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1.
Glycoconj J ; 37(6): 729-744, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32915357

RESUMO

Apolipoprotein L1 (APOL1) wild type (G0) plays a role in the metabolism of sphingolipids, glycosphingolipids, sphingomyelin and ceramide, which constitute bioactive components of the lipid rafts (DRM). We asked whether APOL1 variants (APOL1-Vs) G1 and G2 carry the potential to alter the metabolism of sphingolipids in human podocytes. The sphingolipid pattern in HPs overexpressing either APOL1G0 or APOL1-Vs was analysed by using a thin mono- and bi-dimensional layer chromatography, mass-spectrometry and metabolic labelling with [1-3H]sphingosine. HP G0 and G1/G2-Vs exhibit a comparable decrease in lactosylceramide and an increase in the globotriaosylceramide content. An analysis of the main glycohydrolases activity involved in glycosphingolipid catabolism showed an overall decrease in the activeness of the tested enzymes, irrespective of the type of APOL1-Vs expression. Similarly, the high throughput cell live-based assay showed a comparable increased action of the plasma membrane glycosphingolipid-glycohydrolases in living cells independent of the genetic APOL1 expression profile. Importantly, the most significative modification of the sphingolipid pattern induced by APOL1-Vs occurred in DRM resulted with a drastic reduction of radioactivity associated with sphingolipids. G1/G2-Vs present a decrease amount of globotriaosylceramide and globopentaosylceramide compared to G0. Additionally, ceramide at the DRM site and lactosylceramide in general, showed a greatest fall in G1/G2 in comparison with G0. Additionally, the levels of glucosylceramide decreased only in the DRM of human podocytes overexpressing G1/G2-Vs. These findings suggest that altered sphingolipidsprofiles may contribute to the deranged functionality of the plasma membrane in APOL1 risk milieu.


Assuntos
Apolipoproteína L1/genética , Glicosídeo Hidrolases/genética , Podócitos/metabolismo , Esfingolipídeos/genética , Membrana Celular/genética , Membrana Celular/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Metabolismo , Polimorfismo Genético/genética , Esfingolipídeos/metabolismo
2.
Retrovirology ; 13(1): 63, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27599995

RESUMO

BACKGROUND: Patients of African ancestry with untreated HIV-1 infection and carrying the G1 or G2 kidney disease risk variants (Vs) at the APOL1 gene have a tenfold higher risk of developing HIV-associated nephropathy (HIVAN) compared to those with the non-risk wild type (WT) G0 variant. However, the mechanistic contribution of the APOL1 allelic state to kidney injury in HIV-1 infection remains to be elucidated. RESULTS: Non-risk WT APOL1 is associated with lower intracellular levels of HIV-1 in conditionally immortalized human podocytes, while the over expression of G1 or G2 risk Vs significantly increases viral accumulation. The priming of podocytes with exogenous IL-1ß facilitates HIV-1 entry, via the up-regulation of DC-SIGN. The over expression of APOL1 G1 and G2 risk Vs in combination with an increase in IL-1ß levels causes a greater increase in viral concentration than either condition alone. In turn, HIV-1 and exogenous IL-1ß together induce a de novo secretion of endogenous IL-1ß and an increase of APOL1 gene expression. CONCLUSIONS: Our findings indicate that the presence of risk Vs of APOL1 is permissive of HIV-1 persistence in human podocytes in synergy with IL-1ß, a cytokine that characterizes the inflammatory milieu of acute and chronic phases of HIV-1 infection. The elucidation of these molecular mechanisms explains, at least in part, the higher frequency of HIVAN in populations carrying the risk polymorphic genetic variant of APOL1 gene.


