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1.
BMC Med Genet ; 21(1): 71, 2020 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-32252656

RESUMEN

BACKGROUND: Herein, we collected currently published data to comprehensively evaluate the impact of the FCGR2A (Fc fragment of IgG receptor IIa) rs1801274 and MUC5B (mucin 5B, oligomeric mucus/gel-forming) rs35705950 variations on susceptibility to pneumonia diseases. METHODS: We retrieved case-control studies from three online databases and applied the statistical approach of meta-analysis for a series of pooling analyses. RESULTS: A total of fourteen case-control studies were included for FCGR2A rs1801274; while thirty-one case-control studies were included for MUC5B rs35705950. No significant difference between pneumonia cases and controls for FCGR2A rs1801274 was found. However, MUC5B rs35705950 was significantly associated with pneumonia susceptibility in the whole population under the genetic models of allelic T vs. G [OR (odds ratio) =3.78], carrier T vs. G (OR = 3.31), TT vs. GG (OR = 13.66), GT vs. GG (OR = 4.78), GT + TT vs. GG (OR = 5.05), and TT vs. GG + GT (OR = 6.47) (all P < 0.001, Bonferroni-adjusted P < 0.006; false discovery rate-adjusted P < 0.0010). Furthermore, we observed a similar positive result for subgroup analyses of "Caucasian", "Asian", "population-based control", and "idiopathic pulmonary fibrosis". CONCLUSIONS: MUC5B rs35705950, but not FCGR2A rs1801274, increases susceptibility to clinical pneumonia, especially to idiopathic pulmonary fibrosis, in both the Caucasian and Asian populations.


Asunto(s)
Mucina 5B/genética , Neumonía/genética , Polimorfismo de Nucleótido Simple , Receptores de IgG/genética , Alelos , Grupo de Ascendencia Continental Asiática/genética , Grupo de Ascendencia Continental Asiática/estadística & datos numéricos , Estudios de Casos y Controles , Grupo de Ascendencia Continental Europea/genética , Grupo de Ascendencia Continental Europea/estadística & datos numéricos , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Fibrosis Pulmonar Idiopática/epidemiología , Fibrosis Pulmonar Idiopática/genética , Neumonía/epidemiología
2.
Nat Commun ; 11(1): 15, 2020 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900413

RESUMEN

DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.


Asunto(s)
Proteínas Sanguíneas/genética , Inflamación/genética , Adulto , Anciano , Anciano de 80 o más Años , Quimiocina CXCL10/genética , Estudios de Cohortes , Islas de CpG , Metilación de ADN , Epigenoma , Epigenómica , Femenino , Proteínas Ligadas a GPI/genética , Alemania , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Persona de Mediana Edad , Proteómica , Receptores de IgG/genética
3.
Immunity ; 52(1): 136-150.e6, 2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31940267

RESUMEN

Effector CD8+ T cells are important mediators of adaptive immunity, and receptor-ligand interactions that regulate their survival may have therapeutic potential. Here, we identified a subset of effector CD8+ T cells that expressed the inhibitory fragment crystallizable (Fc) receptor FcγRIIB following activation and multiple rounds of division. CD8+ T cell-intrinsic genetic deletion of Fcgr2b increased CD8+ effector T cell accumulation, resulting in accelerated graft rejection and decreased tumor volume in mouse models. Immunoglobulin G (IgG) antibody was not required for FcγRIIB-mediated control of CD8+ T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcγRIIB on CD8+ T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b+, but not Fcgr2b-/-, CD8+ T cells. Increased expression of FcγRIIB correlated with freedom from rejection following withdrawal from immunosuppression in a clinical trial of kidney transplant recipients. Together, these findings demonstrate a cell-intrinsic coinhibitory function of FcγRIIB in regulating CD8+ T cell immunity.


