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1.
Mol Immunol ; 116: 151-159, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31675522

RESUMO

The interleukin-17 (IL-17) family plays a critical role in host defense, allergic reactions, and even tumorigenesis on different mucous membranes. IL-17 family has been cloned in human and mouse, as well IL-17A, IL-17 F in swine. So far, current knowledge on the cloning and biological functions of porcine IL-17B (poIL-17B) and porcine IL-17E (poIL-17E) is limited. In this study, poIL-17B and poIL-17E, mainly expressed in intestine, were cloned and characterized. Expression of poIL-17B and poIL-17E was upregulated after pathogenic microorganism infection. Moreover, the significant enhanced expression of antibacterial peptides PR-39 and pBD-1 was observed when poIL-17B and poIL-17E were over-expressed in the small intestinal epithelial cell line IPEC-J2. This demonstrated that poIL-17B and poIL-17E might have anti-infective capability. Pathogens infection data showed that pathogens could up-regulate poIL-17B/E expression levels. After stimulating the cells with the pathogen, continued with probiotics, the expression of poIL-17B/E was down-regulated. Meanwhile, the induced expression of poIL-17E was greater than that of poIL-17B. Invasion data indicated that poIL-17B and poIL-17E both could inhibit effectively pathogenic microorganism, while inhibitory capability of poIL-17B was stronger than that of poIL-17E. Therefore, poIL-17B and poIL-17E both could be important members against intestinal infection in the porcine IL-17 family. This study provided a theoretical basis for the prevention of intestinal diseases in pigs and thus achieved healthy farming.


Assuntos
Infecções Bacterianas/imunologia , Interleucina-17/imunologia , Intestinos/imunologia , Intestinos/microbiologia , Animais , Linhagem Celular , Regulação para Baixo/imunologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Humanos , Camundongos , Probióticos/administração & dosagem , Suínos , Regulação para Cima/imunologia
2.
Mol Immunol ; 114: 591-599, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31536880

RESUMO

Human CD63 has been reported to play a role either as an inhibitor or as a co-stimulator of T- cell responses, although the mechanism of this is unclear. In this study, an anti-human CD63 monoclonal antibody (mAb) COS3A was used to monitor the role of CD63 in T-cell activation. MAb COS3A could inhibit CD3-mediated T-cell proliferation and CD25 expression in peripheral blood mononuclear cells (PBMCs), used as a study model, but the suppressive effect was not observed when purified T-cells were used instead of PBMCs. The inhibitory phenomenon was associated with downregulation of IL-2 and IFN-γ by T-cells, but upregulation of IL-10 by monocytes. Neutralizing IL-10 with anti-IL-10 mAb improved the T-cell response, indicating the role of IL-10 in T-cell suppression. In this study, monocytes were demonstrated to play a role in impeding T-cell activation by the anti-CD63 mAb COS3A. This is the first evidence that anti-CD63 mAb induces IL-10 secretion by monocytes, which later play a role in T-cell hypo-responsiveness.


Assuntos
Anticorpos Monoclonais/imunologia , Complexo CD3/imunologia , Interleucina-10/imunologia , Monócitos/imunologia , Linfócitos T/imunologia , Tetraspanina 30/imunologia , Regulação para Cima/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Células Cultivadas , Regulação para Baixo/imunologia , Humanos , Interleucina-2/imunologia , Leucócitos Mononucleares/imunologia , Ativação Linfocitária
3.
Mol Immunol ; 114: 41-48, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31336248

RESUMO

Viral myocarditis, mainly caused by enteroviruses specially coxsackievirus B3 (CVB3) infection, is a common clinical cardiovascular disease and characterized by cardiac massive inflammation. Our previous study showed that CVB3-induced myocardial NLRP3 contributed to the development of viral myocarditis. In this study, we found that beside of being up-regulated in myocardiocytes, NLPR3 was also obviously increased in the cardiac infiltrating macrophages. While whether this accumulated NLRP3 influences, macrophage inflammatory responses remains unknown. By adoptive transfer assays, we found that mice receiving NLRP3 up-regulated macrophages showed much more abundant cardiac IL-1ß production and more severe myocardial inflammation, while those receiving NLRP3 down-regulated macrophages showed much less IL-1ß production and milder myocarditis, indicating that NLRP3 up-regulated macrophages played a pathological role in CVB3-induced myocarditis. In addition, we further found that it was CVB3 capsid proteins VP1 (predominant) and VP2, but not viral RNAs, robustly triggered macrophage NLRP3 up-regulation and activation. Our study demonstrated macrophage NLRP3 inflammasome could be efficiently be activated by CVB3 capsid proteins, and contributed to the pathogenesis of viral myocarditis. It might provide some clues to the development of new therapeutic strategies based on macrophage NLRP3 modulation.