Assuntos
Nefropatia Associada a AIDS/genética , Apolipoproteínas/genética , Infecções por HIV/genética , HIV-1/fisiologia , Interleucina-1beta/imunologia , Lipoproteínas HDL/genética , Podócitos/virologia , Polimorfismo Genético , Nefropatia Associada a AIDS/imunologia , Nefropatia Associada a AIDS/virologia , África , Alelos , Apolipoproteína L1 , Moléculas de Adesão Celular/genética , Feminino , Predisposição Genética para Doença/etnologia , Infecções por HIV/etnologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Interleucina-1beta/biossíntese , Lectinas Tipo C/genética , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/genética , Internalização do Vírus
3.
iScience ; 26(11): 108331, 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-38026202

RESUMO

The C-C chemokine receptor type 5 (CCR5) expressed on immune cells supports inflammatory responses by directing cells to the inflammation site. CCR5 is also a major coreceptor for macrophage tropic human immunodeficiency viruses (R5-HIV-1) and its variants can confer protection from HIV infection, making it an ideal candidate to target for therapy. We developed a stepwise protocol that differentiates induced pluripotent stem cells (iPSCs) from individuals homozygous for the CCR5Δ32 variant and healthy volunteers into myeloid lineage induced monocytes (iMono) and macrophages (iMac). By characterizing iMono and iMac against their primary counterparts, we demonstrated that CCR5Δ32 homozygous cells are endowed with similar pluripotent potential for self-renewal and differentiation as iPSC lines generated from non-variant individuals while also showing resistance to HIV infection. In conclusion, these cells are a platform to investigate CCR5 pathophysiology in HIV-positive and negative individuals and to help develop novel therapies.

4.
Front Immunol ; 10: 946, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114585

RESUMO

The liver is considered a preferential tissue for NK cells residency. In humans, almost 50% of all intrahepatic lymphocytes are NK cells that are strongly imprinted in a liver-specific manner and show a broad spectrum of cellular heterogeneity. Hepatic NK (he-NK) cells play key roles in tuning liver immune response in both physiological and pathological conditions. Therefore, there is a pressing need to comprehensively characterize human he-NK cells to better understand the related mechanisms regulating their effector-functions within the dynamic balance between immune-tolerance and immune-surveillance. This is of particular relevance in the liver that is the only solid organ whose parenchyma is constantly challenged on daily basis by millions of foreign antigens drained from the gut. Therefore, the present review summarizes our current knowledge on he-NK cells in the light of the latest discoveries in the field of NK cell biology and clinical relevance.


Assuntos
Homeostase , Tolerância Imunológica , Imunidade Inata , Vigilância Imunológica , Células Matadoras Naturais/imunologia , Fígado/imunologia , Humanos , Células Matadoras Naturais/patologia , Fígado/fisiopatologia , Especificidade de Órgãos/imunologia
5.
Front Immunol ; 10: 1325, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244860

RESUMO

Dendritic cells (DCs) play a crucial role in initiating and shaping immune responses. The effects of DCs on adaptive immune responses depend partly on functional specialization of distinct DC subsets, and partly on the activation state of DCs, which is largely dictated by environmental signals. Fully activated immunostimulatory DCs express high levels of costimulatory molecules, produce pro-inflammatory cytokines, and stimulate T cell proliferation, whereas tolerogenic DCs express low levels of costimulatory molecules, produce immunomodulatory cytokines and impair T cell proliferation. Relevant to the increasing use of immune checkpoint blockade in cancer treatment, signals generated from inhibitory checkpoint molecules on DC surface may also contribute to the inhibitory properties of tolerogenic DCs. Yet, our knowledge on the expression of inhibitory molecules on human DC subsets is fragmentary. Therefore, in this study, we investigated the expression of three immune checkpoints on peripheral blood DC subsets, in basal conditions and upon exposure to pro-inflammatory and anti-inflammatory stimuli, by using a flow cytometric panel that allows a direct comparison of the activatory/inhibitory phenotype of DC-lineage and inflammatory DC subsets. We demonstrated that functionally distinct DC subsets are characterized by differential expression of activatory and inhibitory molecules, and that cDC1s in particular are endowed with a unique immune checkpoint repertoire characterized by high TIM-3 expression, scarce PD-L1 expression and lack of ILT2. Notably, this unique cDC1 repertoire was subverted in a group of patients with myelodysplastic syndromes included in the study. Applied to the characterization of DCs in the tumor microenvironment, this panel has the potential to provide valuable information to be used for investigating the role of DC subsets in cancer, guiding DC-targeting treatments, and possibly identifying predictive biomarkers for clinical response to cancer immunotherapy.


