Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 117
Filtrar
1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1416-1423, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607292

RESUMO

OBJECTIVE: To investigate the IL-7R gene mutation and clinical features of adult patients with acute lymphoblastic leukemia (ALL). METHODS: One hundred sixty-four cases of newly treated adults with ALL from May 2016 to December 2018 were selected. Targeted and specific next-generation sequencing technology was used to detected a total of 16 types of Ph-like ALL mutations, which include IL-7R mutation, and the cilinical features, rate, types and sites of IL-7R were analyzed. RESULTS: IL-7R mutation was determined in 10 cases of 164 adult patients with ALL and the total mutation frequency was 13 times (6.1%). Out of 10 cases 5 cases were male (50%), 5 cases were female (50%). 6 cases of B-ALL ( 60% ) and 4 cases of T-ALL (40%). The mutation site of all cases was located at exon 6, among which 6 cases had replacement mutations, 3 cases had deletion mutations and 4 cases had insertion mutations. In addition, 1 triple and 1 double mutation of IL-7R were found. Besides, six mutation sites were newly identified, including: c.720_724del, c.723_726del, c.721_722insAGTG, c.727_728insTAACGGCCCCCTGCT, c.727_728insATGCAGGGAGCGAA and c.728_729insAAGTGTCA. CONCLUSION: Six novel mutation sites and a poor manifestation of IL-7R have been explored in this research. Thus more samples are required to study the effects of IL-7R mutation on ALL treatment.


Assuntos
Subunidade alfa de Receptor de Interleucina-7/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Feminino , Humanos , Masculino , Mutação , Transdução de Sinais
2.
Nat Commun ; 10(1): 4575, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594933

RESUMO

IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases.


Assuntos
Autoimunidade/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Interleucina-7/imunologia , Monócitos/imunologia , Espondilite Anquilosante/genética , Alelos , RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Voluntários Saudáveis , Humanos , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Lipopolissacarídeos/imunologia , Monócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de RNA , Análise de Célula Única , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Regulação para Cima/imunologia
3.
Acta Derm Venereol ; 99(6): 579-586, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30809683

RESUMO

Prurigo nodularis is a highly pruritic and hyperplastic chronic dermatosis with unknown pathogenesis. Many pruritogenic mediators, including nerve growth factor, interleukin (IL)-31, thymic stromal lymphopoietin, and endothelin-1, are implicated in chronic itch and inflammation. This study investigated the mRNA levels and immunoreactivity of the nerve growth factor, IL-31, thymic stromal lymphopoietin, and endothelin axes in both lesional and perilesional skin in prurigo nodularis by using quantitative real-time PCR and immunohistochemistry studies. The nerve growth factor high-affinity receptor tyrosine kinase receptor A was upregulated while the low affinity receptor p75 neurotrophin receptor was downregulated in prurigo nodularis lesions. Downregulated expression of IL-31/IL-31 receptor A and endothelin-3/endothelin receptor B and upregulation of thymic stromal lymphopoietin receptor were found in prurigo nodularis lesions. Aberrant expression of nerve growth factor, IL-31, thymic stromal lymphopoietin and endothelin axes was found in prurigo nodularis lesions, especially in the epidermis, indicating the importance of keratinocytes in prurigo nodularis pathogenesis.


Assuntos
Epiderme/metabolismo , Queratinócitos/metabolismo , Prurigo/genética , Prurigo/metabolismo , Adulto , Citocinas/genética , Citocinas/metabolismo , Regulação para Baixo , Endotelina-3/genética , Endotelina-3/metabolismo , Feminino , Expressão Gênica , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prurigo/complicações , RNA Mensageiro/metabolismo , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Regulação para Cima
5.
Methods Mol Biol ; 1899: 43-54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30649764

