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1.
Adv Exp Med Biol ; 1204: 197-214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32152948

RESUMO

Siglecs are sialic acid (Sia) recognizing immunoglobulin-like receptors expressed on the surface of all the major leukocyte lineages in mammals. Siglecs recognize ubiquitous Sia epitopes on various glycoconjugates in the cell glycocalyx and transduce signals to regulate immunological and inflammatory activities of these cells. The subset known as CD33-related Siglecs is principally inhibitory receptors that suppress leukocyte activation, and recent research has shown that a number of bacterial pathogens use Sia mimicry to engage these Siglecs as an immune evasion strategy. Conversely, Siglec-1 is a macrophage phagocytic receptor that engages GBS and other sialylated bacteria to promote effective phagocytosis and antigen presentation for the adaptive immune response, whereas certain viruses and parasites use Siglec-1 to gain entry to immune cells as a proximal step in the infectious process. Siglecs are positioned in crosstalk with other host innate immune sensing pathways to modulate the immune response to infection in complex ways. This chapter summarizes the current understanding of Siglecs at the host-pathogen interface, a field of study expanding in breadth and medical importance, and which provides potential targets for immune-based anti-infective strategies.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/imunologia , Animais , Glicocálix/imunologia , Humanos , Leucócitos/citologia , Leucócitos/imunologia , Macrófagos/imunologia , Fagocitose , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia
2.
Cell Mol Life Sci ; 77(4): 593-605, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31485715

RESUMO

The mammalian immune system evolved to tightly regulate the elimination of pathogenic microbes and neoplastic transformed cells while tolerating our own healthy cells. Here, we summarize experimental evidence for the role of Siglecs-in particular CD33-related Siglecs-as self-receptors and their sialoglycan ligands in regulating this balance between recognition of self and non-self. Sialoglycans are found in the glycocalyx and extracellular fluids and matrices of all mammalian cells and can be considered as self-associated molecular patterns (SAMPs). We also provide an overview of the known interactions of Siglec receptors and sialoglycan-SAMPs. Manipulation of the Siglec-SAMP axis offers new therapeutic opportunities for the treatment of inflammatory conditions, autoimmune diseases and also cancer immunotherapy.


Assuntos
Imunidade , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/imunologia , Animais , Doenças Autoimunes/imunologia , Autoimunidade , Humanos , Inflamação/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia
3.
Blood ; 135(2): 85-96, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31765470

RESUMO

The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other additions include reapproval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway, and a liposomal formulation of daunorubicin and cytarabine (CPX-351). Genomically heterogeneous AML has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centered around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by hematologists in this era of new drugs include (1) the timely identification of actionable mutations at diagnosis and at relapse; (2) deciding which drug to use among several therapeutic options; and (3) increasing awareness of how to anticipate, mitigate, and manage common complications associated with these new agents. This article will use 3 case presentations to discuss some of the new treatment challenges encountered in AML management, with the goal of providing practical guidance to aid the practicing physician.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Mutação , Adulto , Idoso , Aminopiridinas/uso terapêutico , Compostos de Anilina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Feminino , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Prognóstico , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Sulfonamidas/uso terapêutico , Triazinas/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética
4.
J Surg Res ; 245: 552-563, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472311

RESUMO

BACKGROUND: It is elusive which subtypes of immune cells are pivotal in cancer progression and prognosis in gastric cancer (GC). The aim of this study is to clarify clinical impact of immature myeloid-derived immune cells in patients with GC who underwent curative gastrectomy with curative lymphadenectomy and treated with S-1 (tegafur/gimeracil/oteracil) postoperatively. METHODS: The prognostic impact of recruited CD33+ immature myeloid-derived cells were clinicopathologically analyzed in curatively resected stage II and III GC. Correlation of preoperative peripheral leukocyte fractions with recruited CD33+ immature cells was also assessed. RESULTS: Patients with high CD33+ cell counts in primary tumor showed dramatically worse prognosis (5-y recurrence-free survival 29.0%) than that of the counterparts (79.4%). High CD33+ cell counts independently predicted poor prognosis in stage II/III (hazard ratio, 4.34; P < 0.001). In analyses of each stage, high CD33+ cell count was pivotally associated with poor prognosis in both stages. There was no significant correlation of each peripheral leukocyte fraction with CD33+ cell recruitment. Of note, high CD33+ cell count was significantly correlated with hematogenous recurrence. CONCLUSIONS: Recruitment of CD33+ immature myeloid cells critically predict hematogenous recurrences in curatively resected advanced GC. These results give rational to focusing on CD33+ myeloid-derived cells as a novel approach to tackle advanced GC.