Assuntos
Proteínas do Capsídeo/imunologia , Infecções por Coxsackievirus/imunologia , Enterovirus/imunologia , Inflamassomos/imunologia , Macrófagos/imunologia , Miocardite/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Transferência Adotiva/métodos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo/imunologia , Células HeLa , Coração/virologia , Humanos , Inflamação/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/virologia , Miocárdio/imunologia , Células RAW 264.7 , Regulação para Cima/imunologia , Viroses/imunologia , Viroses/virologia
4.
Immunopharmacol Immunotoxicol ; 41(4): 490-496, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31303072

RESUMO

Background: Immunotherapy utilizing T cells genetically modified to express chimeric antigen receptors (CARs) is rapidly emerging as a promising novel treatment for hematological and nonhematological malignancies. In order to target the TKI-insensitive leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) by CAR T cells, we chose CD26 as a cell surface tumor-associated antigen due to preferentially expression on LSCs. Additionally, CD26 has also been suggested to be a multipurpose therapeutic target for other cancer. Therefore, developing the CD26-targeting CAR T cells may be a promising therapy for not only LSCs but also other CD26+ cancer cells. Methods: We designed the second-generation CD26-targeting CAR utilizing 4-1BB (CD137) as costimulatory domain, and transduced T cells with CD26-CAR containing lentiviral. Then we evaluated the transduction efficiency and expansion ability, and demonstrated the existence of self-antigen-driven fratricide by cytokine assay and cytotoxicity assay. Results: Anti-CD26-4-1BB-CAR T cells exhibited poor viability, multiple cytokine secretion, down-regulation of CD26 and direct cytotoxicity against themselves, indicating self-antigen-driven fratricide. Conclusion: Eradicating CML-LSCs via anti-CD26-4-1BB-CAR T cells is not applicable, and optimized design or alternative target is needed.


Assuntos
Dipeptidil Peptidase 4/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Citotoxicidade Imunológica/imunologia , Regulação para Baixo/imunologia , Humanos , Imunoterapia/métodos , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
5.
APMIS ; 127(9): 642-652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274210

RESUMO

Hepatitis C virus (HCV) infection always leads to chronic hepatitis via dysregulation of host immunity. Notch signaling also modulates the response of monocytes/macrophages. Thus, we aimed to investigate the regulatory role of Notch signaling to CD14+ monocytes. Forty patients with chronic hepatitis C and twenty normal controls (NC) were enrolled. CD14+ monocytes and CD4+ T cells were purified from peripheral bloods. Notch receptors' mRNA expression in CD14+ monocytes was semi-quantified by real-time PCR. Cytokine production by CD14+ monocytes in response to γ-secretase inhibitor (GSI) was investigated by ELISA. GSI-induced CD14+ monocytes activity to HCV clearance in Huh7.5 cells and to CD4+ T cell differentiation was also assessed in direct and indirect contact co-culture system. Notch1 mRNA relative level was approximately 10-fold elevated in CD14+ monocytes from chronic hepatitis C patients when compared with NC. GSI stimulation resulted in enhanced cytokines production by CD14+ monocytes from chronic hepatitis C patients. GSI-stimulated CD14+ monocytes from chronic hepatitis C patients induced suppression of HCV RNA replication in both direct and indirect contact co-culture system of CD14+ monocytes and HCVcc-infected Huh7.5 cells, and this process was accompanied by elevation of interferon-γ production but not increased target cell death. Moreover, GSI stimulation also enhanced CD14+ monocytes-induced Th1 and Th17 cells activation, and this process required direct cell-to-cell contact. Effective antiviral therapy down-regulated Notch1 mRNA expression and promoted cytokine production by CD14+ monocytes from chronic hepatitis C. Current data revealed an important immunoregulatory property of Notch signaling to CD14+ monocytes in chronic HCV infection.


Assuntos
Hepatite C Crônica/imunologia , Monócitos/imunologia , Receptor Notch1/imunologia , Transdução de Sinais/imunologia , Adulto , Linfócitos T CD4-Positivos , Diferenciação Celular/imunologia , Técnicas de Cocultura , Regulação para Baixo/imunologia , Feminino , Hepacivirus/imunologia , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th17/imunologia , Adulto Jovem
6.
Fish Shellfish Immunol ; 92: 600-611, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31252046

