therapeutic approach for HNSCCs by targeting tumor angiogenesis.


Assuntos
Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Linfotoxina-alfa/metabolismo , Fosfofrutoquinase-2/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/irrigação sanguínea , Animais , Linfócitos B/metabolismo , Ciclo Celular/fisiologia , Técnicas de Cocultura , Feminino , Glicólise , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral , Linfotoxina-alfa/biossíntese , Linfotoxina-alfa/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Linfócitos T/metabolismo , Regulação para Cima
4.
Brain Behav Immun ; 76: 268-274, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30496778

RESUMO

Negative symptoms are common in individuals at clinical high-risk (CHR) for psychosis and are associated with worse functional outcomes. Inflammation may be one mechanism underlying negative symptoms. Inflammatory markers are altered in individuals at CHR and are associated with negative symptoms in patients with schizophrenia. We thus hypothesized that baseline inflammatory markers would predict the development of negative symptoms in individuals at CHR for psychosis. Thirty seven individuals from the North American Prodromal Longitudinal Study who met CHR criteria were included in the study. Inflammatory cytokines, including interferon (IFN)-λ, Interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1RA), IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF) were measured at baseline. Negative symptoms as measured by the Scale of Prodromal Symptoms, were measured at baseline and six and twelve months. Associations between inflammatory markers and the trajectory of negative symptoms (slope) over the first year of follow-up, were assessed using linear regression models controlling for age, sex, race and depressive symptom severity (as assessed by the Calgary Depression Scale for Schizophrenia). Baseline TNF (beta = 0.361, p = 0.007) and IL-6 (beta = -0.306, p = 0.026) predicted negative symptoms slopes, along with depressive symptom severity at baseline (beta = -0.596, p = 0.000). These findings demonstrate that inflammatory cytokines may underlie the development of negative symptoms in some individuals at CHR for psychosis. TNF predicted the development of negative symptoms independent of baseline depression. Given the heterogeneity of the CHR population, the comorbidity of negative symptoms and depression in this population, and the particular challenges in treating negative symptoms, immune markers could represent potential biomarkers that underlie the development of negative symptoms, representing a potential treatment target.


Assuntos
Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/imunologia , Adolescente , Afeto/fisiologia , Biomarcadores/sangue , Comorbidade , Citocinas/análise , Citocinas/sangue , Depressão/diagnóstico , Progressão da Doença , Feminino , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Interleucina-6/sangue , Interleucina-6/metabolismo , Estudos Longitudinais , Linfotoxina-alfa/metabolismo , Masculino , Sintomas Prodrômicos , Escalas de Graduação Psiquiátrica , Fatores de Risco , Esquizofrenia/diagnóstico , Esquizofrenia/imunologia , Esquizofrenia/fisiopatologia , Adulto Jovem
5.
Hum Cell ; 32(2): 185-192, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30560508

RESUMO

We previously reported the diversity of structure and integration sites of human T-cell leukemia virus type 1 (HTLV-1) provirus among different MT-2 cell lines. This raised the question as to whether cell phenotypes also differed among MT-2 cell lines. The influence of two different MT-2 cell lines (MT-2J and MT-2B) on the growth of the promonocytic leukemia cell line, U937, was investigated. Protein levels and mRNA expression of cytokines were also investigated. In addition, Western blot analysis of HTLV-1 regulatory proteins, Tax and HBZ, was also performed. Culture supernatant from MT-2B, but not MT-2J, cells showed marked suppressive effects on U937 cell growth. MT-2B showed high tumor necrosis factor (TNF)-α, TNF-ß, and interferon (IFN)-γ both in protein levels of the culture supernatant and mRNA levels of the cells. Analysis using recombinant cytokines indicated that the suppressive effects of MT-2B were due, at least in part, to high levels of TNF-ß and its synergic effects with IFN-γ in the culture supernatant. Protein levels of HTLV-1 Tax and HBZ were higher in MT-2B than those in MT-2J cells. These molecules have been reported to affect the cytokine production of HTLV-1 infected cells; therefore, the difference in these molecules may have accounted for the differences in cytokine production between MT-2J and MT-2B cells. Furthermore, because MT-2 cells showed a large variation of integrated HTLV-1 proviruses as well as cell phenotypes, it is important to exercise caution in the assessment and interpretation of experimental data from MT-2 cells.