Assuntos
Células Supressoras Mieloides/imunologia , Recidiva Local de Neoplasia/diagnóstico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Neoplasias Gástricas/terapia , Estômago/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Gastrectomia , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Prognóstico , Estômago/citologia , Estômago/cirurgia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem
5.
Neurochem Res ; 44(11): 2670-2680, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31630317

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in memory and cognitive impairment. The use of somatostatin receptor subtype-4 (SSTR4) agonists have been proposed for AD treatment. This study investigated the effects of selective SSTR4 agonist NNC 26-9100 on mRNA expression of key genes associated with AD pathology (microglia mediators of Aß phagocytosis, amyloid-beta (Aß)-degrading enzymes, anti-oxidant enzymes and pro-inflammatory cytokines) in 3xTg-AD mice. Mice were administered NNC 26-9100 (0.2 µg, i.c.v.) or vehicle control, with cortical and subcortical brain tissue collected at 6 h and 24 h post-treatment. At 6 h, NNC 26-9100 treatment decreased cortical expression of cluster of differentiation-33 (Cd33) by 25%, while increasing cortical and subcortical macrophage scavenger receptor-1 (Msr1) by 1.8 and 2.0-fold, respectively. The Cd33 downregulation and Msr1 upregulation support a state of microglia associated Aß phagocytosis. At 24 h, NNC 26-9100 treatment increased the cortical expression of Sstr4 (4.9-fold), Aß-degrading enzymes neprilysin (9.3-fold) and insulin degrading enzyme (14.8-fold), and the antioxidant catalase (3.6-fold). Similar effects at 24 h were found in subcortical tissue with NNC 26-9100 treatment, but did not reach statistical significance. No changes in pro-inflammatory cytokine expression were found. These data demonstrated NNC 26-9100 facilitates transcriptional changes in brain tissue identified with Aß phagocytosis and clearance, further supporting SSTR4 as a treatment target for AD.


Assuntos
Encéfalo/metabolismo , Microglia/metabolismo , RNA Mensageiro/metabolismo , Receptores de Somatostatina/metabolismo , Doença de Alzheimer/patologia , Aminopiridinas/farmacologia , Animais , Encéfalo/citologia , Catalase/genética , Regulação para Baixo/efeitos dos fármacos , Insulisina/genética , Camundongos Transgênicos , Neprilisina/genética , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Receptores Depuradores Classe A/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Tioureia/análogos & derivados , Tioureia/farmacologia , Regulação para Cima/efeitos dos fármacos
6.
Neuron ; 103(5): 747-749, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487521

RESUMO

TREM2 and CD33 are microglial receptors associated with Alzheimer's disease (AD) risk. In this issue of Neuron, Griciuc et al. (2019) demonstrate opposing effects of CD33 and TREM2 on AD phenotypes, where CD33 deletion promotes neuroprotection in a manner dependent on TREM2.


Assuntos
Doença de Alzheimer , Humanos , Glicoproteínas de Membrana , Microglia , Neuroproteção , Fenótipo , Receptores Imunológicos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico
7.
Gen Physiol Biophys ; 38(5): 369-378, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31411573

RESUMO

CD33 is a myeloid-associated marker and belongs to the sialic acid-binding immunoglobulin (Ig)-like lectin (Siglec) family. Such types of receptors are highly expressed in acute myeloid leukemia, which could be used in its treatment. CD33 shows high variability in its expression levels with still unknown reasons. Here, we investigated the CD33 expression of monocytes in human blood samples processed at different temperatures and in dependence on their phagocytic activity against opsonized Escherichia coli. The samples were stained by fluorescently labelled anti-human CD14 to specify the monocyte population, anti-human CD33 antibodies to evaluate CD33 expression and analyzed by flow cytometry and confocal laser scanning microscopy. In blood samples kept at 37°C or first pre-chilled at 0°C with subsequent warming up to 37°C, the percentage of CD33-positive monocytes as well as their relative fluorescence intensity was up-regulated compared to samples kept constantly at 0°C. After exposure to E. coli the CD33 relative fluorescence intensity of the monocytes activated at 37°C was 3 to 4 times higher than that of those cells kept inactive at 0°C. Microscopic analysis showed internalisation of CD33 due to its enhanced expression on the surface followed by engulfment of E. coli.