RESUMO

Autophagy is an essential and conserved process that plays an important role in physiological homeostasis, adaptive response to stress and the immune response. Autophagy-related proteins (ATGs) are key components of the autophagic machinery. In the study, grass carp (Ctenopharyngodon idella) autophagy-related gene 5 (ATG5) and 12 (ATG12) were identified. In the gill and intestine, ATG5 and ATG12 were highly expressed, but after grass carp reovirus (GCRV) infection, they were decreased significantly. In Ctenopharyngodon idella kidney (CIK) cells, the sharp variation of ATG5 and ATG12 expression was observed after poly(I:C) infection. Subcellular localisation showed that ATG5 and ATG12 were evenly distributed in the cytoplasm and nucleus. However, the interaction between ATG5 and ATG12 was only found in cytoplasm in both 293T cells and CIK cells. In addition, the overexpression of ATG5 or ATG12 in 293T cells showed enhanced autophagy, and autophagic process was facilitated when ATG5 and ATG12 were simultaneously overexpressed. Dual-luciferase activity assay indicated that both ATG5 and ATG12 remarkably suppressed the promoter activity of IRF3, IRF7, and IFN-I. Further, ATG5 and ATG12 conjugate showed far stronger inhibitory affection on the expression of IFN-I than either ATG5 or ATG12 in response to poly(I:C) or GCRV infection. Taken together, the results demonstrate that grass carp ATG5 and ATG12 play an important role in innate immunity and autophagy.


Assuntos
Proteína 12 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Autofagia/genética , Carpas/genética , Carpas/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Animais , Proteína 12 Relacionada à Autofagia/imunologia , Proteína 5 Relacionada à Autofagia/imunologia , Regulação para Baixo/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Transdução de Sinais
7.
Immunopharmacol Immunotoxicol ; 41(2): 349-360, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31056982

RESUMO

Traumatic brain injury (TBI) is a common neurotrosis disorder of the central nervous system (CNS), which has dramatic consequences on the integrity of damaged tissue. In this study, we investigated the neuroprotective effect and anti-inflammatory actions of osthole, a natural coumarin derivative, in both in vivo and in vitro TBI models. We first prepared a mouse model of cortical stab wound brain injury, investigated the capacity for osthole to prevent secondary brain injury and further examined the underlying mechanism. We revealed that osthole significantly improved the neurological function, increased the number of neurons beside injured site. Additionally, osthole treatment reduced the expression of microglia and glial scar, lowered the level of the proinflammatory cytokines interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α), and blocked the activation of nuclear factor kappa B (NF-κB). Furthermore, the protective effect of osthole was also examined in SH-SY5Y cells subjected to scratch injury. Treatment of osthole prominently suppressed cell apoptosis and inflammatory factors release by blocking injury-induced IκB-α phosphorylation and NF-κB translocation, and upregulated the IκB-α which functions in the NF-κB signaling pathway of SH-SY5Y cells. However, NF-κB signaling pathway was inhibited by pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, the anti-inflammatory effect of osthole was abolished. In conclusion, our findings demonstrated that osthole attenuated inflammatory response by inhibiting the NF-κB pathway in TBI.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Cumarínicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , NF-kappa B/imunologia , Transdução de Sinais/efeitos dos fármacos , Animais , Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/patologia , Linhagem Celular , Citocinas/imunologia , Regulação para Baixo/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Camundongos , Transdução de Sinais/imunologia
8.
Immunopharmacol Immunotoxicol ; 41(2): 267-276, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31056985

RESUMO

Context: Mentha longifolia (L.) Huds., has shown anti-inflammatory effects. Objective: To evaluate the immunomodulatory effects of menthol, the major constituent of Mentha longifolia on T cells as the main cells affecting the inflammatory responses. Methods: Effect of menthol on: proliferation and viability of the peripheral blood human mononuclear cells (PBMCs) by BrdU and propidium iodide (PI) staining, respectively, interferone (IFN)γ and interleukin (IL)-4 cytokine production in lymphocytes stimulated with phytohemagglutinin (PHA) and phorbol myristate acetate/calcium ionophore (PMA/CI) by ELISA; intracellular staining of CD4+ cells for IFNγ expression by flow cytometry and gene expressions of T heper (Th) cell transcription factors was measured using real time-PCR. Results: Menthol dose-dependently inhibited lymphocytes proliferation from 88.7% at 50 µg/ml to 3.63% at 800 µg/ml (p < .05). According to the results of PI staining, this inhibitory effect was not due to cell death. Menthol dose-dependently decreased IFNγ but not IL-4 production in culture of PHA- and PMA/CI-stimulated lymphocytes to more than 80% at 800 µg/ml. In flow cytometry analysis, menthol reduced the number of IFN-γ-expressing CD4+T cells stimulated either with PHA or PMA/CI. Treatment of PBMCs with 800 µg/ml of menthol decreased levels of T-bet from 14.5 ± 2.26 fold in untreated control to 2.76 ± 1.74 fold (p < .001). Foxp-3 expression decreased to nearly half, but GATA3 did not significantly change. Ratios of T-bet to GATA3 and T-bet to Foxp3 gene expressions were dose-dependently declined. Conclusion: Decreased IFNγ expression plus T-bet down-regulation suggested the inhibitory effect of menthol on Th1 cells differentiation and hence imply its possible therapeutic usefulness in inflammatory diseases.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Interferon gama/imunologia , Mentol/farmacologia , Proteínas com Domínio T/imunologia , Células Th1/imunologia , Adulto , Regulação para Baixo/imunologia , Fatores de Transcrição Forkhead/imunologia , Fator de Transcrição GATA3/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Células Th1/patologia
9.
Mol Immunol ; 111: 209-219, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31096062