Assuntos
Células Dendríticas/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígeno B7-H1/metabolismo , Linhagem da Célula/imunologia , Citocinas/biossíntese , Células Dendríticas/classificação , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo/métodos , Voluntários Saudáveis , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia , Adulto Jovem
6.
JCI Insight ; 4(24)2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31689241

RESUMO

γδ T cells account for a large fraction of human intestinal intraepithelial lymphocytes (IELs) endowed with potent antitumor activities. However, little is known about their origin, phenotype, and clinical relevance in colorectal cancer (CRC). To determine γδ IEL gut specificity, homing, and functions, γδ T cells were purified from human healthy blood, lymph nodes, liver, skin, and intestine, either disease-free, affected by CRC, or generated from thymic precursors. The constitutive expression of NKp46 specifically identifies a subset of cytotoxic Vδ1 T cells representing the largest fraction of gut-resident IELs. The ontogeny and gut-tropism of NKp46+/Vδ1 IELs depends both on distinctive features of Vδ1 thymic precursors and gut-environmental factors. Either the constitutive presence of NKp46 on tissue-resident Vδ1 intestinal IELs or its induced expression on IL-2/IL-15-activated Vδ1 thymocytes are associated with antitumor functions. Higher frequencies of NKp46+/Vδ1 IELs in tumor-free specimens from CRC patients correlate with a lower risk of developing metastatic III/IV disease stages. Additionally, our in vitro settings reproducing CRC tumor microenvironment inhibited the expansion of NKp46+/Vδ1 cells from activated thymic precursors. These results parallel the very low frequencies of NKp46+/Vδ1 IELs able to infiltrate CRC, thus providing insights to either follow-up cancer progression or to develop adoptive cellular therapies.


Assuntos
Neoplasias Colorretais/imunologia , Mucosa Intestinal/citologia , Linfócitos Intraepiteliais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Linfócitos T Citotóxicos/imunologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos Ly/metabolismo , Colo/citologia , Colo/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Feminino , Humanos , Íleo/citologia , Íleo/imunologia , Imunoterapia Adotiva/métodos , Mucosa Intestinal/imunologia , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/transplante , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Globulina de Ligação a Hormônio Sexual , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/transplante , Adulto Jovem
7.
AIDS ; 31(17): 2317-2330, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-28926399

RESUMO

: Natural killer (NK) cells are important effectors of innate immunity playing a key role in the eradication and clearance of viral infections. Over the recent years, several studies have shown that HIV-1 pathologically changes NK cell homeostasis and hampers their antiviral effector functions. Moreover, high levels of chronic HIV-1 viremia markedly impair those NK cell regulatory features that normally regulate the cross talks between innate and adaptive immune responses. These pathogenic events take place early in the infection and are associated with a pathologic redistribution of NK cell subsets that includes the expansion of anergic CD56/CD16 NK cells with an aberrant repertoire of activating and inhibitory receptors. Nevertheless, the presence of specific haplotypes for NK cell receptors and the engagement of NK cell antibody-dependent cell cytotocity have been reported to control HIV-1 infection. This dichotomy can be extremely useful to both predict the clinical outcome of the infection and to develop alternative antiviral pharmacological approaches. Indeed, the administration of antiretroviral therapy in HIV-1-infected patients restores NK cell phenotype and functions to normal levels. Thus, antiretroviral therapy can help to develop NK cell-directed therapeutic strategies that include the use of broadly neutralizing antibodies and toll-like receptor agonists. The present review discusses how our current knowledge of NK cell pathophysiology in HIV-1 infection is being translated both in experimental and clinical trials aimed at controlling the infection and disease.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Células Matadoras Naturais/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Antígeno CD56/análise , Proteínas Ligadas por GPI/análise , Humanos , Imunidade Inata , Células Matadoras Naturais/química , Subpopulações de Linfócitos/imunologia , Receptores de IgG/análise
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