Assuntos
Citocinas/metabolismo , Leucemia/metabolismo , Leucemia/patologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular , Expressão Gênica , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Interferon gama/metabolismo , Leucemia/genética , Linfotoxina-alfa/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas dos Retroviridae/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células U937
6.
Mol Carcinog ; 58(3): 411-425, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30488488

RESUMO

Head and neck squamous cell carcinomas (HNSCC) preferentially spread to regional cervical tissues and lymph nodes. Here, we hypothesized that lymphotoxin-ß (LTß), receptor LTßR, and NF-κB-inducing kinase (NIK), promote the aberrant activation of alternative NF-κB2/RELB pathway and genes, that enhance migration and invasion of HNSCC. Genomic and expression alterations of the alternative NF-kB pathway were examined in 279 HNSCC tumors from The Cancer Genome Atlas (TCGA) and a panel of HNSCC lines. LTßR is amplified or overexpressed in HNSCC of the larynx or oral cavity, while LTß, NIK, and RELB are overexpressed in cancers arising within lymphoid oropharyngeal and tonsillar sites. Similarly, subsets of HNSCC lines displayed overexpression of LTßR, NIK, and RELB proteins. Recombinant LTß, and siRNA depletion of endogenous LTßR and NIK, modulated expression of LTßR, NIK, and nuclear translocation of NF-κB2(p52)/RELB as well as functional NF-κB promoter reporter activity. Treatment with a NIK inhibitor (1,3[2H,4H]-Iso-Quinoline Dione) reduced the protein expression of NIK and NF-κB2(p52)/RELB, and blocked LTß induced nuclear translocation of RELB. NIK and RELB siRNA knockdown or NIK inhibitor slowed HNSCC migration or invation in vitro. LTß-induces expression of migration and metastasis related genes, including hepatocyte growth/scatter factor receptor MET. Knockdown of NIK or MET similarly inhibited the migration of HNSCC cell lines. This may help explain why HNSCC preferentially migrate to local lymph nodes, where LTß is expressed. Our findings show that LTß/LTßR promotes activation of the alternative NIK-NF-κB2/RELB pathway to enhance MET-mediated cell migration in HNSCC, which could be potential therapeutic targets in HNSCC.


Assuntos
Carcinoma de Células Escamosas/secundário , Neoplasias de Cabeça e Pescoço/patologia , Receptor beta de Linfotoxina/metabolismo , Linfotoxina-alfa/metabolismo , Linfotoxina-beta/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição RelB/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Receptor beta de Linfotoxina/genética , Linfotoxina-alfa/genética , Linfotoxina-beta/genética , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Fator de Transcrição RelB/genética , Células Tumorais Cultivadas
7.
Innate Immun ; 24(7): 439-447, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30176756

RESUMO

Genetic factors play a role in periodontitis. Here we examined whether the risk haplotype of MHC class III region BAT1-NFKBIL1-LTA and lymphotoxin-α polymorphisms associate with salivary biomarkers of periodontal disease. A total of 455 individuals with detailed clinical and radiographic periodontal health data were included in the study. A 610 K genotyping chip and a Sequenom platform were used in genotyping analyses. Phospholipid transfer protein activity, concentrations of lymphotoxin-α, IL-8 and myeloperoxidase, and a cumulative risk score (combining Porphyromonas gingivalis, IL-1ß and matrix metalloproteinase-8) were examined in saliva samples. Elevated IL-8 and myeloperoxidase concentrations and cumulative risk scores associated with advanced tooth loss, deepened periodontal pockets and signs of periodontal inflammation. In multiple logistic regression models adjusted for periodontal parameters and risk factors, myeloperoxidase concentration (odds ratio (OR); 1.37, P = 0.007) associated with increased odds for having the risk haplotype and lymphotoxin-α concentration with its genetic variants rs2857708, rs2009658 and rs2844482. In conclusion, salivary levels of IL-8, myeloperoxidase and cumulative risk scores associate with periodontal inflammation and tissue destruction, while those of myeloperoxidase and lymphotoxin-α associate with genetic factors as well.