Assuntos
Monócitos/imunologia , Monócitos/metabolismo , Fagocitose , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Temperatura , Escherichia coli/imunologia , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Monócitos/citologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/análise
9.
Neuron ; 103(5): 820-835.e7, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31301936

RESUMO

The microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer's disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenuated amyloid beta (Aß) pathology and improved cognition in 5xFAD mice, both of which were abrogated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Aß pathology and neurodegeneration but reduced Iba1+ cell numbers, all of which could not be rescued by additional CD33 knockout. RNA-seq profiling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upregulated in 5xFAD;CD33-/- and downregulated in 5xFAD;TREM2-/- mice. Differential gene expression in 5xFAD;CD33-/- microglia depended on the presence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 includes regulation of the IL-1ß/IL-1RN axis and a gene set in the "receptor activity chemokine" cluster. Our results should facilitate AD therapeutics targeting these receptors.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Cognição , Glicoproteínas de Membrana/genética , Microglia/metabolismo , Placa Amiloide/patologia , Receptores Imunológicos/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Reação de Fase Aguda/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Camundongos , Camundongos Knockout , Microglia/patologia , Fagocitose/genética
10.
Int J Pharm ; 568: 118518, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319147

RESUMO

Most antibody-based therapies for AML target a single antigen on the surface of AML cells, which has a limited clinical benefit due to unsatisfied targeting ability and antigen-negative escape. Here we described the development and specific targeting of daunorubicin (DNR)-loaded CD123/CD33 dual-antibody modified liposome, CD123/CD33-LP-DNR. Since the majority of AML cells carries at least one of the antigens of CD123 and CD33, it is promising to treat AML using the dual-targeting agents. In this study, antibody mixture of CD123 and CD33 (1:1, molar ratio) were thiolated and coupled to Mal-PEG2000-DSPE, then the antibody-Mal-PEG2000-DSPE conjugations were inserted on the DNR-loaded PEGylated liposomes (PEG-LP-DNR) via a post insertion method to prepare CD123/CD33-LP-DNR (antibody/S100PC, molar ratio, 0.06%). The cellular uptake and cytotoxicity were evaluated in THP-1 (CD123brightCD33bright) and HL-60 (CD123dimCD33bright) cells. Compared to the unmodified liposome, CD123/CD33-LP-DNR showed higher cellular uptake which was 1.8-times and 1.6-times in both THP-1 and HL-60 cells, respectively, while the cellular uptake increased to 1.5-times only in the CD123bright cells for the single-antibody modified liposome, CD123-LP-DNR. MTT assay indicated stronger cytotoxicity of CD123/CD33-LP-DNR than CD123-LP-DNR on AML cells. The results indicated that CD123/CD33-LP-DNR might present an effective delivery strategy to enhance the targeting ability against AML cells and potentially reduce the antigen-negative escape.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Daunorrubicina/administração & dosagem , Subunidade alfa de Receptor de Interleucina-3 , Leucemia Mieloide Aguda/tratamento farmacológico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Antibióticos Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Daunorrubicina/química , Liberação Controlada de Fármacos , Células HL-60 , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Lipossomos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Células THP-1 , Evasão Tumoral
11.
Mol Cell Biol ; 39(18)2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208978

RESUMO

A single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer's disease (AD) and causal for elevated mRNA lacking exon 2. In contrast to full-length CD33, transcripts lacking exon 2 result in CD33 protein unable to suppress activation responses in myeloid cells, including microglia. Currently, little is known about the regulation of CD33 exon 2 splicing. Using functional genomics and proteomic approaches, we found that SRSF1 and PTBP1 act as splicing enhancers to increase CD33 exon 2 inclusion in mRNA. Binding of PTBP1 to RNA sequences proximal to the intron 1-exon 2 splice junction is altered by the SNP and represents a potential mechanism behind the SNP-genotype dependent alternative splicing. Our studies also reveal that binding of SRSF1 to the CD33 RNA is not altered by the SNP genotype. Instead, a putative SRSF1 binding sequence at the 3' end of exon 2 directs CD33 exon 2 inclusion into the mRNA, indicating that PTBP1 and SRSF1 promote full-length isoform expression through different mechanisms. Our findings shed light on molecular interactions that regulate CD33 exon 2 splicing, ultimately impacting receptor expression on the cell surface. These data aid in the understanding of CD33's regulation of microglial signaling underpinning the AD genetic associations.