Asunto(s)
Apoptosis/inmunología , Linfocitos T CD8-positivos/inmunología , Fibrinógeno/inmunología , Receptores de IgG/inmunología , Adulto , Anciano , Animales , Caspasa 3/inmunología , Caspasa 7/inmunología , Línea Celular Tumoral , Femenino , Fibrinógeno/genética , Rechazo de Injerto/inmunología , Humanos , Inmunoglobulina G/inmunología , Inmunosupresión , Masculino , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Receptores de IgG/genética , Adulto Joven
6.
BMC Infect Dis ; 19(1): 1053, 2019 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-31842762

RESUMEN

BACKGROUND: HIV-specific Antibody Dependent Cell Cytotoxicity (ADCC) has shown to be important in HIV control and resistance. The ADCC is mediated primarily by natural killer cell activated through the binding of FcγRIIIa receptor to the Fc portion of antibody bound to the antigen expressed on the infected cells. However, no data is available on the influence of the polymorphism in FcγRIIIa receptor on HIV-specific ADCC response. METHODS: The Sanger's method of sequencing was used to sequence the exon of FcγRIIIa receptor while the ADCC activity was determined using NK cell activation assay. The polymorphism in FcγRIIIa receptor was assessed in HIV-infected Indian individuals with or without HIV-specific ADCC antibodies and its influence on the magnitude of HIV-specific ADCC responses was analyzed. RESULTS: Two polymorphisms: V176F (rs396991) and Y158H (rs396716) were observed. The Y158H polymorphism is reported for the first time in Indian population. Both, V176F (V/V genotype) (p = 0.004) and Y158H (Y/H genotype) (p = 0.032) were found to be significantly associated with higher magnitude of HIV-specific ADCC response. CONCLUSION: The study underscores the role of polymorphism in the FcγRIIIa receptor on HIV-specific ADCC response and suggests that the screening of the individuals for FcγRIIIa-V176F and Y158H polymorphisms could be useful for prediction of efficient treatment in monoclonal antibody-based therapies aimed at ADCC in HIV infection.


Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/genética , Infecciones por VIH/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Células Asesinas Naturales/inmunología , Polimorfismo de Nucleótido Simple/genética , Receptores de IgG/genética , Adolescente , Adulto , Anticuerpos Monoclonales/uso terapéutico , Femenino , Frecuencia de los Genes/genética , Genotipo , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/terapia , Humanos , Inmunoterapia , India , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento , Proteínas del Envoltorio Viral/farmacología , Adulto Joven
7.
Nat Commun ; 10(1): 4206, 2019 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-31562320

RESUMEN

Human immunoglobulin G (IgG) agonistic antibodies targeting costimulatory immunoreceptors represent promising cancer immunotherapies yet to be developed. Whether, and how, human IgG hinge and Fc impact on their agonistic functions have been disputed. Here, we show that different natural human IgGs confer divergent agonistic anti-CD40 immunostimulatory and antitumour activities in FcγR-humanized mice, including inactive IgG3 and superior IgG2. This divergence is primarily due to their CH1-hinges despite all human IgGs requiring Fc-FcγR binding for optimal agonistic activities. Unexpectedly, biophysical flexibility of these CH1-hinges inversely correlates with, and can modulate, their agonistic potency. Furthermore, IgG Fcs optimized for selective FcγR binding synergize with and still require IgG hinge, selected for rigidity, to confer improved anti-CD40 immunostimulatory and antitumour activities. These findings highlight the importance of both hinge rigidity and selective FcγR binding in antibody agonistic function, and the need for newer strategies to modulate antibody agonism for improved clinical application.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Antígenos CD40/inmunología , Inmunoglobulina G/inmunología , Neoplasias/inmunología , Receptores de IgG/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoterapia/métodos , Ratones Noqueados , Ratones Transgénicos , Neoplasias/metabolismo , Neoplasias/terapia , Unión Proteica , Receptores de IgG/agonistas , Receptores de IgG/genética
8.
Stem Cell Res ; 40: 101571, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31520889

RESUMEN

Autism spectrum disorder (ASD) is a neurological disorder with complex etiologies. In this study, urine cells were collected from a 16-year-old male with ASD and reprogrammed with the human SKOM transcription factors. The patient has a heterozygous C > T mutation of FCGR1B gene that was confirmed by sequencing analysis. The pluripotency was verified by gene expression and capacity of differentiation towards the three germ layers. This kind of iPSC will be valuable for further understanding the pathogenesis of ASD and help to develop drugs for treating ASD.