Assuntos
Infecções por Bacteroidaceae/genética , Genótipo , Periodontite/genética , Porphyromonas gingivalis/fisiologia , Glândulas Salivares/fisiologia , Idoso , RNA Helicases DEAD-box/genética , Feminino , Predisposição Genética para Doença , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Interleucina-8/metabolismo , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Masculino , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Periodontite/diagnóstico , Polimorfismo de Nucleotídeo Único , Risco , Saliva/metabolismo
8.
J Virol ; 92(14)2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29743364

RESUMO

B cell-derived lymphotoxin (LT) is required for the development of follicular dendritic cell clusters for the formation of primary and secondary lymphoid follicles, but the role of T cell-derived LT in antibody response has not been well demonstrated. We observed that lymphotoxin ß-receptor (LTßR) signaling is essential for optimal humoral immune response and protection against an acute herpes simplex virus 1 (HSV-1) infection. Blocking the LTßR pathway caused poor maintenance of germinal center B (GC-B) cells and follicular helper T (Tfh) cells. Using bone marrow chimeric mice and adoptive transplantation, we determined that T cell-derived LT played an indispensable role in the humoral immune response to HSV-1. Upregulation of gamma interferon by the LTßR-Ig blockade impairs the sustainability of Tfh-like cells, leading to an impaired humoral immune response. Our findings have identified a novel role of T cell-derived LT in the humoral immune response against HSV-1 infection.IMPORTANCE Immunocompromised people are susceptible to HSV-1 infection and lethal recurrence, which could be inhibited by anti-HSV-1 humoral immune response in the host. This study sought to explore the role of T cell-derived LT in the anti-HSV-1 humoral immune response using LT-LTßR signaling-deficient mice and the LTßR-Ig blockade. The data indicate that the T cell-derived LT may play an essential role in sustaining Tfh-like cells and ensure Tfh-like cells' migration into primary or secondary follicles for further maturation. This study provides insights for vaccine development against infectious diseases.


Assuntos
Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Imunidade Humoral/imunologia , Receptor beta de Linfotoxina/fisiologia , Linfotoxina-alfa/metabolismo , Linfócitos T/metabolismo , Animais , Centro Germinativo , Herpes Simples/metabolismo , Herpes Simples/virologia , Camundongos , Camundongos Knockout , Transdução de Sinais
9.
J Pathol Clin Res ; 4(2): 124-134, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29665320

RESUMO

Cytokine production is essential for follicular dendritic cell (FDC) maintenance and organization of germinal centres. In follicular lymphoma, FDCs are often disarrayed and may lack antigens indicative of terminal differentiation. We investigated the in situ distribution of cells producing lymphotoxin-beta (LTB), lymphotoxin-alpha (LTA), and tumour necrosis factor-alpha (TNFA) transcripts in human reactive lymph nodes and in follicular lymphomas with follicular or diffuse growth pattern. LTB was the cytokine most abundantly produced in germinal centres. LTB was present in nearly 90% of germinal centre cells whereas LTA and TNFA were detected in 30 and 50%, respectively. Moreover, the amount of LTB expressed in reactive germinal centre cells was 80-fold higher than that of LTA and 20-fold higher than that of TNFA. LTB-positive cells were more numerous in the germinal centre dark zone, whereas expression of the FDC proteins CD21, CD23, VCAM, and CXCL13 was more intense in the light zone. Tumour cells of follicular lymphomas produced less LTB than reactive germinal centre cells. The results of the in situ study were confirmed by RT-PCR; LTB was significantly more abundant in reactive lymph nodes than in follicular lymphoma, with the lowest values detected in predominantly diffuse follicular lymphoma. In neoplastic follicles, low production of LTB by tumour B cells was associated with weaker expression of CD21+/CD23+ by FDCs. Our findings detail for the first time the distribution of LTA-, LTB-, and TNFA-producing cells in human reactive germinal centres and in follicular lymphoma. They suggest the possibility that impaired tumour-cell LTB production may represent a determinant of FDC phenotype loss and for defective follicular organization in follicular lymphoma.