Assuntos
Doença de Alzheimer/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Polimorfismo de Nucleotídeo Único , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Idade de Início , Processamento Alternativo , Doença de Alzheimer/metabolismo , Sítios de Ligação , Éxons , Predisposição Genética para Doença , Células HeLa , Humanos , Células K562 , Proteômica/métodos , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/química , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Células THP-1
12.
Nat Commun ; 10(1): 2759, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227717

RESUMO

Langerhans cells (LC) are thought to be the only mononuclear phagocyte population in the epidermis where they detect pathogens. Here, we show that CD11c+ dendritic cells (DCs) are also present. These cells are transcriptionally similar to dermal cDC2 but are more efficient antigen-presenting cells. Compared to LCs, epidermal CD11c+ DCs are enriched in anogenital tissues where they preferentially interact with HIV, express the higher levels of HIV entry receptor CCR5, support the higher levels of HIV uptake and replication and are more efficient at transmitting the virus to CD4 T cells. Importantly, these findings are observed using both a lab-adapted and transmitted/founder strain of HIV. We also describe a CD33low cell population, which is transcriptionally similar to LCs but does not appear to function as antigen-presenting cells or acts as HIV target cells. Our findings reveal that epidermal DCs in anogenital tissues potentially play a key role in sexual transmission of HIV.


Assuntos
Células Dendríticas/virologia , Células Epidérmicas/virologia , Infecções por HIV/transmissão , HIV-1/imunologia , Apresentação do Antígeno/imunologia , Antígeno CD11c/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epidérmicas/imunologia , Células Epidérmicas/metabolismo , Epiderme/imunologia , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/patogenicidade , Voluntários Saudáveis , Humanos , Masculino , Cultura Primária de Células , Receptores CCR5/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Linfócitos T/imunologia , Internalização do Vírus
13.
Artigo em Inglês | MEDLINE | ID: mdl-31174697

RESUMO

TLRs, Siglecs and CD163 are cell surface receptors that play an important role in immune response and sepsis. The objective of this study was to assess changes in the expression levels of several of these receptors (TLR2, TLR4, CD163, Siglec-1, Siglec-3, Siglec-5 and Siglec-10) on the surface of peripheral blood mononuclear cells from pigs with sepsis caused by Haemophilus parasuis. Flow cytometry was employed to analyze samples from an experimental infection and from cell cultures. A significant increase in CD163, TLR2 and Siglec-3 expression during infection was seen. However, in vitro exposure of peripheral blood monocytes to bacteria or sera from infected pigs did not increase the expression of these receptors. These changes may be due to recruitment of monocytes into the blood compartment in response to H. parasuis-induced sepsis.


Assuntos
Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Infecções por Haemophilus/veterinária , Monócitos/imunologia , Receptores de Superfície Celular/genética , Sepse/veterinária , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Doenças dos Suínos/imunologia , Receptor 2 Toll-Like/genética , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Células Cultivadas , Infecções por Haemophilus/imunologia , Haemophilus parasuis , Monócitos/microbiologia , Receptores de Superfície Celular/imunologia , Sepse/imunologia , Sepse/microbiologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Suínos , Doenças dos Suínos/microbiologia , Receptor 2 Toll-Like/imunologia
14.
Biomed Pharmacother ; 115: 108903, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054508