Asunto(s)
Línea Celular/citología , Células Madre Pluripotentes Inducidas/metabolismo , Adolescente , Trastorno del Espectro Autista/genética , Diferenciación Celular , Línea Celular/metabolismo , Células Cultivadas , Heterocigoto , Humanos , Células Madre Pluripotentes Inducidas/citología , Masculino , Mutación , Receptores de IgG/genética , Receptores de IgG/metabolismo
9.
BMC Cancer ; 19(1): 899, 2019 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-31500586

RESUMEN

BACKGROUND: Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients' selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. METHODS/DESIGN: CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses' duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients' cetuximab-mediated ADCC and characterize the tumor microenvironment. DISCUSSION: The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results' interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. TRIAL REGISTRATION: The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number ( NCT03874062 ).


Asunto(s)
Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Irinotecán/uso terapéutico , Receptores de IgG/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Humanos , Polimorfismo Genético , Resultado del Tratamiento
10.
Int J Immunogenet ; 46(6): 437-443, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31433132

RESUMEN

Numerous single nucleotide polymorphisms (SNPs) were explored in the Algerian population to evaluate associated ankylosing spondylitis (AS) genetic risk factors, but no study has identified the impact of copy number variations (CNVs). The aim of the study was to determine whether CNVs of CCL3L1, FCGR3A and FCGR3B genes were also associated with the susceptibility of AS disease in Algerian population. The data set of the current study is composed of 81 patients with AS and 119 healthy controls. All samples were genotyped by digital droplet PCR (ddPCR). Chi-square test and OR calculation were used to evaluate association between CNVs and AS and the risk associated with copy numbers (CN). In results, FCGR3A CN less than two copies (<2) was significantly increased in spondylitis patients (p = .0001, OR = 7.74 [2.32-25.74]). Additionally, FCGR3A CN < 2 copies association was present only in HLA-B27 (-) patients. We have concluded that FCGR3A deletions have an independent effect on AS regarding HLA-B27 status. This is the first study that investigated the CCL3L1 CNVs in relation to AS risk disease. It reveals that CCL3L1 and FCGR3B CNVs may not be involved in susceptibility to AS risk in the Algerian population.


Asunto(s)
Quimiocinas CC/genética , Receptores de IgG/genética , Espondilitis Anquilosante/genética , Adulto , Factores de Edad , Argelia , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Proteínas Ligadas a GPI/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Antígeno HLA-B27/genética , Humanos , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Factores Sexuales
11.
J Pharm Pharmacol ; 71(10): 1584-1598, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31373006

RESUMEN

OBJECTIVES: It has been confirmed that morphine was detrimental to patients with cancers. Hence, we aimed to reveal a certain mechanism of morphine in cancer development. METHODS: Microarray and GSEA analysis were utilized to seek for differently expressed genes and pathway. KEY FINDINGS: Bioinformatics analysis identified that downregulation of MARCKS and upregulation of miR-543 in samples treated with morphine. FcγR-mediated phagocytosis pathway was illustrated to be upregulated in the control. PANC-1 and DU145 cell viability was increased but apoptosis was declined as morphine concentration went up from 10-8 to 10-6  mol/l. On the other curve, the viability was reduced and apoptosis was elevated from 10-6 to 10-5  mol/l. The expression of miR-543 ran the same trend as cell viability. Assays in vivo and in vitro validated that miR-543 facilitated cell viability, tumour growth, levels of CA199 and PSA, whereas inhibited apoptosis. MARCKS could target and inhibit miR-543 expression, which exhibited an opposite effect on cancer progression. MiR-543 blocked but MARCKS activated FcγR-mediated phagocytosis pathway. CONCLUSIONS: Morphine at 10-6  mol/l could benefit miR-543 expression to inhibit MARCKS expression, consequently, blocking FcγR-mediated phagocytosis pathway, which contributed to the cancer progression in vitro and in vivo.