Assuntos
Linfoma Folicular/metabolismo , Linfotoxina-beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Células Dendríticas Foliculares/metabolismo , Feminino , Centro Germinativo/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Linfonodos/metabolismo , Linfoma Folicular/patologia , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Linfotoxina-beta/genética , Masculino , Pessoa de Meia-Idade , Fenótipo
10.
Nat Commun ; 9(1): 1262, 2018 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-29593265

RESUMO

Medullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4+ thymocyte crosstalk regulates the thymus homing of SHPS-1+ conventional DCs (cDC), plasmacytoid DCs (pDC) and macrophages. This homing process is controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently, Ltα-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-κB subunits and increased thymic recruitment of cDCs, pDCs and macrophages. This enhanced migration depends mainly on the chemokine receptor CCR2, and increases thymic clonal deletion. Altogether, this study identifies a fine-tuning mechanism of T cell repertoire selection and paves the way for therapeutic interventions to treat autoimmune disorders.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Deleção Clonal , Linfotoxina-alfa/metabolismo , Timo/imunologia , Animais , Antígenos/imunologia , Células da Medula Óssea/imunologia , Quimiocinas/imunologia , Técnicas de Cocultura , Células Dendríticas/imunologia , Feminino , Deleção de Genes , Tolerância Imunológica , Ligantes , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal , NF-kappa B/metabolismo , Receptores CCR2/metabolismo , Linfócitos T/imunologia , Timócitos/imunologia
11.
PLoS One ; 13(1): e0189396, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29300739

RESUMO

The kidney is the most frequently transplanted solid organ. Recruitment of inflammatory cells, ranging from diffuse to nodular accumulations with defined microarchitecture, is a hallmark of acute and chronic renal allograft injury. Lymphotoxins (LTs) mediate the communication of lymphocytes and stromal cells and play a pivotal role in chronic inflammation and formation of lymphoid tissue. The aim of this study was to assess the expression of members of the LT system in acute rejection (AR) and chronic renal allograft injury such as transplant glomerulopathy (TG) and interstitial fibrosis/tubular atrophy (IFTA). We investigated differentially regulated components in transcriptomes of human renal allograft biopsies. By microarray analysis, we found the upregulation of LTß, LIGHT, HVEM and TNF receptors 1 and 2 in AR and IFTA in human renal allograft biopsies. In addition, there was clear evidence for the activation of the NFκB pathway, most likely a consequence of LTß receptor stimulation. In human renal allograft biopsies with transplant glomerulopathy (TG) two distinct transcriptional patterns of LT activation were revealed. By quantitative RT-PCR robust upregulation of LTα, LTß and LIGHT was shown in biopsies with borderline lesions and AR. Immunohistochemistry revealed expression of LTß in tubular epithelial cells and inflammatory infiltrates in transplant biopsies with AR and IFTA. Finally, activation of LT signaling was reproduced in a murine model of renal transplantation with AR. In summary, our results indicate a potential role of the LT system in acute renal allograft rejection and chronic transplant injury. Activation of the LT system in allograft rejection in rodents indicates a species independent mechanism. The functional role of the LT system in acute renal allograft rejection and chronic injury remains to be determined.