RESUMO

Regulatory T cells (Tregs) are a population of lymphocytes that exerts suppressive effects upon the immune system. In human peripheral blood, the major population of T lymphocytes with suppressive capacity are defined by expression of the T cell co-receptor CD4 and the interleukin-2 receptor α-chain (CD25), combined with minimal expression of the interleukin-7 receptor α subunit (CD127). We begin by outlining the method for isolating peripheral blood mononuclear cells (PBMCs) from human blood by centrifugation of whole blood overlayed on a hydrophilic polysaccharide, with an additional erythrocyte lysis step. The protocol that follows utilizes Fluorescence-Activated Cell Sorting (FACS) for the isolation of this CD4+CD25+CD127lo population of regulatory T cells, with high yield and purity, from immunostained PBMCs. Prior to FACS isolation, this protocol exploits magnetic immunoselection for pre-enrichment of CD25+ PBMC, which reduces the duration of the subsequent FACS isolation.


Assuntos
Separação Celular/métodos , Citometria de Fluxo/métodos , Linfócitos T Reguladores/citologia , Antígenos CD4/genética , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Leucócitos Mononucleares/citologia , Contagem de Linfócitos , Linfócitos T Reguladores/imunologia
6.
J Mol Neurosci ; 67(1): 38-47, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30443838

RESUMO

Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease that affects myelin fibers within the central nervous system resulting in neurological impairment. Although the etiology of MS is not fully understood, environmental and genetic factors are thought to play important roles. IL7R gene polymorphisms which are associated with several autoimmune diseases have also been implicated as a genetic factor for MS following genome-wide association studies. To further examine this association, we investigated the association between MS and IL7R gene - 449 (A/G), - 504 (T/C), and - 1085 (G/T) promoter polymorphisms in Turkish population. Three hundred sixty-four MS patients and 191 healthy controls were involved in this study. Three polymorphic regions in the promoter of IL7R were identified and these regions were amplified by appropriate primers. The PCR products were digested by PstI enzyme for - 504 (T/C) SNP and HphI enzyme for - 1085 (G/T) and - 449 (A/G) SNPs and genotyping was done based on digested PCR product sizes. Genotype distributions and allele frequencies of - 449 polymorphism did not show any significant association with MS directly (p = 0.120 and p = 0.490, respectively). But the genotypes of IL7R - 449 GA for AOMS and AA for EOMS were a risk factor in according to age of onset (p = 0.002, OR = 4.021, 95% CI = 1.642-9.845). Furthermore, IL7R - 449 A allele was found to be a risk factor for EOMS (p = 0.011, OR = 1.3, 95% CI = 1.107-1.527). Significant association was seen between IL7R - 504 TC heterozygote genotype and MS (p = 0.02, OR = 1.702, 95% CI = 1.169-2.478). The IL7R - 1085 (G/T) polymorphism did not show association with MS; however, the haplotype of ACG may be susceptibility to MS and RRMS (p = 0.035, OR = 1.349, 95% CI = 1.020-1.785, and p = 0.041, OR = 1.368, 95% CI = 1.012-1.850, respectively) and the haplotypes of ACG, ATT, and GTG demonstrate a protective effect in EOMS (p = 0.008, OR = 0.326, 95% CI = 0.136-0.782, p = 0.012 and p = 0.012, OR = 0.462, 95% CI = 0.249-0.859, respectively). RRMS frequency in the Turkish population was decreased and SPMS frequency was strongly increased based on comparison to results from other populations. Furthermore, male patients had an increased frequency of SPMS significantly (p = 0.033, OR = 1.667, 95% CI = 1.036-2.682). In conclusion, this is the first study to show a significant association between the IL7R promoter polymorphisms and the age of onset of MS.