RESUMO

We have previously reported Israa, immune-system-released activating agent, as a novel gene nested in intron 8 of the mouse Zmiz1 gene. We have also shown that Israa encodes for a novel FYN-binding protein and might be involved in the regulation of T-cell activation. In this report, we demonstrate that Israa gene product regulates the expression of a pool of genes involved in T-cell activation and signaling. Real time PCR and GFP knock-in expression analysis showed that Israa is transcribed and expressed in the spleen mainly by CD3+CD8+ cells as well as in the thymus by CD3+ (DP and DN), CD4+SP and CD8+SP cells at different developmental stages. We also showed that Israa is downregulated in T-cells following activation of T-cell receptor. Using yeast two-hybrid analysis, we identified ELF1, a transcription factor involved in T-cell regulation, as an ISRAA-binding partner. Transcriptomic analysis of an EL4 cell line overexpressing ISRAA revealed differential expression of several genes involved in T-cell signaling, activation and development. Among these genes, Prkcb, Mib2, Fos, Ndfip2, Cxxc5, B2m, Gata3 and Cd247 were upregulated whereas Itk, Socs3, Tigit, Ifng, Il2ra and FoxJ1 were downregulated. Our findings support the existence in mouse of a novel FYN-related T-cell regulation pathway involving the product of an intron-nested gene.


Assuntos
Íntrons/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Linfocinas/imunologia , Genes Inseridos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Regulação para Baixo/imunologia , Feminino , Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/imunologia , Fatores de Transcrição/imunologia , Regulação para Cima/imunologia
10.
Cancer Immunol Immunother ; 68(6): 983-990, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30993371

RESUMO

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer in which PD-1/PD-L1 blockade has shown remarkable response rates. However, a significant proportion of patients shows primary or secondary resistance against PD-1/PD-L1 inhibition, with HLA class-I downregulation and insufficient influx of CD8+ T cells into the tumor as possible immune escape mechanisms. Histone deacetylase inhibitors (HDACi) have been demonstrated to reverse low HLA class-I expression caused by epigenetic downregulation of the antigen machinery (APM) in vitro and in pre-clinical models in vivo. CASE PRESENTATIONS: We report four cases of patients with metastatic MCC who did not respond to immunotherapy by PD-1/PD-L1 blockade. Two of the patients received, subsequently, the HDACi panobinostat in combination with PD-1/PD-L1 blockade. Tumor biopsies of the patients were analyzed for cellular and molecular markers of antigen processing and presentation as well as the degree of T-cell infiltration. RESULTS AND CONCLUSION: Low expression of APM-related genes associated with low HLA class-I surface expression was observed in all MCC patients, progressing on PD-1/PD-L1 blockade. In one evaluable patient, of the two treated with the combination therapy of the HDACi, panobinostat and PD-1/PD-L1 blockade, reintroduction of HLA class-I-related genes, enhanced HLA class-I surface expression, and elevated CD8+ T-cell infiltration into the MCC tumor tissue were observed; however, these changes did not translate into a clinical benefit. Our findings suggest that HDACi may be useful to overcome HLA class-I downregulation as a resistance mechanism against anti-PD-1/PD-L1 antibodies in MCC patients. Prospective clinical trials are needed to evaluate this notion.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Célula de Merkel/tratamento farmacológico , Antígenos de Histocompatibilidade Classe I/imunologia , Inibidores de Histona Desacetilases/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/imunologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Inibidores de Histona Desacetilases/imunologia , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia
11.
J Immunol ; 202(9): 2609-2615, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902899

RESUMO

Cholecystokinin (CCK) is a peptide hormone that functions in digestive organs and the CNS. We previously showed that CCK downregulates peripheral pruritus by suppressing degranulation of mast cells. In this study, we demonstrated that CCK octapeptide (CCK8) was constitutively expressed in the epidermis of normal skin, whereas its expression was lost in acanthotic lesions of psoriasis. In contrast, CCKA receptor (CCKAR), a high-affinity receptor for CCK, was constitutively expressed in the epidermis of psoriatic skin lesions. Expression of CCK was also reduced in skin lesions of an imiquimod (IMQ)-induced psoriatic mouse model. Notably, the expression level of CCK inversely correlated with the severity of epidermal inflammation, raising the possibility that CCK from epidermal keratinocytes suppresses the psoriatic inflammation. To verify this hypothesis, we investigated the effects of sulfated CCK octapeptide (CCK8S) on the development of IMQ-induced psoriatic inflammation. i.p. injection of CCK8S suppressed the IMQ-induced psoriatic inflammation accompanied by reduced mRNA expression of IL-17, IL-22, and IL-6 but not of IL-23. The suppressive effect of CCK8S was completely restored by administration of CCKAR antagonist. In vitro studies showed that exogenous CCK8S suppressed IL-6 production in CCKAR-expressing cultured human keratinocytes, and blocking the endogenous CCK signaling with CCKAR antagonist markedly enhanced IL-6 production. When keratinocytes were stimulated with IL-17, the expression of endogenous CCK was significantly decreased. These findings suggest that CCK physiologically functions as a negative regulator of keratinocyte-based inflammation in an autocrine or paracrine manner, although decreased CCK may pathologically contribute to continuous and aggravated skin lesions such as psoriasis.