Assuntos
Transplante de Rim , Rim/metabolismo , Linfotoxina-alfa/metabolismo , Animais , Biópsia , DNA Complementar/genética , Rejeição de Enxerto , Humanos , Glomérulos Renais/patologia , Transplante de Rim/efeitos adversos , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Homólogo
12.
Oral Dis ; 24(5): 761-771, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29297959

RESUMO

OBJECTIVE: Interleukin-14α-transgenic (IL-14αTG) mice develop an autoimmune exocrinopathy with characteristics similar to Sjögren's syndrome, including sialadenitis and hyposalivation. The P2Y2 receptor (P2Y2 R) for extracellular ATP and UTP is upregulated during salivary gland inflammation (i.e., sialadenitis) where it regulates numerous inflammatory responses. This study investigated the role of P2Y2 Rs in autoimmune sialadenitis in the IL-14αTG mouse model of Sjögren's syndrome. MATERIALS AND METHODS: IL-14αTG mice were bred with P2Y2 R-/- mice to generate IL-14αTG × P2Y2 R-/- mice. P2Y2 R expression, lymphocytic focus scores, B- and T-cell accumulation, and lymphotoxin-α expression were evaluated in the submandibular glands (SMG) along with carbachol-stimulated saliva secretion in IL-14αTG, IL-14αTG × P2Y2 R-/- , and C57BL/6 control mice at 9 and 12 months of age. RESULTS: Genetic ablation of P2Y2 Rs in IL-14αTG mice significantly reduced B and T lymphocyte infiltration of SMGs. However, reduced sialadenitis did not restore saliva secretion in IL-14αTG × P2Y2 R-/- mice. Decreased sialadenitis in IL-14αTG × P2Y2 R-/- mice correlated with decreased lymphotoxin-α levels, a critical proinflammatory cytokine associated with autoimmune pathology in IL-14αTG mice. CONCLUSIONS: The results of this study suggest that P2Y2 Rs contribute to the development of salivary gland inflammation in IL-14αTG mice and may also contribute to autoimmune sialadenitis in humans.


Assuntos
Linfócitos B , Receptores Purinérgicos P2Y2/genética , Receptores Purinérgicos P2Y2/metabolismo , Sialadenite/genética , Linfócitos T , Animais , Cálcio/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais , Feminino , Expressão Gênica , Interleucinas/genética , Contagem de Linfócitos , Linfotoxina-alfa/metabolismo , Camundongos , Camundongos Knockout , Saliva/metabolismo , Síndrome de Sjogren/genética , Glândula Submandibular/metabolismo , Glândula Submandibular/patologia , Uridina Trifosfato/farmacologia
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.
Stem Cells ; 36(3): 337-348, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29226476

RESUMO

Cornea is a clear outermost layer of the eye which enables transmission of light onto the retina. The transparent corneal epithelium is regenerated by limbal stem cells (LSCs), whose loss/dysfunction results in LSCs deficiency (LSCD). Ex vivo expansion of autologous LSCs obtained from patient's healthy eye followed by transplantation onto the LSCs damaged/deficient eye, has provided a successful treatment for unilateral LSCD. However, this is not applicable to patient with total bilateral LSCD, where LSCs are lost/damaged from both eyes. We investigated the potential of human induced pluripotent stem cell (hiPSC) to differentiate into corneal epithelial-like cells as a source of autologous stem cell treatment for patients with total bilateral LSCD. Our study showed that combined addition of bone morphogenetic protein 4 (BMP4), all trans-retinoic acid and epidermal growth factor for the first 9 days of differentiation followed by cell-replating on collagen-IV-coated surfaces with a corneal-specific-epithelial cell media for an additional 11 days, resulted in step wise differentiation of human embryonic stem cells (hESC) to corneal epithelial progenitors and mature corneal epithelial-like cells. We observed differences in the ability of hiPSC lines to undergo differentiation to corneal epithelial-like cells which were dependent on the level of endogenous BMP signaling and could be restored via the activation of this signaling pathway by a specific transforming growth factor ß inhibitor (SB431542). Together our data reveal a differential ability of hiPSC lines to generate corneal epithelial cells which is underlined by the activity of endogenous BMP signaling pathway. Stem Cells 2018;36:337-348.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células 3T3 , Animais , Benzamidas/farmacologia , Proteínas Morfogenéticas Ósseas/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Dioxóis/farmacologia , Epitélio Anterior/citologia , Epitélio Anterior/metabolismo , Imunofluorescência , Humanos , Linfotoxina-alfa/antagonistas & inibidores , Linfotoxina-alfa/metabolismo , Camundongos , Reação em Cadeia da Polimerase em Tempo Real
15.
Retina ; 38(1): 187-191, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28106707