Assuntos
Subunidade alfa de Receptor de Interleucina-7/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idade de Início , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Regiões Promotoras Genéticas , Turquia
7.
Mol Carcinog ; 58(3): 358-365, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30362635

RESUMO

Interleukin-7(IL-7) can regulate proliferation and apoptosis of cell and also regulate tumor lymphangiogenesis, but whether it regulating autophagy of tumor cells is not well known. We study the relationship between IL-7 and some autophagy-related markers, Beclin 1 and mammalian target of rapamycin (mTOR) and the mechanism of IL-7 in regulating autophagy of human lung cancer cells. We detected expression of Beclin 1 and mTOR in lung cancer cells and their impact on the prognosis of lung cancer patients. Using Western blot and Reverse Transcription PCR, we found that IL-7 activates PI3 K/Akt/mTOR signaling pathway by downregulated the expression of Beclin 1 in lung cancer cell lines. In addition, the expressions of Beclin 1 and mTOR were well correlated with clinical stages and survival of human non-small cell lung cancer (NSCLC) patients. IL-7R, mTOR, and tumor stage were the independent prognosticators in lung cancer. Taken together, our results provided evidence that IL-7 activates PI3 K/Akt/mTOR signaling pathway via Beclin 1 to regulate autophagy in lung cancer cells.


Assuntos
Proteína Beclina-1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Neoplasias Pulmonares/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Apoptose , Proteína Beclina-1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Taxa de Sobrevida , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
8.
J Neuroimmunol ; 324: 81-89, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30248528

RESUMO

Neuromyelitis optica (NMO) is a chronic inflammatory demyelinating autoimmune disease of the central nervous system that most commonly affects the optic nerves and spinal cord. To characterize the immunological pathways involved in NMO, whole blood RNA expression array was performed using Nanostring nCounter technology. Two major clusters of genes were found associated with NMO: T cell-associated genes and the TNF/NF-kB signaling pathway. Analysis of the genes within the first cluster confirmed significantly reduced expression of IL7Ra (CD127) in the peripheral blood of NMO patients vs that in healthy controls. IL7Ra upstream transcription factors and its downstream survival signaling pathway were also markedly reduced. In line with the essential role of IL7Ra in T cell maturation and survival, a significantly lower number of naïve T cells, and reduced T cell survival signaling mediated by increased BID (BH3-interacting domain death agonist) expression and increased apoptosis was observed. Cumulatively, these findings indicate that the IL7Ra signaling pathway may play a role in the autoimmune process in NMO.


Assuntos
Subunidade alfa de Receptor de Interleucina-7/biossíntese , Neuromielite Óptica/metabolismo , Transdução de Sinais/fisiologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Estudos de Coortes , Feminino , Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/genética , Neuromielite Óptica/imunologia , Subpopulações de Linfócitos T/imunologia
9.
Int J Mol Sci ; 19(9)2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30149646

RESUMO

Interleukin-7 (IL-7) is essential for lymphocyte development. To identify the functional subdomains in the cytoplasmic tail of the IL-7 receptor (IL-7R) α chain, here, we constructed a series of IL-7Rα deletion mutants. We found that IL-7Rα-deficient hematopoietic progenitor cells (HPCs) gave rise to B cells both in vitro and in vivo when a wild-type (WT) IL-7Rα chain was introduced; however, no B cells were observed under the same conditions from IL-7Rα-deficient HPCs with introduction of the exogenous IL-7Rα subunit, which lacked the amino acid region at positions 414⁻441 (d414⁻441 mutant). Signal transducer and activator of transcription 5 (STAT5) was phosphorylated in cells with the d414⁻441 mutant, similar to that in WT cells, in response to IL-7 stimulation. In contrast, more truncated STAT5 (tSTAT5) was generated in cells with the d414⁻441 mutant than in WT cells. Additionally, the introduction of exogenous tSTAT5 blocked B lymphopoiesis but not myeloid cell development from WT HPCs in vivo. These results suggested that amino acids 414⁻441 in the IL-7Rα chain formed a critical subdomain necessary for the supportive roles of IL-7 in B-cell development.