Assuntos
Colecistocinina/imunologia , Regulação para Baixo/imunologia , Epiderme/imunologia , Queratinócitos/imunologia , Psoríase/imunologia , Transdução de Sinais/imunologia , Animais , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/imunologia , Epiderme/patologia , Feminino , Humanos , Imiquimode/farmacologia , Inflamação/imunologia , Inflamação/patologia , Interleucina-17/imunologia , Interleucina-6/imunologia , Queratinócitos/patologia , Masculino , Camundongos , Oligopeptídeos/imunologia , Oligopeptídeos/farmacologia , Comunicação Parácrina/efeitos dos fármacos , Comunicação Parácrina/imunologia , Psoríase/patologia
12.
BMC Cancer ; 19(1): 81, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30654767

RESUMO

BACKGROUND: Age-related genetic changes in lymphocyte subsets are not currently well documented. BACH2 is a transcription factor that plays an important role in immune-mediated homeostasis by tightly regulating PRDM1 expression in both B-cells and T-cells. BACH2 gene expression is highly sensitive to DNA damage in aged mice. This concept led us to investigate the variation in BACH2 and also PRDM1 expression in major lymphocyte subsets with age. METHODS: Lymphocyte subsets from 60 healthy donors, aged from 20 to 90 years, and 41 untreated chronic lymphocytic leukemia patients were studied. BACH2 and PRDM1 gene expression was analyzed by real-time quantitative PCR. BACH2 gene expression was correlated with its protein expression. Lymphocyte apoptosis was evaluated after intracellular oxidative stress-inducing etoposide treatment of T and B cells. RESULTS: Our analysis shows BACH2 mRNA downregulation with age in healthy donor CD4+, CD8+ T-cells and CD19+ B-cells. Decreased BACH2 expression was also correlated with an age-related reduction in CD8 + CD28+ T-cells. We found a strong correlation between age-related BACH2 downregulation and decreased CD4+ T-cell and CD19+ B-cell apoptosis. PRDM1, as expected, was significantly upregulated in CD4+ T-cells, CD8+ T-cells and CD19+ B-cells, and inversely correlated with BACH2. A comparison of untreated chronic lymphocytic leukemia patients with age-matched healthy donors reveals that BACH2 mRNA expression was further reduced in CD4+ T-cells, CD8+ T-cells and leukemic-B cells. PRDM1 gene expression was consequently significantly upregulated in CD4+ and CD8+ T-cells in chronic lymphocytic leukemia patients but not in their leukemic B-cells. CONCLUSION: Overall, our data suggest that BACH2 and PRDM1 genes are significantly correlated with age in human immune cells and may be involved in immunosenescence.


Assuntos
Envelhecimento/imunologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Subpopulações de Linfócitos/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Senescência Celular/imunologia , Regulação para Baixo/imunologia , Feminino , Voluntários Saudáveis , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/patologia , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , RNA Mensageiro/metabolismo , Regulação para Cima/imunologia , Adulto Jovem
13.
J Immunol ; 202(4): 1039-1044, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30642977

RESUMO

The ICOS pathway has been implicated in the development and functions of regulatory T (Treg) cells, including those producing IL-10. Treg cell-derived IL-10 is indispensable for the establishment and maintenance of intestinal immune homeostasis. We examined the possible involvement of the ICOS pathway in the accumulation of murine colonic Foxp3- and/or IL-10-expressing cells. We show that ICOS deficiency does not impair induction of IL-10 by intestinal CD4 T cells but, instead, triggers substantial reductions in gut-resident and peripherally derived Foxp3+ Treg cells. ICOS deficiency is associated with reduced demethylation of Foxp3 CNS2 and enhanced loss of Foxp3. This instability significantly limits the ability of ICOS-deficient Treg cells to reverse ongoing inflammation. Collectively, our results identify a novel role for ICOS costimulation in imprinting the functional stability of Foxp3 that is required for the retention of full Treg cell function in the periphery.