RESUMO

CD33 is a susceptibility locus for late-onset Alzheimer's disease (AD). However, how the neural mechanism of CD33 affects cognition in the AD spectrum population remains unclear. We aimed to investigate the primary and interactive effects of the CD33 (rs3865444) genotype on brain function in patients with AD using global functional connectivity density (gFCD) mapping via resting-state functional magnetic resonance imaging. Furthermore, we used a conditional process analysis to identify the relationship among the CD33 genotype, gFCD, and cognition performance across the AD spectrum population. Compared to cognitively normal (CN) and mild cognitively impaired (MCI) subjects, patients with AD showed higher gFCD in the default mode network, and the CD33 genotype primarily influenced brain function in the fronto-striatal circuit. Importantly, an interaction between the CD33 genotype and AD was observed in the parahippocampal gyrus. During disease progression, the gFCD trajectories of the CD33 A + allele gradually decreased, whereas those of the CD33 CC allele displayed an inverted U-shaped curve. Furthermore, gFCD in the dorsal anterior cingulate cortex positively mediated the relationship between the CD33 genotype and cognition, while gFCD in the precuneus bidirectionally moderated the mediation in the AD spectrum. These findings provide new insights into the neural mechanisms underlying the influence of the CD33 genotype on cognitive performance and highlight the importance of precise therapeutic strategies for high-risk AD populations.


Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Giro do Cíngulo/fisiopatologia , Vias Neurais/fisiopatologia , Giro Para-Hipocampal/fisiopatologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Idoso , Doença de Alzheimer/fisiopatologia , Mapeamento Encefálico , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Feminino , Genótipo , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Giro Para-Hipocampal/diagnóstico por imagem , Polimorfismo de Nucleotídeo Único
15.
J Immunol Res ; 2019: 6032141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143782

RESUMO

CD33 (siglec-3), a well-known target in leukemia therapy, is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including NK cells. It may constitute a control mechanism of the innate immune system; nevertheless, its role as an inhibitory receptor remains elusive. Using human NK cells as a cellular model, we analyzed CD33 inhibitory function upon different activating receptors. In high-cytotoxicity NKL cells, CD33 displayed a prominent inhibition on cytotoxicity triggered by the activating receptors NKG2D and, in a lower extent, 2B4, whereas it did not inhibit NKp46-induced cytotoxicity. NKp46 was partially inhibited by CD33 only when low-cytotoxicity NKL cells were tested. CD33 triggering did not inhibit IFN-γ secretion, contrasting with ILT-2 and CD94/NKG2A inhibitory receptors that inhibited cytotoxicity and IFN-γ secretion induced by all activating receptors tested. CD33-mediated inhibition of NKG2D-induced triggering involved Vav1 dephosphorylation. Our results support the role of CD33 as an inhibitory receptor preferentially regulating the NKG2D/DAP10 cytotoxic signaling pathway, which could be involved in self-tolerance and tumor and infected cell recognition.


Assuntos
Infecções/imunologia , Células Matadoras Naturais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Citotoxicidade Imunológica , Humanos , Células K562 , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-vav/metabolismo , Receptores Imunológicos/metabolismo , Tolerância a Antígenos Próprios , Transdução de Sinais
16.
Expert Opin Biol Ther ; 19(7): 707-720, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31081696

RESUMO

INTRODUCTION: Enthusiasm for developing therapeutic bispecific antibodies (BsAbs) for cancer applications has become intense in the past decade facilitated by advances in molecular biology, hybridoma technology, and protein engineering. The central strategy in BsAb engineering is to combine the specificities directed at effector cells, and at a tumor target associated antigen (TAA) into a single construct. AREAS COVERED: This article highlights the clinical use of BsAbs to target effector cells to multiple myeloma (MM), non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). We discuss the successes, challenges, and future strategies. Secondary literature search was performed using Pubmed, clinicaltrials.gov and non-proprietary internet search engines. EXPERT OPINION: The use of BsAb constructs to target hematologic malignancies has achieved limited success to date. There continues to be a high level of enthusiasm for developing and applying new constructs to overcome the challenges in engineering and clinical application for hematologic malignancies.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Humanos , Imunoterapia , Subunidade alfa de Receptor de Interleucina-3/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
17.
Neurobiol Dis ; 127: 432-448, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30951849

RESUMO

Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aß). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1ß). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aß antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aß vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.