Assuntos
Linfócitos B/metabolismo , Diferenciação Celular , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Linfócitos B/citologia , Diferenciação Celular/genética , Proliferação de Células , Citoplasma/metabolismo , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/química , Subunidade alfa de Receptor de Interleucina-7/genética , Ativação Linfocitária , Mutação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais
10.
Biosci Rep ; 38(3)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29720427

RESUMO

The long-term chronic inflammation of cervical intraepithelial neoplasia (CIN) induces the initiation and progression of cervical cancer. Long non-coding RNAs (LncRNAs) are being identified to be involved into inflammation and carcinogenesis and could function as cancer biomarkers in clinical. However, the significance of inflammation-related LncRNA (e.g. LncRNA-IL7R) in cervical cancer is limited. We, here, investigated the clinical role of inflammation-related LncRNA-IL7R (Lnc-IL7R) in healthy cervical tissue (n=15), CIN 1/2/3 (n=35), cervical cancer (n=70), and clarified its function via knockdown in vitro and in vivo The results showed that the expression of Lnc-IL7R was increased from normal tissues to neoplastic lesions and cervical cancer. Up-regulated Lnc-IL7R positively correlated to tumor size, International Federation of Gynaecology and Obstetrics (FIGO) stage, and lymph node metastasis (LNM). Patients with high expression of Lnc-IL7R had poor prognosis with short overall survival (OS) time, and Cox regression analysis revealed that Lnc-IL7R could be independent prognostic factor for cervical cancer. Moreover, knockdown of Lnc-IL7R by two different siRNAs in cervical cancer cell lines Hela and SiHa induced impaired cell vitality and caspase-3-dependent apoptosis in vitro Furthermore, inhibition of Lnc-IL7R in vivo significantly restricted the tumor growth with decreased expressions of proliferation index Ki-67 and Lnc-IL7R These data indicated that Lnc-IL7R predicts a poor clinical outcome of cervical cancer patients, and knockdown of Lnc-IL7R is amenable to the treatment of cervical cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasia Intraepitelial Cervical/genética , Regulação Neoplásica da Expressão Gênica , Subunidade alfa de Receptor de Interleucina-7/genética , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética , Adulto , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Neoplasia Intraepitelial Cervical/complicações , Neoplasia Intraepitelial Cervical/metabolismo , Neoplasia Intraepitelial Cervical/mortalidade , Feminino , Células HeLa , Xenoenxertos , Humanos , Inflamação , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Metástase Linfática , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidade
11.
PLoS One ; 13(5): e0197115, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29742149

RESUMO

The polymorphisms at the α-chain of the IL-7 receptor (IL7RA) have been related to T-cell homeostasis and development and may contribute to immune system deregulation. In the present study, we analyzed the association between IL7RA polymorphisms and the progression of liver fibrosis in patients infected with HCV. We carried out a retrospective study with a design consisting of repeated measurements in 187 HCV-infected patients, to study the risk prediction of liver fibrosis progression using genetic factors. We genotyped the rs6897932, rs987106 and rs3194051 IL7RA polymorphisms using the Agena Bioscience's MassARRAY. Transient elastography was used to measure liver stiffness. The used cut-offs were: <7.1 kPa (F0-F1), 7.1-9.4 kPa (F2; significant fibrosis), 9.5-12.4 kPa (F3; advanced fibrosis), and ≥12.5 kPa (F4; cirrhosis). All HCV genotypes were analyzed. The median of follow-up time was 47.9 months. Baseline liver stiffness measurement (LSM) values did not show significant statistical differences for IL7RA genotypes (p>0.05). In univariate analysis, the rs6897932 T allele had a positive relationship with an increase in LSM (arithmetic mean ratio (AMR) = 1.21 (95%CI = 1.08; 1.36); p = 0.001), progression to advanced fibrosis (F≥3) (odds ratio (OR) = 2.51 (95%CI = 1.29; 4.88); p = 0.006) and progression to cirrhosis (F4) (OR = 2.71 (95%CI = 0.94; 5.03); p = 0.069). In multivariable analysis, the rs6897932 T allele was related to a higher increase of LSM values during follow-up (adjusted AMR = 1.27 (95%CI = 1.13; 1.42); p<0.001) and higher odds of progression to advanced fibrosis [adjusted OR = 4.46 (95%CI = 1.87; 10.62); p = 0.001], and progression to cirrhosis [adjusted OR = 3.92 (95%CI = 1.30; 11.77); p = 0.015]. Regarding IL7RA rs987106 and rs3194051 polymorphisms, we did not find significant results except for the relationship between IL7RA rs987106 and the increase in LSM values [adjusted OR = 1.12 (95%CI = 1.02; 1.23); p = 0.015]. The IL7RA rs6897932 polymorphism seems to be related to increased risk of liver fibrosis progression in HCV-infected patients. Thus, the rs6897932 polymorphism could be related to the physiopathology of CHC and might be used to successfully stratify the risk of CHC progression.