Asunto(s)
MicroARNs/genética , Morfina/farmacología , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada/genética , Fagocitosis/efectos de los fármacos , Receptores de IgG/genética , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Biología Computacional/métodos , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Regulación hacia Arriba/efectos de los fármacos
12.
PLoS One ; 14(7): e0219999, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31323052

RESUMEN

While pigs and rabbits are used as models for human immune diseases, FcγR binding is poorly characterized in both test species. To evaluate antibody binding to FcγRIIIA, a receptor involved in antibody-dependent cellular cytotoxicity, chimerized antibodies were generated by grafting the variable regions of a human IgG1 onto scaffolds from both species. The affinities of the parent and chimeric antibodies to the FcγRIIIA proteins from all three species were determined. While the human IgG1 and rabbit IgG had similar affinities for each FcγRIIIA with notable differences across species, pig IgG1 only bound pig FcγRIIIA with appreciable affinity. Also, the functional pig and rabbit proteins described here can be used in future experiments, such as pharmacology and mechanism of action studies.


Asunto(s)
Afinidad de Anticuerpos/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Receptores de IgG/metabolismo , Proteínas Recombinantes de Fusión , Animales , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Humanos , Inmunoglobulina G/aislamiento & purificación , Unión Proteica , Conejos , Receptores de IgG/genética , Receptores de IgG/aislamiento & purificación , Resonancia por Plasmón de Superficie , Porcinos
13.
J Toxicol Sci ; 44(7): 471-479, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31270303

RESUMEN

M1-microglia (neurotoxic microglia) regulate neuronal development and cell death and are involved in many pathologies in the brain. Although organotypic brain slice cultures are widely used to study the crosstalk between neurons and microglia, little is known about the properties of microglia in the mouse cerebral cortex slices. Here, we aimed to optimize the mouse cerebral slice cultures that reflect microglial functions and evaluate the effects of neurotoxic metals on M1-microglial activation. Most microglia in the cerebral slices prepared from postnatal day (P) 7 mice were similar to mature microglia in adult mice brains, but those in the slices prepared from P2 mice were immature, which is a conventional preparation condition. The degree of expression of M1-microglial markers (CD16 and CD32) and inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) by lipopolysaccharide, a representative microglia activator, in the cerebral slices of P7 mice were higher than that in the slices of P2 mice. These results indicate that M1-microglial activation can be evaluated more accurately in the cerebral slices of P7 mice than in those of P2 mice. Therefore, we next examined the effects of various neurotoxic metals on M1-microglial activation using the cerebral slices of P7 mice and found that methylmercury stimulated the activation to M1-microglia, but arsenite, lead, and tributyltin did not induce such activation. Altogether, the optimized mouse cerebral slice cultures used in this study can be a helpful tool to study the influence of various chemicals on the central nervous system in the presence of functionally mature microglia.


Asunto(s)
Corteza Cerebral/citología , Metales/toxicidad , Microglía/efectos de los fármacos , Microglía/fisiología , Animales , Animales Recién Nacidos , Arsenitos/toxicidad , Células Cultivadas , Corteza Cerebral/metabolismo , Citocinas/metabolismo , Expresión Génica , Mediadores de Inflamación/metabolismo , Plomo/toxicidad , Compuestos de Metilmercurio/toxicidad , Ratones Endogámicos C57BL , Microglía/metabolismo , Neuronas/fisiología , Receptores de IgG/genética , Receptores de IgG/metabolismo , Compuestos de Trialquiltina/toxicidad
14.
Elife ; 82019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31343409

RESUMEN

FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB's TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further reveal that such tilting by I232T unexpectedly bends the FcγRIIB's ectodomain toward plasma membrane to allosterically impede FcγRIIB's ligand association. I232T substitution reduces in situ two-dimensional binding affinities and association rates of FcγRIIB to interact with its ligands, IgG1, IgG2 and IgG3 by three to four folds. This allosteric regulation by an SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients.