Assuntos
Regulação para Baixo , Fatores de Transcrição Forkhead/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucina-10/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Regulação para Baixo/imunologia , Fatores de Transcrição Forkhead/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/deficiência , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-10/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia
14.
J Virol ; 93(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602611

RESUMO

The HIV accessory protein Nef modulates key immune evasion and pathogenic functions, and its encoding gene region exhibits high sequence diversity. Given the recent identification of early HIV-specific adaptive immune responses as novel correlates of HIV reservoir size, we hypothesized that viral factors that facilitate the evasion of such responses-namely, Nef genetic and functional diversity-might also influence reservoir establishment and/or persistence. We isolated baseline plasma HIV RNA-derived nef clones from 30 acute/early-infected individuals who participated in a clinical trial of early combination antiretroviral therapy (cART) (<6 months following infection) and assessed each Nef clone's ability to downregulate CD4 and human leukocyte antigen (HLA) class I in vitro We then explored the relationships between baseline clinical, immunological, and virological characteristics and the HIV reservoir size measured 48 weeks following initiation of suppressive cART (where the reservoir size was quantified in terms of the proviral DNA loads as well as the levels of replication-competent HIV in CD4+ T cells). Maximal within-host Nef-mediated downregulation of HLA, but not CD4, correlated positively with post-cART proviral DNA levels (Spearman's R = 0.61, P = 0.0004) and replication-competent reservoir sizes (Spearman's R = 0.36, P = 0.056) in univariable analyses. Furthermore, the Nef-mediated HLA downregulation function was retained in final multivariable models adjusting for established clinical and immunological correlates of reservoir size. Finally, HIV subtype B-infected persons (n = 25) harbored significantly larger viral reservoirs than non-subtype B-infected persons (2 infected with subtype CRF01_AE and 3 infected with subtype G). Our results highlight a potentially important role of viral factors-in particular, HIV subtype and accessory protein function-in modulating viral reservoir establishment and persistence.IMPORTANCE While combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent HIV reservoir and are therefore not curative. As HIV cure or remission should be more readily achievable in individuals with smaller HIV reservoirs, achieving a deeper understanding of the clinical, immunological, and virological determinants of reservoir size is critical to eradication efforts. We performed a post hoc analysis of 30 participants of a clinical trial of early cART who had previously been assessed in detail for their clinical, immunological, and reservoir size characteristics. We observed that the HIV subtype and autologous Nef-mediated HLA downregulation function correlated with the viral reservoir size measured approximately 1 year post-cART initiation. Our findings highlight virological characteristics-both genetic and functional-as possible novel determinants of HIV reservoir establishment and persistence.


Assuntos
Infecções por HIV/imunologia , HIV/imunologia , Evasão da Resposta Imune/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Adulto , Antirretrovirais/farmacologia , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Antígenos HLA/imunologia , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Latência Viral/efeitos dos fármacos , Latência Viral/imunologia , Adulto Jovem
15.
J Exp Med ; 216(1): 99-116, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30559128

RESUMO

Natural killer (NK) cells are innate lymphocytes that are thought to kill cells that down-regulate MHC class I (MHC-I) through "missing-self" recognition. NK cells from B2m-/- mice that lack surface MHC-I, however, are not autoreactive as predicted by the missing-self hypothesis. As a result, it is unclear if MHC-I down-regulation in vivo induces NK cell reactivity or tolerance to missing-self. Here, we generated a floxed B2m mouse to acutely down-regulate MHC-I in vivo in a host that normally expresses MHC-I. Global down-regulation of MHC-I induced NK cell hyporesponsiveness and tolerance to missing-self without overt missing-self reactivity. In contrast, down-regulation of MHC-I on a small fraction of hematopoietic cells triggered missing-self reactivity. Surprisingly, down-regulation of MHC-I only on CD4+ T cells predominately induced tolerance to missing-self without resetting NK cell responsiveness. In this setting, inflammation triggered substantial missing-self reactivity. These results show that MHC-I down-regulation can induce either NK cell tolerance or killing in vivo and that inflammation promotes missing-self reactivity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Regulação para Baixo/imunologia , Tolerância Imunológica , Células Matadoras Naturais/imunologia , Microglobulina beta-2/imunologia , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Microglobulina beta-2/genética
16.
Front Immunol ; 9: 2772, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555465

RESUMO

Chemerin [RARRES2 [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon exposure to the synthetic retinoid tazarotene. Its secreted pro-form, prochemerin, is widely expressed, found systemically, and is readily converted into active chemerin by various proteases. Subsequent studies elucidated major roles of chemerin as both a leukocyte chemoattractant as well as an adipokine. Chemerin's main chemotactic receptor, the G-protein coupled receptor CMKLR1, is expressed on macrophages, dendritic, and NK cells. With respect to its role in immunology, chemerin mediates trafficking of these cells to sites of inflammation along its concentration gradient, and likely helps coordinate early responses, as it has been shown to have antimicrobial and angiogenic properties, as well. Recently, there has been mounting evidence that chemerin is an important factor in various cancers. As with its role in immune responses-where it can act as both a pro- and anti-inflammatory mediator-the potential functions or correlations chemerin has in or with cancer appears to be context dependent. Most studies, however, suggest a downregulation or loss of chemerin/RARRES2 in malignancies compared to the normal tissue counterparts. Here, we perform a comprehensive review of the literature to date and summarize relevant findings in order to better define the roles of chemerin in the setting of the tumor microenvironment and tumor immune responses, with an ultimate focus on the potential for therapeutic intervention.