Assuntos
Predisposição Genética para Doença , Hepatite C Crônica/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Cirrose Hepática/genética , Adulto , Progressão da Doença , Feminino , Estudos de Associação Genética , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Int J Oncol ; 53(1): 395-403, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29749437

RESUMO

The interleukin-7 receptor (IL7R) is generally expressed in immune cells and is critical in survival, development and homeostasis in the immune system. Advanced genome-wide cancer studies have reported that IL7R is genetically amplified in human esophageal squamous cell carcinoma (ESCC), however, the exact role of IL7R in ESCC has not been investigated. In the present study, it was found that IL7R was overexpressed in ESCC cohorts and the loss of IL7R induced anti-oncogenic effects in ESCC cell lines. A small panel of epigenetic drugs were screened for their ability to downregulate the expression of IL7R. Unexpectedly, apicidin, a histone deacetylase (HDAC) inhibitor, effectively downregulated the expression of IL7R in a dose-dependent manner at an early time-point, as determined by quantitative polymerase chain reaction and IL7R immunostaining, and did not require de novo protein synthesis. Of note, apicidin induced the acetylation of Forkhead box-containing protein, O subfamily 1, which acts as a repressor at the IL7R promoter, accompanied with depleted active histone modifications based on chromatin immunoprecipitation assay. Taken together, these results demonstrated that targeting oncogenic IL7R in ESCC by HDAC inhibitors may be a valuable therapeutic approach.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Proteína Forkhead Box O1/genética , Inibidores de Histona Desacetilases/farmacologia , Subunidade alfa de Receptor de Interleucina-7/genética , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos Cíclicos/farmacologia
13.
Front Immunol ; 9: 196, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29541070

RESUMO

γδ T cells, known to be an important source of innate IL-17 in mice, provide critical contributions to host immune responses. Development and function of γδ T cells are directed by networks of diverse transcription factors (TFs). Here, we examine the role of the zinc finger TFs, Kruppel-like factor 10 (KLF10), in the regulation of IL-17-committed CD27- γδ T (γδ27--17) cells. We found selective augmentation of Vγ4+ γδ27- cells with higher IL-17 production in KLF10-deficient mice. Surprisingly, KLF10-deficient CD127hi Vγ4+ γδ27--17 cells expressed higher levels of CD5 than their wild-type counterparts, with hyper-responsiveness to cytokine, but not T-cell receptor, stimuli. Thymic maturation of Vγ4+ γδ27- cells was enhanced in newborn mice deficient in KLF10. Finally, a mixed bone marrow chimera study indicates that intrinsic KLF10 signaling is requisite to limit Vγ4+ γδ27--17 cells. Collectively, these findings demonstrate that KLF10 regulates thymic development of Vγ4+ γδ27- cells and their peripheral homeostasis at steady state.