Assuntos
Doença de Alzheimer/genética , Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/efeitos dos fármacos , Curcumina/farmacologia , Expressão Gênica/efeitos dos fármacos , Imunidade Inata/genética , Microglia/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Fagocitose/efeitos dos fármacos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Receptores Imunológicos/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo
18.
Cancer Immunol Immunother ; 68(6): 937-949, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953118

RESUMO

Gliomas appear to be highly immunosuppressive tumors, with a strong myeloid component. This includes MDSCs, which are a heterogeneous, immature myeloid cell population expressing myeloid markers Siglec-3 (CD33) and CD11b and lacking markers of mature myeloid cells including MHC II. Siglec-3 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family and has been suggested to promote MDSC expansion and suppression. Siglecs form a recently defined family of receptors with potential immunoregulatory functions but only limited insight in their expression on immune regulatory cell subsets, prompting us to investigate Siglec expression on MDSCs. We determined the expression of different Siglec family members on monocytic-MDSCs (M-MDSCs) and polymorphnuclear-MDSCs (PMN-MDSCs) from blood of glioma patients and healthy donors, as well as from patient-derived tumor material. Furthermore, we investigated the presence of sialic acid ligands for these Siglecs on MDSCs and in the glioma tumor microenvironment. Both MDSC subsets express Siglec-3, -5, -7 and -9, with higher levels of Siglec-3, -7 and -9 on M-MDSCs and higher Siglec-5 levels on PMN-MDSCs. Similar Siglec expression profiles were found on MDSCs from healthy donors. Furthermore, the presence of Siglec-5 and -9 was also confirmed on PMN-MDSCs from glioma tissue. Interestingly, freshly isolated glioma cells predominantly expressed sialic acid ligands for Siglec-7 and -9, which was confirmed in situ. In conclusion, our data show a distinct Siglec expression profile for M- and PMN-MDSCs and propose possible sialic acid-Siglec interactions between glioma cells and MDSCs in the tumor microenvironment.


Assuntos
Neoplasias Encefálicas/imunologia , Glioma/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/imunologia , Transcriptoma/imunologia , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Feminino , Glioma/genética , Glioma/terapia , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
19.
J Clin Invest ; 129(3): 955-957, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776022

RESUMO

IgE-mediated activation of mast cells is a hallmark of an anaphylactic reaction to allergen. In this issue of the JCI, Duan et al. describe an approach for suppressing IgE-dependent mast cell activation, thereby suppressing anaphylaxis. Specifically, the authors show that delivery of liposomes containing both the specific antigen recognized by the mast cell-bound IgE and a high-affinity glycan ligand of the inhibitory receptor CD33 (CD33L) to targeted mast cells inhibits antigen-induced, FcεRI-dependent spleen tyrosine kinase (Syk) phosphorylation and downstream protein tyrosine kinase (PTK) phosphorylation, Ca++ flux, and ß-hexosaminidase release (i.e., degranulation). However, this strategy only worked if both the antigen (reactive with the mast cell-bound IgE) and CD33L were on the same liposome. This approach promises to rapidly reduce IgE-dependent mast cell activation in response to challenge with offending allergens.


Assuntos
Anafilaxia , Mastócitos/imunologia , Alérgenos , Degranulação Celular , Humanos , Imunoglobulina E , Receptores de IgE , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Quinase Syk
20.
J Mol Biol ; 431(9): 1805-1817, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30738892

RESUMO

Research into the function of microglia has dramatically accelerated during the last few years, largely due to recent genetic findings implicating microglia in virtually every neurodegenerative disorder. In Alzheimer's disease (AD), a majority of risk loci discovered through genome-wide association studies were found in or near genes expressed most highly in microglia leading to the hypothesis that microglia play a much larger role in disease progression than previously thought. From this body of work produced in the last several years, we find that almost every function of microglia has been proposed to influence the progression of AD from altered phagocytosis and synaptic pruning to cytokine secretion and changes in trophic support. By studying key Alzheimer's risk genes such as TREM2, CD33, ABCA7, and MS4A6A, we will be able to distinguish true disease-modulatory pathways from the full range of microglial-related functions. To successfully carry out these experiments, more advanced microglial models are needed. Microglia are quite sensitive to their local environment, suggesting the need to more fully recapitulate an in vivo environment to study this highly plastic cell type. Likely only by combining the above approaches will the field fully elucidate the molecular pathways that regulate microglia and influence neurodegeneration, in turn uncovering potential new targets for future therapeutic development.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Microglia/metabolismo , Receptores Imunológicos/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Progressão da Doença , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Microglia/patologia , Plasticidade Neuronal/genética , Especificidade de Órgãos , Fagocitose/genética , Fenótipo , Receptores Imunológicos/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo
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