RESUMO

PURPOSE: To report the results of an association study between single-nucleotide polymorphisms of the p53 and LTA genes and the risk of proliferative vitreoretinopathy (PVR)/retinal detachment (RD) in a Mexican cohort. METHODS: A total of 380 unrelated subjects were studied, including 98 patients with primary rhegmatogenous RD without PVR, 82 patients with PVR after RD surgery, and 200 healthy, ethnically matched subjects. Genotyping of single-nucleotide polymorphisms rs1042522 (p53 gene) and rs2229094 (LTA gene) was performed by direct nucleotide sequencing. Allele frequencies, genotype frequencies, and Hardy-Weinberg equilibrium were assessed with HaploView software. RESULTS: No significant differences in the allelic distributions of the previously identified risk C allele for LTA rs2229094 were observed between RD subjects and controls (odds ratio [95% confidence interval] = 0.8 [0.5-1.2]; P = 0.3). Conversely, the C allele for rs1042522 in p53 was positively associated with an increased risk for RD (odds ratio [95% confidence interval] = 1.4 [1.01-1.9]; P = 0.04). No significant differences were observed when the subgroup of 82 RD + PVR subjects was compared with the subgroup of 98 patients with RD. CONCLUSION: The C allele for rs1042522 in p53 was genetically associated with a higher risk for RD but not for PVR in this cohort. This is the first association study attempting replication of PVR-associated risk alleles in a nonwhite population.


Assuntos
DNA/genética , Predisposição Genética para Doença , Linfotoxina-alfa/genética , Polimorfismo de Nucleotídeo Único , Descolamento Retiniano/genética , Proteína Supressora de Tumor p53/genética , Vitreorretinopatia Proliferativa/genética , Idoso , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Incidência , Linfotoxina-alfa/metabolismo , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/epidemiologia , Fatores de Risco , Proteína Supressora de Tumor p53/metabolismo , Vitreorretinopatia Proliferativa/diagnóstico , Vitreorretinopatia Proliferativa/epidemiologia , Corpo Vítreo/patologia
16.
J Immunol Res ; 2017: 9891348, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29201923

RESUMO

Chronic inflammation is associated with an increased number of leukocytes in the spleen, which are then redirected to the site of inflammation. However, it remains unknown how leukocyte recruitment is regulated. Herein, chronic inflammation was induced by intraperitoneal injection of pristane into mice. Leukocytes in the spleen or in the peritoneal cavity were quantified by flow cytometry. We found that the loss of IL-6 decreased macrophage recruitment to the spleen and the peritoneal cavity during pristane-induced inflammation. The loss of TNFα delayed the recruitment of neutrophils and macrophages to the spleen and inhibited the recruitment of neutrophils, macrophages, B cells, and T cells. The recruitment of neutrophils and macrophages into the spleen or peritoneal cavity was largely inhibited in the absence of LTα. The loss of TNFα receptor 1/2 resulted in reduced recruitment of neutrophils, macrophages, and dendritic cells into the spleen, but only neutrophil recruitment was inhibited in the peritoneal cavity. Similarly, a lack of B cells significantly impeded the recruitment of neutrophils, macrophages, and dendritic cells to the spleen. However, only macrophage recruitment was inhibited in the absence of T cells in the spleen. These data provide insight into the development of chronic inflammation induced by noninfectious substances.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Cavidade Peritoneal/patologia , Baço/imunologia , Animais , Movimento Celular , Separação Celular , Citometria de Fluxo , Inflamação/induzido quimicamente , Interleucina-6/genética , Interleucina-6/metabolismo , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Camundongos , Camundongos Knockout , Terpenos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
Cell Rep ; 21(9): 2500-2514, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29186687