Assuntos
Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Interleucina-17/imunologia , Fatores de Transcrição Kruppel-Like/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Transdução de Sinais , Linfócitos T/imunologia , Animais , Células da Medula Óssea/imunologia , Antígenos CD5/genética , Regulação da Expressão Gênica , Homeostase , Subunidade alfa de Receptor de Interleucina-7/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
14.
Pediatr Diabetes ; 19(5): 955-962, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29484785

RESUMO

BACKGROUND: Interleukin-7 receptor α-chain (IL7RA) haplotypes are associated with susceptibility for development of autoimmune diseases, including type 1 diabetes (T1D). A protective IL7RA haplotype which causes lower soluble IL-7R (sIL-7R) serum levels is hypothesized to restrict IL-7-availability for self-reactive T cells. Functional mechanisms affected by a risk-associated IL7RA haplotype are unknown. METHODS: We investigated the influence of IL7RA haplotypes (tagged by rs6897932T for the protective or by rs1494555G for the risk haplotype) on sIL-7R and IL-7 serum concentrations as well as disease manifestation of children with T1D (n = 259). Possible effects of differential IL-7 serum concentrations on IL-7-mediated in vitro T cell functions (i.e. IL-7R regulation and cytokine expression) were measured in a second study group of children with T1D (n = 42). RESULTS: We detected lower sIL-7R serum concentrations in children with T1D carrying protective or risk haplotypes as compared to reference haplotypes. sIL-7R levels were lowest in T1D children with the protective haplotype and lower IL-7 serum levels were exclusively detected in this study group. We found no evidence for dependency between IL-7 and sIL-7R serum concentrations and no association with T1D manifestation. Neither IL-7 nor sIL-7R serum levels were associated with mIL-7R regulation or IL-7-promoted T cell cytokine expression. CONCLUSIONS: Children with T1D carrying autoimmunity risk- or protection-associated IL7RA haplotypes had both lower sIL-7R serum concentrations as compared to the reference haplotype, but only T1D children with the protective haplotype had lower IL-7 serum levels. Our results suggest additional functional mechanisms of autoimmunity-associated IL7RA variants independent from sIL-7R mediated regulation of IL-7 availability for T cells.


Assuntos
Diabetes Mellitus Tipo 1/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Interleucina-7/sangue , Adolescente , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Haplótipos , Humanos , Subunidade alfa de Receptor de Interleucina-7/sangue , Polimorfismo de Nucleotídeo Único , Linfócitos T/metabolismo , Adulto Jovem
15.
Dev Comp Immunol ; 81: 244-251, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29247721

RESUMO

Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for T cell development in the thymus, and changes in the IL-7/IL-7R pathway have been implicated in age-associated thymic involution which results in a reduction of naïve T cell output. The aim of this study was to investigate the relationship between IL7 and IL7R genetic variation and thymic output in dogs. No single nucleotide polymorphisms (SNPs) were identified in the canine IL7 gene, but a number were present in the canine IL7R gene. Polymorphisms in the IL7R exon 8 and 3'UTR were found to be associated with signal joint T cell receptor excision circle (sj-TREC) values (a biomarker of thymic output) in young and geriatric Labrador retrievers. Additionally, one of the SNPs in the IL7R 3'UTR (SNP 14 c.1371 + 446 A > C) was found to cause a change in the seed-binding site for microRNA 185 which, a luciferase reporter assay demonstrated, caused changes in post-transcriptional regulation, and therefore might be capable of influencing IL-7R expression. The research findings suggest a genetic link between IL7R genotype and thymic output in dogs, which might impact on immune function as these animals age and provide further evidence of the involvement of IL-7/IL-7R pathway in age-associated thymic involution.