Asunto(s)
Inmunoglobulina G/metabolismo , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación Missense , Receptores de IgG/genética , Receptores de IgG/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Humanos , Simulación de Dinámica Molecular , Proteínas Mutantes/química , Polimorfismo de Nucleótido Simple , Unión Proteica , Receptores de IgG/química
15.
Zool Res ; 40(5): 404-415, 2019 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-31343855

RESUMEN

Classical Fc receptors (FcRs) mediate the binding to and recognition of the Fc portion of antibodies and play an important role during immune responses in mammals. Although proteins similar to soluble FcRs have been identified in fish, little is known about the role of such proteins in fish immunity. Here, we cloned a cDNA sequence encoding a soluble Fc receptor for an immunoglobulin G (FcγR) homolog from ayu (Plecoglossus altivelis) (PaFcγRl). The predicted protein was composed of two immunoglobulin C2-like domains but lacked a transmembrane segment and a cytoplasmic tail. The PaFcγRl transcripts were distributed at low levels in all tested tissues, but significantly increased after Vibrio anguillarum infection. The PaFcγRl protein was expressed in the head kidney, trunk kidney, and neutrophils. Recombinant PaFcγRl (rPaFcγRl) was secreted when transfected into mammalian cells and the native protein was also detected in serum upon infection. rPaFcγRl was also demonstrated to bind to ayu IgM, as assessed by cell transfection. Suppressive activity of the recombinant mature protein of PaFcγRl (rPaFcγRlm) on in vitro anti-sheep red blood cell (SRBC) responses was detected by a modified hemolytic plaque forming cell assay. In conclusion, our study revealed that PaFcγRl is closely involved in the negative regulation of IgM production in the ayu spleen.


Asunto(s)
Peces/fisiología , Inmunoglobulina M/metabolismo , Receptores de IgG/metabolismo , Bazo/citología , Animales , Receptores de IgG/genética
16.
Int J Biol Macromol ; 138: 198-206, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31284005

RESUMEN

Antibody-dependent enhancement (ADE) in porcine reproductive and respiratory syndrome virus (PRRSV) infection is a significant obstacle to the development of effective vaccines for controlling PRRS. Our previous results have demonstrated that porcine FcγRIIb (poFcγRIIb) play an important role in mediating ADE of PRRSV infection in vitro. However, the underlying mechanisms involved in poFcγRIIb mediated-ADE are still not clear. In this study, MARC-145 cel1 lines stably expressing mutated poFcγRIIb (MARC-poFcγRIIb-T and MARC-poFcγRIIb-CT) in cytoplasm were established and the capacity of poFcγRIIb mutants in mediating ADE of PRRSV was investigated. Our results showed that removal of cytoplasmic domain or disruption the tyrosine residue within ITIM (immunoreceptor tyrosine-based inhibition motif) of the poFcγRIIb abolished the ability of poFcγRIIb to mediate ADE of PRRSV. Furthermore, we found that SHIP1 and TBK1 were involved in poFcγRIIb-mediated ADE of PRRSV infection. Taken together, our findings indicated that poFcγRIIb mediated the ADE pathway of PRRSV infection through recruiting SHIP-1, which further inhibited of TBK-1-IRF3-IFN-ß signaling pathway to enhance PRRSV infection. These findings will contribute to the molecular mechanism of ADE infection and provide some implications for vaccine development.


Asunto(s)
Acrecentamiento Dependiente de Anticuerpo , Citoplasma/metabolismo , Interferón beta/metabolismo , Virus del Síndrome Respiratorio y Reproductivo Porcino/fisiología , Receptores de IgG/metabolismo , Transducción de Señal , Secuencia de Aminoácidos , Animales , Línea Celular , Chlorocebus aethiops , Mutación , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/deficiencia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , ARN Interferente Pequeño/genética , Receptores de IgG/química , Receptores de IgG/genética , Porcinos , Replicación Viral
17.
Mucosal Immunol ; 12(5): 1212-1219, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31239514

RESUMEN

Gut-associated lymphoid tissue (GALT) is a key location for the HIV reservoir. The observation that B-cell-T-cell doublets are enriched for CD32a (a low-affinity IgG receptor) in peripheral blood raises interesting questions, especially as these cells have been associated with HIV DNA in some studies. We sought to determine if similar doublets were present in GALT, the significance of these doublets, and their implications for the HIV reservoir. Given the importance of GALT as a reservoir for HIV, we looked for expression of CD32 on gut CD4 T cells and for evidence of doublets, and any relationship with HIV DNA in HIV + individuals initiated on antiretroviral therapy (ART) during primary HIV infection (PHI). Tonsil tissue was also available for one individual. As previously shown for blood, CD32high CD4 cells were mainly doublets of CD4 T cells and B cells, with T-cell expression of ICOS in tonsil and gut tissue. CD4 T cells associated with CD32 (compared with 'CD32-' CD4 cells) had higher expression of follicular markers CXCR5, PD-1, ICOS, and Bcl-6 consistent with a T follicular helper (TFH) phenotype. There was a significant correlation between rectal HIV DNA levels and CD32 expression on TFH cells. Together, these data suggest that CD32high doublets are primarily composed of TFH cells, a subset known to be preferentially infected by HIV.