Assuntos
Quimiocinas/imunologia , Regulação para Baixo/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Macrófagos/imunologia , Macrófagos/patologia , Neoplasias/patologia , Receptores de Quimiocinas/imunologia
17.
PLoS One ; 13(12): e0208472, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566481

RESUMO

OBJECTIVES: Several studies have indicated that early pet keeping could protect the infant from later allergy development. Here, we investigate if there is a dose-dependent association between cat- and dog-keeping during the first year of life and subsequent allergy development. METHODS: Two cohorts were investigated: a cross-sectional questionnaire-based study of 7- to 8-year-old children (N = 1029) from Mölndal and Kiruna, and a birth-cohort of children from the Västra Götaland county clinically evaluated for asthma and allergy by paediatricians up to the age of 8-9 years (N = 249). The cross-sectional study asked validated questions on asthma and allergy that had been used in two previous studies of children from the same areas. In the birth-cohort study, a diagnosis of asthma and allergy was based on predefined clinical criteria, and laboratory evaluation included blood eosinophils, skin-prick tests and specific immunoglobulin E analyses. Information on pets during first year of life was collected retrospectively in the Cross-Sectional Cohort and prospectively in the Birth Cohort. RESULTS: A dose-response association was seen, with less allergic manifestations (any of asthma, allergic rhinoconjunctivitis, or eczema) with increasing number of household cats and dogs during the first year of life. In the Cross-Sectional Cohort, allergy ever decreased from 49% in those with no pets to zero in those with five or more pets (P-value for trend 0.038), and from 32% to zero for allergy last year (P-value for trend 0.006). The same pattern was seen in Birth Cohort. Sensitization to animals, as well as pollens, also decreased with increasing number of animals in the household. CONCLUSION: The prevalence of allergic disease in children aged 7-9 years is reduced in a dose-dependent fashion with the number of household pets living with the child during their first year of life, suggesting a "mini-farm" effect, whereby cats and dogs protect against allergy development.


Assuntos
Vínculo Homem-Animal de Estimação , Hipersensibilidade/epidemiologia , Hipersensibilidade/prevenção & controle , Animais de Estimação/fisiologia , Alérgenos/farmacologia , Animais , Gatos , Criança , Estudos Transversais , Cães , Relação Dose-Resposta Imunológica , Regulação para Baixo/imunologia , Feminino , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/imunologia , Masculino , Prevalência , Estudos Retrospectivos , Fatores de Risco , Testes Cutâneos , Inquéritos e Questionários
18.
Cell Immunol ; 334: 42-48, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30327138

RESUMO

Ulcerative colitis (UC) is a persistent inflammatory illness, which is clinically categorised as Inflammatory bowel disease (IBD), affecting millions of people worldwide. The precise cause behind the pathology of the disease remains unknown. However, the involvement of multiple factors including genetic predisposition, immunological deregulations, microbiota imbalance, and environmental triggers has been suggested. Amongst all these factors, the over-active immunological response reported in UC patients seems to be a promising target for therapy. Moreover, identification of gene signatures associated with disease onset and progression would help in better understanding of the molecular mechanisms involved in the disease pathogenesis. Here, we have conducted meta-analysis of gene expression profiles of UC patient microarray datasets accessible in public databases and further validated the in-silico findings in UC patients' blood samples. Our study reveals that UC pathogenesis perturbs expression of several inflammatory genes. In addition, we report a novel gene signature comprising of TIA1 (T cell restricted intracellular antigen) and TIAR (TIA1 related protein; also known as TIAL1), which were found to be significantly downregulated in UC patients. TIA1 and TIAR are RNA-binding proteins (RBPs), which function as a translational represser by binding to ARE sequences in the 3' UTR of mRNAs encoding inflammatory mediators including cytokines. Our findings demonstrate that deletion of TIAR using gene specific siRNAs in-vitro results in enhanced production of inflammatory cytokine IL-1ß. In conclusion, the findings of this study reveal that down regulation of TIA1/TIAR genes could be responsible for UC associated inflammation. This study highlights the usefulness of the meta-analysis approach in the identification of unique gene signatures that might deliver mechanistic insights into UC pathogenesis and possibly assist in discovery of prognostic markers and therapeutic interventions.