Assuntos
Regiões 3' não Traduzidas/genética , Genótipo , Subunidade alfa de Receptor de Interleucina-7/genética , MicroRNAs/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/fisiologia , Timo/fisiologia , Animais , Cruzamento , Diferenciação Celular , Seleção Clonal Mediada por Antígeno , Cães , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Polimorfismo de Nucleotídeo Único , Transdução de Sinais
16.
Hum Antibodies ; 26(2): 43-48, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-28582853

RESUMO

BACKGROUND: Interleukin 7 receptor alpha (IL7RA) gene that encodes a subunit of IL7 receptor has been reported to be associated with different immunologic disease. OBJECTIVE: Multiple Sclerosis (MS) patients have shown an aberrant blood level of soluble form of IL7R protein. The genomic changes in the sequence of this gene have been suggested to be correlated with its altered splicing specially, variants in the exon 6 of the gene have been reported to influence the maintenance or skipping of this exon and control the soluble or insoluble form of the final product. In order to evaluate this changes in the IL7RA gene and to determine a possible correlation between these changes and the MS susceptibility the whole sequence of the exon 6 and 7 and their flanking sequences were analyzed. METHODS: In this regard, we investigate the sequence changes of the exon 6 and 7 of the IL7RA gene in 75 relapsing-remitting MS patients and compare the results with 75 healthy control using sequence analyzing. RESULTS: The results of the sequence analysis were used in two aspects. The allelic and genotypic estimated frequencies of a reported risk variant rs6897932 in patients and controls in our population confirmed its association with the disease (P= 0.009, OR = 6.273, for TT genotype). Also, we report a possible hazardous cutoff for changes in a potential exon splicing silencer element (ESS (nt. 20-24)) and its correlation with rs6897932 to confer the risk of developing MS. CONCLUSION: In conclusion our results confirm the association between IL7RA exon 6 sequence changes and increased susceptibility for multiple sclerosis.


Assuntos
Éxons , Predisposição Genética para Doença , Subunidade alfa de Receptor de Interleucina-7/genética , Esclerose Múltipla Recidivante-Remitente/genética , Adulto , Alelos , Processamento Alternativo , Estudos de Casos e Controles , Feminino , Expressão Gênica , Frequência do Gene , Humanos , Subunidade alfa de Receptor de Interleucina-7/sangue , Masculino , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/patologia
17.
Cytokine ; 103: 121-126, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28964592

RESUMO

Interleukin-7 (IL-7) exerts crucial functions on lymphoid cells' development and maintenance. In breast cancer (BC), IL-7 promotes growth of tumor cells in culture through the activation of JAK1/3-STAT5 and PI3K/AKT pathways, and expression of IL-7 signaling components was associated with worst prognosis. AC>T polymorphism (rs6897932; Thr244Ile) at exon 6 of IL-7 receptor alpha (IL-7Rα) gene (IL7RA) shifts the balance between the membrane-bound and soluble IL-7Rα splicing variants and was previously associated with autoimmune diseases, but has not been studied in cancer, including BC, so far. Therefore, the present study aimed to investigate the possible association of this polymorphism with the susceptibility and clinicopathological parameters of BC subgroups. IL7RA Thr244Ile was genotyped through PCR-RFLP in 403 women without neoplasia, no personal history of malignancy or family history of BC and in 338 BC patients with clinicopathological data available. BC patients were stratified according to their positivity for estrogen (ER) and/or progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Age-adjusted logistic regression was performed for case-control analyses, and correlations with clinicopathological parameters were assessed through Kendall's Tau-b coefficient. All analyses were two-tailed and had 95% confidence interval. In ER-PR-HER2- BCs, TT genotype was associated with increased susceptibility both in genotypic (TT vs. CC: OR=3.07; CI=1.01-9.38; p=0.05) and recessive (TT vs. CC+CT: OR=3.59; CI=1.19-10.85; p=0.02) models and negatively correlated with disease stage (Tau-b=-0.27; p=0.05). Whereas T allele was positively correlated with histopathological grade (Tau-b=0.29; p=0.03) and lymph node metastasis (Tau-b=0.35; p=0.02) in ER/PR+HER2+BCs and with Ki67 (Tau-b=0.51; p=0.008) in ER-PR-HER2+ subgroup. These data indicate that IL-7Rα is involved in BC, and that IL7RA polymorphism may play distinct roles in breast carcinogenesis according to BC subtype, pointing this genetic variant as an interesting marker for breast carcinogenesis to be validated by further mechanistic and prospective studies with larger samples.