Asunto(s)
Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/fisiología , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/virología , Receptores de IgG/genética , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/virología , Adulto , Anciano , Terapia Antirretroviral Altamente Activa , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores , Recuento de Linfocito CD4 , Femenino , Expresión Génica , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Ganglios Linfáticos Agregados/inmunología , Receptores de IgG/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Carga Viral
18.
J Biol Chem ; 294(26): 10365-10378, 2019 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-31113864

RESUMEN

Receptor-interacting protein 2 (RIP2) is a kinase that mediates signaling downstream of the bacterial peptidoglycan sensors NOD1 and NOD2. Genetic loss or pharmaceutical inhibition of RIP2 has been shown to be beneficial in multiple inflammatory disease models with the effects largely attributed to reducing proinflammatory signaling downstream of peptidoglycan recognition. However, given the widespread expression of this kinase and its reported interactions with numerous other proteins, it is possible that RIP2 may also function in roles outside of peptidoglycan sensing. In this work, we show that RIP2 undergoes tyrosine phosphorylation and activation in response to engagement of the Fc γ receptor (FcγR). Using bone marrow-derived macrophages from WT and RIP2-KO mice, we show that loss of RIP2 leads to deficient FcγR signaling and reactive oxygen species (ROS) production upon FcγR cross-linking without affecting cytokine secretion, phagocytosis, or nitrate/nitrite production. The FcγR-induced ROS response was still dependent on NOD2, as macrophages deficient in this receptor showed similar defects. Mechanistically, we found that different members of the Src family kinases (SFKs) can promote RIP2 tyrosine phosphorylation and activation. Altogether, our findings suggest that RIP2 is functionally important in pathways outside of bacterial peptidoglycan sensing and that involvement in such pathways may depend on the actions of SFKs. These findings will have important implications for future therapies designed to target this kinase.


Asunto(s)
Macrófagos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/fisiología , Receptores de IgG/metabolismo , Animales , Citocinas/metabolismo , Inmunidad Innata/inmunología , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis , Fosforilación , Receptores de IgG/genética , Transducción de Señal
20.
Nat Commun ; 10(1): 2141, 2019 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-31105267

RESUMEN

Costimulation of T cell responses with monoclonal antibody agonists (mAb-AG) targeting 4-1BB showed robust anti-tumor activity in preclinical models, but their clinical development was hampered by low efficacy (Utomilumab) or severe liver toxicity (Urelumab). Here we show that isotype and intrinsic agonistic strength co-determine the efficacy and toxicity of anti-4-1BB mAb-AG. While intrinsically strong agonistic anti-4-1BB can activate 4-1BB in the absence of FcγRs, weak agonistic antibodies rely on FcγRs to activate 4-1BB. All FcγRs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating FcγR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting 4-1BB+ cells. This suggests balancing agonistic activity with the strength of FcγR interaction as a strategy to engineer 4-1BB mAb-AG with optimal therapeutic performance. As a proof of this concept, we have developed LVGN6051, a humanized 4-1BB mAb-AG that shows high anti-tumor efficacy in the absence of liver toxicity in a mouse model of cancer immunotherapy.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Inmunoterapia/métodos , Melanoma Experimental/terapia , Receptores de IgG/metabolismo , Neoplasias Cutáneas/terapia , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/antagonistas & inhibidores , Células 3T3 , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Línea Celular Tumoral/trasplante , Ensayos de Selección de Medicamentos Antitumorales , Técnicas de Sustitución del Gen , Humanos , Hígado/efectos de los fármacos , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de IgG/genética , Neoplasias Cutáneas/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
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