Assuntos
Colite Ulcerativa/imunologia , Proteínas de Ligação a RNA/imunologia , Transcriptoma/imunologia , Regiões 3' não Traduzidas/imunologia , Regulação para Baixo/imunologia , Expressão Gênica/imunologia , Humanos , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-1beta/imunologia , RNA Mensageiro/imunologia , Antígeno-1 Intracelular de Células T/imunologia
19.
Sci Rep ; 8(1): 13543, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30201974

RESUMO

T lymphocytes have a crucial role in initiating and promoting type I allergies. Their responses are tightly regulated by numerous activating and inhibitory signals provided by APCs. Here we have addressed the role of the major coinhibitory receptors PD-1, CTLA-4, BTLA and LAG-3 in allergen-specific CD4+ T cell responses. PBMCs of healthy individuals and 41 patients allergic to house dust mites, birch, grass or mugwort pollen were stimulated with allergenic extracts and expression of coinhibitory receptors on responding CD4+ T cells was assessed. Blocking antibodies to PD-1, CTLA-4, BTLA and LAG-3 were used to evaluate the role of coinhibitory pathways. Allergen-specific CD4+ T cells showed strong upregulation of PD-1, LAG-3 and CTLA-4 upon stimulation, whereas BTLA was downregulated. Blockade of PD-1 strongly enhanced proliferation and cytokine production (IL-10; TH1 cytokines IFN-γ, TNF-α; TH2 cytokines IL-5, IL-13) of allergen-specific CD4+ T cells derived from allergic as well as non-allergic individuals. BTLA blockade enhanced proliferation but not cytokine production in response to house dust mite extract. Blocking LAG-3 was ineffective and surprisingly, we observed reduced proliferation and cytokine production in presence of a CTLA-4 antibody. Our results point to a unique potency of PD-1 pathways to dampen allergen-specific human T cells.


Assuntos
Alérgenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Hipersensibilidade/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Adulto , Antígenos CD/efeitos dos fármacos , Antígenos CD/imunologia , Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Proliferação de Células/efeitos dos fármacos , Estudos de Coortes , Citocinas/imunologia , Citocinas/metabolismo , Regulação para Baixo/imunologia , Feminino , Voluntários Saudáveis , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/tratamento farmacológico , Ativação Linfocitária , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/efeitos dos fármacos , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/imunologia
20.
Cell Death Dis ; 9(9): 885, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158514

RESUMO

Nucleoside diphosphate kinase 1 (NME1) is well-known as a tumor suppressor that regulates p53 function to prevent cancer metastasis and progression. However, the role of NME1 in virus-infected cells remains unknown. Here, we showed that NME1 suppresses viral replication in foot-and-mouth disease virus (FMDV)-infected cells. NME1-enhanced p53-mediated transcriptional activity and induction of interferon-inducible antiviral genes expression. FMDV infection decreased NME1 protein expression. The 2B and VP4 proteins were identified as the viral factors that induced reduction of NME1. FMDV 2B protein has a suppressive effect on host protein expression. We measured, for the first time, VP4-induced lysosomal degradation of host protein; VP4-induced degradation of NME1 through the macroautophagy pathway, and impaired p53-mediated signaling. p53 plays significant roles in antiviral innate immunity by inducing several interferon-inducible antiviral genes expression, such as, ISG20, IRF9, RIG-I, and ISG15. VP4 promoted interaction of p53 with murine double minute 2 (MDM2) through downregulation of NME1 resulting in destabilization of p53. Therefore, 5-flurouracil-induced upregulation of ISG20, IRF9, RIG-I, and ISG15 were suppressed by VP4. VP4-induced reduction of NME1 was not related to the well-characterized blocking effect of FMDV on cellular translation, and no direct interaction was detected between NME1 and VP4. The 15-30 and 75-85 regions of VP4 were determined to be crucial for VP4-induced reduction of NME1. Deletion of these VP4 regions also inhibited the suppressive effect of VP4 on NME1-enhanced p53 signaling. In conclusion, these data suggest an antiviral role of NME1 by regulation of p53-mediated antiviral innate immunity in virus-infected cells, and reveal an antagonistic mechanism of FMDV that is mediated by VP4 to block host innate immune antiviral response.


Assuntos
Antivirais/imunologia , Vírus da Febre Aftosa/imunologia , Febre Aftosa/imunologia , Regulação da Expressão Gênica/imunologia , Interferons/imunologia , Lisossomos/imunologia , Nucleosídeo NM23 Difosfato Quinases/imunologia , Proteína Supressora de Tumor p53/imunologia , Animais , Linhagem Celular , Regulação para Baixo/imunologia , Células HEK293 , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/imunologia , Transdução de Sinais/imunologia , Regulação para Cima/imunologia , Proteínas Virais/imunologia , Replicação Viral/imunologia
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