RESUMO

T and B cell compartmentalization is a hallmark of secondary lymphoid organs and is maintained by chemokine-expressing stromal cells. How this stromal cell network initially develops and differentiates into two distinct subsets is poorly known, especially for the splenic white pulp (WP). Here, we show that perivascular fibroblast precursors are triggered by LTα1ß2 signals to expand, express CCL19/21, and then differentiate into two functionally distinct fibroblast subsets responsible for B and T cell clustering and WP compartmentalization. Failure to express or sense CCL19 leads to impaired T zone development, while lack of B cells or LTα1ß2 leads to an earlier and stronger impairment in WP development. We therefore propose that WP development proceeds in multiple steps, with LTα1ß2+ B cells acting as major inducer cells driving the expansion and gradual differentiation of perivascular fibroblasts into T and B zone organizer cells.


Assuntos
Diferenciação Celular/fisiologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Animais , Quimiocina CCL19/metabolismo , Quimiocina CXCL13/metabolismo , Quimiocinas CXC/metabolismo , Linfotoxina-alfa/metabolismo , Camundongos , Baço/citologia , Baço/metabolismo
18.
Am J Pathol ; 187(11): 2602-2615, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28837798

RESUMO

Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-κB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classic and alternative NF-κB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-κB activation. Moreover, in vitro data demonstrated LTs accelerated the proliferation of human dermal LECs (HdLECs) through activation of NF-κB. In addition, lipopolysaccharide (LPS) up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered LPS-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidence from the LM rat models demonstrated LTα and LPS enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTα and lymphotoxin ß receptor may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs.


Assuntos
Proliferação de Células , Endotélio Linfático/metabolismo , Linfangiogênese , Vasos Linfáticos/metabolismo , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Linfático/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Linfangiogênese/efeitos dos fármacos , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/patologia , Linfotoxina-alfa/metabolismo , Regulação para Cima
19.
Curr Protoc Immunol ; 117: 6.10.1-6.10.7, 2017 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-28369681

RESUMO

The tumor necrosis factor (TNF) superfamily of cytokines plays critical roles in all aspects of the immune response. TNF and the lymphotoxins (LT), LTα and LTß, are particularly important as major effector cytokines and mediators or lymphoid organ development. One of the classical methods for the measurement of TNF and LTα activity is by demonstrating their ability to lyse certain target cells. A detailed protocol for the measurement of this activity using a highly sensitive indicator cell line is presented. More recently, ELISA assays have been developed to measure the protein concentration of these cytokines in any type of biologic fluid. © 2017 by John Wiley & Sons, Inc.


Assuntos
Linfotoxina-alfa/metabolismo , Fatores de Necrose Tumoral/metabolismo , Animais , Morte Celular , Linhagem Celular , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Fibroblastos/metabolismo , Humanos
20.
EMBO Mol Med ; 9(6): 835-851, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28455312

RESUMO

Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed de novo thymopoiesis and a prolonged period of T-cell immunodeficiency. Understanding the mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantation (BMT). Here, we show that RANK ligand (RANKL) is upregulated in CD4+ thymocytes and lymphoid tissue inducer (LTi) cells during the early phase of thymic regeneration. Importantly, whereas RANKL neutralization alters TEC recovery after irradiation, ex vivo RANKL administration during BMT boosts the regeneration of TEC subsets including thymic epithelial progenitor-enriched cells, thymus homing of lymphoid progenitors, and de novo thymopoiesis. RANKL increases specifically in LTi cells, lymphotoxin α, which is critical for thymic regeneration. RANKL treatment, dependent on lymphotoxin α, is beneficial upon BMT in young and aged individuals. This study thus indicates that RANKL may be clinically useful to improve T-cell function recovery after BMT by controlling multiple facets of thymic regeneration.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Células Epiteliais/fisiologia , Ligante RANK/administração & dosagem , Radioterapia/efeitos adversos , Regeneração , Timo/fisiologia , Animais , Linfotoxina-alfa/metabolismo , Camundongos , Resultado do Tratamento
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