Assuntos
Neoplasias da Mama/genética , Éxons , Predisposição Genética para Doença , Subunidade alfa de Receptor de Interleucina-7/genética , Proteínas de Neoplasias/genética , Polimorfismo Genético , Adulto , Idoso , Alelos , Feminino , Humanos , Pessoa de Meia-Idade
18.
Clin Immunol ; 187: 15-25, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28941836

RESUMO

Genetic variants within some cytokine receptor genes have been associated with MS susceptibility, including IL7RA and IL2RA. As these genes are expressed by cells targeted by immune-modulatory drugs, we explored the potential role of their gene products as biomarkers in monitoring MS treatment. We assessed the impact of natalizumab followed by fingolimod on the intra-individual changes of plasma protein levels of sIL-7Rα, sIL-2Rα and also sIL-6R and sgp130 in MS patients. During natalizumab treatment we observed a decline in sgp130 and sIL-7Rα levels, while subsequent fingolimod treatment lead to increased sgp130 and sIL-7Rα and decreased sIL-2Rα levels. In addition, during fingolimod treatment sIL-7Rα levels were increasing significantly more in patients homozygous for the MS risk genotype of rs6897932. We also observed an effect of the MS associated rs71624119 on sgp130 levels. These results may elucidate the pharmacodynamics of treatments and help identify biomarkers for MS outcomes.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Natalizumab/uso terapêutico , Adolescente , Adulto , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/imunologia , Feminino , Variação Genética , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Testes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
Immunity ; 47(4): 680-696.e8, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29045900

RESUMO

The classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127- and CD127+ early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127- and CD127+ ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127- ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127+ ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a "two-family" model of human lymphoid development that differs from the prevailing model of hematopoiesis.


Assuntos
Linfócitos B/metabolismo , Células Matadoras Naturais/metabolismo , Células Progenitoras Linfoides/metabolismo , Linfopoese/genética , Linfócitos T/metabolismo , Adolescente , Adulto , Animais , Linfócitos B/citologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Células Matadoras Naturais/citologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/transplante , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Transplante de Células-Tronco , Linfócitos T/citologia , Transplante Heterólogo , Adulto Jovem
20.
Cell Immunol ; 319: 3-9, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28844471

RESUMO

The immunological mechanism(s) of action whereby teplizumab preserves C-peptide levels in the progression of patients with recent onset type 1 diabetes (T1D) is still not well understood. In the present study, we evaluated the kinetics of T cell modulation in peripheral blood following two 14-day courses of teplizumab therapy one year apart in recent onset T1D participants in the AbATE clinical trial. Transient rises in PD-1+Foxp3+ Treg and potentially anergic (CD57-KLRG1-PD-1+) cells in the circulating CD4 T cell compartment were paralleled by more profound increases in circulating CD8 T cells with traits of exhaustion (CD57-KLRG1+PD-1+, TIGIT+KLRG1+, and persistent down-modulation of CD127). The observed phenotypic changes across cell types were associated with favorable response to treatment in the subgroup of study participants that did not develop anti-drug antibodies after the first course of therapy. These findings provide new insights on the duration and complexity of T cell modulation with teplizumab therapy in recent onset T1D, and in addition, suggest that coordinated immune mechanisms of tolerance that favor CD4 Treg function and restrain CD4 non-Treg and CD8 T cell activation may contribute to treatment success.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Tolerância Imunológica/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Adolescente , Adulto , Peptídeo C/agonistas , Peptídeo C/genética , Peptídeo C/imunologia , Complexo CD3/genética , Complexo CD3/imunologia , Antígenos CD57/genética , Antígenos CD57/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Expressão Gênica , Humanos , Imunomodulação , Imunoterapia/métodos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Masculino , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Transativadores/genética , Transativadores/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA