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1.
Immunol Cell Biol ; 98(4): 287-304, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32157732

RESUMEN

The human fragment crystallizable (Fc)γ receptor (R) interacts with antigen-complexed immunoglobulin (Ig)G ligands to both activate and modulate a powerful network of inflammatory host-protective effector functions that are key to the normal physiology of immune resistance to pathogens. More than 100 therapeutic monoclonal antibodies (mAbs) are approved or in late stage clinical trials, many of which harness the potent FcγR-mediated effector systems to varying degrees. This is most evident for antibodies targeting cancer cells inducing antibody-dependent killing or phagocytosis but is also true to some degree for the mAbs that neutralize or remove small macromolecules such as cytokines or other Igs. The use of mAb therapeutics has also revealed a "scaffolding" role for FcγR which, in different contexts, may either underpin the therapeutic mAb action such as immune agonism or trigger catastrophic adverse effects. The still unmet therapeutic need in many cancers, inflammatory diseases or emerging infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires increased effort on the development of improved and novel mAbs. A more mature appreciation of the immunobiology of individual FcγR function and the complexity of the relationships between FcγRs and antibodies is fueling efforts to develop more potent "next-gen" therapeutic antibodies. Such development strategies now include focused glycan or protein engineering of the Fc to increase affinity and/or tailor specificity for selective engagement of individual activating FcγRs or the inhibitory FcγRIIb or alternatively, for the ablation of FcγR interaction altogether. This review touches on recent aspects of FcγR and IgG immunobiology and its relationship with the present and future actions of therapeutic mAbs.


Asunto(s)
Anticuerpos Monoclonales , Inmunoterapia , Receptores de IgG/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/terapia
2.
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
3.
J Virol ; 94(5)2020 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-31826992

RESUMEN

Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.


Asunto(s)
Anticuerpos Antivirales/inmunología , Acrecentamiento Dependiente de Anticuerpo , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Línea Celular , Dipeptidil Peptidasa 4/metabolismo , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , Péptido Hidrolasas/metabolismo , Proproteína Convertasas/antagonistas & inhibidores , Proproteína Convertasas/metabolismo , Conformación Proteica , Dominios Proteicos , Multimerización de Proteína , Receptores Fc/metabolismo , Receptores de IgG/inmunología , Receptores de IgG/metabolismo , Receptores Virales/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Tripsina/metabolismo
4.
Life Sci ; 242: 117223, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31881222

RESUMEN

Acute lymphoblastic leukemia (ALL) is an aggressive cancer in children and adults which possess higher CD47 expression than normal cells. ALL chemotherapy has a lot of side effects and in most cases is ineffective. However arrival of Natural killer (NK) cell immunotherapy raised hopes for successful treatment of cancers, tailoring NK cells to meet clinical requirements is still under investigation. Of note, CD16+ (FCγIIIa) NK cells eliminate tumor cells with antibody dependent cell cytotoxicity (ADCC) mechanism. Therefore, we evaluated ADCC effect of cord blood stem cell derived CD16+ NK cells with using anti CD47 blocking antibody. CD16+ NK cells generated efficiently from CD34 positive cord blood cells in vitro using IL-2, IL-15 and IL-21 cytokines, although it was not dose dependent. CD16+ cells derived from CD34+ cells in day 14 of culture efficiently increased apoptosis in ALL cells, produced INFγ and increased CD107-a expression when used anti CD47 antibody (increased around 30-40%). Interestingly, CD16+ NK cell cytotoxicity slightly increased in combination with macrophages against ALL cells (around 10%). Taken together, our findings induced this hope that cord blood stem cell derived CD16+ NK cells exploit antitumor immune response in cancer therapy with using anti-CD47 antibody.


Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Antígeno CD47/inmunología , Trasplante de Células Madre de Sangre del Cordón Umbilical , Células Asesinas Naturales/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Receptores de IgG/inmunología , Anticuerpos Antiidiotipos/inmunología , Western Blotting , Línea Celular Tumoral , Citometría de Flujo , Humanos , Inmunoterapia/métodos , Microscopía Fluorescente , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
5.
Immunol Res ; 67(4-5): 373-381, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31773491

RESUMEN

The aim of this study was to evaluate the changes in the three subsets of monocyte (classical, intermediate, and non-classical) and the expression of human leukocyte antigen-DR (HLA-DR) on monocyte subsets during MP pneumonia in children. Monocyte subsets were analyzed in the peripheral blood of healthy volunteers and MP pneumonia patients at the stages of admission and remission after clinical therapy. They were defined as classical (CD14+CD16-), intermediate (CD14brightCD16+), and non-classical (CD14dimCD16+) using flow cytometry. Furthermore, three subsets of monocyte were analyzed for the expression of HLA-DR. Patients with MP pneumonia at admission had a higher proportion of intermediate and non-classical monocytes than healthy subjects (all P < 0.05). The proportion of intermediate subset and non-classical subset was lower in MP pneumonia patients at remission than at admission (all P < 0.05). In comparison with the other monocyte subsets, intermediate subset showed a significantly higher percentage of HLA-DR in MP pneumonia patients at admission (P < 0.05). Further analysis revealed that the expression of HLA-DR on intermediate subset was lower in severe patients than in non-severe patients (P < 0.05).Our data has shown for the first time that MP pneumonia is associated with the increased proportion of non-classical and intermediate monocytes, indicating the involvement of monocyte-related mechanisms in the pathogenesis of this disease. Additionally, the decreased expression of HLA-DR on CD14brightCD16+ subset may be a potential indicator of the severity of MP pneumonia.


Asunto(s)
Citometría de Flujo , Antígenos HLA-DR , Receptores de Lipopolisacáridos , Monocitos , Mycoplasma pneumoniae , Neumonía por Mycoplasma , Receptores de IgG , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Antígenos HLA-DR/sangre , Antígenos HLA-DR/inmunología , Humanos , Receptores de Lipopolisacáridos/sangre , Receptores de Lipopolisacáridos/inmunología , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/patología , Mycoplasma pneumoniae/inmunología , Mycoplasma pneumoniae/metabolismo , Neumonía por Mycoplasma/sangre , Neumonía por Mycoplasma/inmunología , Neumonía por Mycoplasma/patología , Receptores de IgG/sangre , Receptores de IgG/inmunología
6.
Cancer Immunol Immunother ; 68(11): 1769-1778, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31616964

RESUMEN

Various immune cells are recruited in the tumor microenvironment. It is well established that cellular immune responses, such as cytotoxic or suppressive activities, play an important role in regulating tumor growth and metastasis. However, the contribution of humoral immune responses against tumors is poorly understood. Fc receptors constitute critical elements for the up- or downregulation of immune responses through immune complexes. Here, we examined the potential role of the inhibitory Fc receptor, Fcγ receptor IIB (FcγRIIB), in tumor immunity using a mouse model. Our findings indicated that tumor-specific antibodies are induced in tumor-bearing mice and control tumor immunity. FcγRIIB deletion significantly improved both cellular and humoral immunity against tumors and delayed tumor growth. These findings indicated that spontaneous antibodies against tumors create a suppressive tumor microenvironment through FcγRIIB signaling, thus suggesting an attractive therapeutic target for cancer immunotherapy.


Asunto(s)
Anticuerpos/inmunología , Carcinoma Pulmonar de Lewis/terapia , Inmunoterapia , Receptores de IgG/fisiología , Timoma/terapia , Neoplasias del Timo/terapia , Microambiente Tumoral/inmunología , Animales , Carcinoma Pulmonar de Lewis/inmunología , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de IgG/inmunología , Timoma/inmunología , Timoma/metabolismo , Timoma/patología , Neoplasias del Timo/inmunología , Neoplasias del Timo/metabolismo , Neoplasias del Timo/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Med Sci Monit ; 25: 7728-7734, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31612870

RESUMEN

BACKGROUND The aim of this study was to determine the relationship between the expression of CD35 and CD64 from white blood cells (neutrophil, monocytes, and lymphocytes) and acute infectious diseases in children. MATERIAL AND METHODS The blood samples were collected from 104 children with infections (42 viral infections and 62 bacterial infections). Blood samples were stained with CD45-PC5, CD35-FITC, and CD64-PE, and the fluorescence intensities were measured by flow cytometer, and then the ratio of CD35 to CD64 was calculated. RESULTS The ratio of CD64/CD35 on neutrophils (NCD35/NCD64) was significantly different between the bacterial group, the virus group, and the healthy control group. According to receiver operating characteristic (ROC) analysis, a cutoff value of 7.256 (sensitivity: 90.0%, specificity: 93.7%) was determined for the NCD35/NCD64 ratio. CONCLUSIONS This study shows that NCD35/NCD64 is helpful in the differential diagnosis of acute viral infection and bacterial infection in children.


Asunto(s)
Infecciones Bacterianas/diagnóstico , Neutrófilos/inmunología , Receptores de Complemento 3b/inmunología , Receptores de IgG/inmunología , Virosis/diagnóstico , Infecciones Bacterianas/sangre , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Biomarcadores/sangre , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Citometría de Flujo/métodos , Humanos , Recuento de Leucocitos/métodos , Leucocitos/metabolismo , Linfocitos/metabolismo , Masculino , Monocitos/metabolismo , Neutrófilos/citología , Neutrófilos/metabolismo , Receptores de Complemento 3b/sangre , Receptores de IgG/sangre , Virosis/sangre , Virosis/inmunología , Virosis/microbiología
8.
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
9.
Reprod Biol Endocrinol ; 17(1): 72, 2019 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-31472670

RESUMEN

BACKGROUND: Peripheral and uterine natural killer cells (pNK and uNK cells) are key players in the establishment and maintenance of pregnancy and are disturbed in patients with recurrent miscarriage (RM). Different immunologic risk factors have been proposed between patients with primary RM (pRM, no previous live birth) and secondary RM (sRM, ≥ 1 previous live birth). However, so far, the study populations mainly consisted of small subgroups. Therefore, we aimed to analyse pNK and uNK cells in a large, well defined study population within a prospective study. METHODS: In total, n = 575 RM patients (n = 393 pRM, n = 182 sRM) were screened according to a standard protocol for established risk factors as well as pNK and uNK cells. Peripheral blood levels of CD45+CD3-CD56+CD16+ NK cells were determined by flow cytometry and uterine CD56+ NK cells by immunohistochemistry in mid-luteal non-pregnant RM patients. Exclusion of patients with ≥1 established risk factor revealed n = 248 idiopathic RM patients (iRM, n = 167 primary iRM (ipRM), n = 81 secondary iRM (isRM)). RESULTS: Patients with pRM and ipRM showed significant higher absolute numbers and percentages of pNK cells compared to sRM and isRM patients (pRM/ipRM vs sRM/isRM, mean ± SD /µl: 239.1 ± 118.7/244.9 ± 112.9 vs 205.1 ± 107.9/206.0 ± 105.6, p = 0.004/ p = 0.009; mean ± SD %: 12.4 ± 5.5/12.8 ± 5.4 vs 11.1 ± 4.6/11.1 ± 4.3, p = 0.001; p = 0.002). Only patients with isRM showed significantly higher uNK levels compared to patients with ipRM (mean ± SD /mm2 288.4 ± 239.3 vs 218.2 ± 184.5, p = 0.044). CONCLUSIONS: The demonstrated differences in pNK and uNK cells in RM patients depending on previous live birth might indicate differences in NK cell recruitment and potentially different underlying immune disorders between pRM and sRM. As there is an overlap in the distribution of the NK cell results, further studies with focus on NK cell function are needed in order to clearly identify RM patients with distinct immune abnormalities. The clinical relevance of our findings should be interpreted cautiously until specificity and sensitivity are further evaluated.


Asunto(s)
Aborto Habitual/inmunología , Células Asesinas Naturales/inmunología , Nacimiento Vivo , Paridad/inmunología , Útero/inmunología , Aborto Habitual/sangre , Adulto , Complejo CD3/inmunología , Complejo CD3/metabolismo , Antígeno CD56/inmunología , Antígeno CD56/metabolismo , Femenino , Humanos , Células Asesinas Naturales/metabolismo , Antígenos Comunes de Leucocito/inmunología , Antígenos Comunes de Leucocito/metabolismo , Recuento de Leucocitos , Embarazo , Estudios Prospectivos , Receptores de IgG/inmunología , Receptores de IgG/metabolismo , Factores de Riesgo
10.
Med Oncol ; 36(10): 84, 2019 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-31493232

RESUMEN

As the prognosis of colorectal cancer (CRC) does not always coincide with the pathology and/or surgical findings, a reliable noninvasive prediction tool for the prognosis of CRC is needed. Patients admitted for initial treatment of CRC between January 1, 2015 and December 31, 2015 were retrieved and reviewed. Records of circulating CD16+ CD56+ natural killer (NK) cells were analyzed before and after the initial chemotherapy of FOLFOX plan. Patients were followed up until June 30, 2019. One hundred and twenty-four cases after the FOLFOX chemotherapy were enrolled into this study. There were no significant differences in gender, age, or number of metastasis cases between the survival group and the nonsurvival group (p > 0.05), but significant differences in pre-chemotherapy, post-chemotherapy, and the differences between pre- and post-chemotherapy circulating CD16+ CD56+ NK cells between the survival group and the nonsurvival group (p < 0.01, p < 0.01, and p < 0.05, respectively) were observed. For the prediction of survival and nonsurvival CRC cases, the Areas Under the Curve were 0.626 and 0.759 in the Receiver-Operating Characteristic curves for the pre- and post-chemotherapy circulating CD16+ CD56+NK cells, respectively. Using an optimal cutoff value of 11.8% in post-chemotherapy circulating CD16+CD56+NK cells to differentiate survival and nonsurvival cases, the odds ratio was 0.12 (0.05, 0.27), p < 0.001. The percentages of both pre-chemotherapy and post-chemotherapy circulating CD16+CD56+NK cells were negatively correlated with the prognosis of CRC. The percentage of post-chemotherapy circulating CD16+CD56+NK cells was able to effectively predict the prognosis of CRC cases.


Asunto(s)
Antígeno CD56/inmunología , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Células Asesinas Naturales/patología , Receptores de IgG/inmunología , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Femenino , Proteínas Ligadas a GPI/inmunología , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos
11.
Cells ; 8(9)2019 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-31514375

RESUMEN

In patients with active lupus, spontaneous endotoxemia and possibly tolerance to lipopolysaccharide (LPS) is a potentially adverse complication. Similarly, previous reports have demonstrated that FcGRIIb deficient mice (FcGRIIb-/-; a lupus mouse model) are susceptible to LPS tolerance-induced decreased cytokine responses that inadequate for the organismal control. Thus, understanding the relationship between FcGRIIb and LPS tolerance could improve the therapeutic strategy for lupus. LPS tolerance can be induced through sequential LPS stimulations in either cells or a model organism. In RAW264.7 (a mouse macrophage cell-line), sequential LPS stimulation induced the secretion of Lipocalin-2 (Lcn-2) despite reduced cytokine secretion and severe energy depletion, as measured by the extracellular flux analysis, typical of LPS tolerance. In contrast, treatment with recombinant Lcn-2 (rLcn-2) attenuated LPS tolerance, as shown by an increase in secreted cytokines and altered macrophage polarization toward M1 (increased iNOS and TNF-α) in RAW264.7 cells. These results suggest a role of Lcn-2 in LPS tolerance attenuation. In bone marrow derived macrophages, Lcn-2 level was similar in LPS tolerant FcGRIIb-/- and wild-type (WT) cells despite the increased LPS tolerance of FcGRIIb-/- cells, suggesting relatively low basal levels of Lcn-2 produced in FcGRIIb-/- cells. In addition, attenuation of LPS tolerance effectuated by granulocyte-monocyte colony stimulating factor (GM-CSF) reduced Lcn-2 in both cell types, implying an inverse correlation between Lcn-2 and the severity of LPS tolerance. Consequently, rLcn-2 improved LPS tolerance only in FcGRIIb-/- macrophages and attenuated disease severity of cecal ligation and puncture (CLP) sepsis pre-conditioning with sequential LPS injection (LPS-CLP model) only in FcGRIIb-/- mice, but not in WT mice. To summarize, inadequate Lcn-2 production in FcGRIIb-/- macrophage might, at least in part, be responsible for the inordinate LPS tolerance compared with WT cells. Additionally, supplementation of rLcn-2 attenuates LPS tolerance in FcGRIIb-/- macrophages in vitro, and in FcGRIIb-/- mice with LPS-CLP sepsis in vivo. In conclusion, Lcn-2 secreted by macrophages is possibly an autocrine signal to counter the reduced cytokine secretion in LPS tolerance.


Asunto(s)
Endotoxemia/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Lipocalina 2 , Lipopolisacáridos/inmunología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Receptores de IgG/inmunología , Animales , Citocinas/inmunología , Modelos Animales de Enfermedad , Endotoxemia/etiología , Lipocalina 2/farmacología , Lipocalina 2/fisiología , Lupus Eritematoso Sistémico/complicaciones , Macrófagos , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Proteínas Recombinantes/farmacología
12.
mSphere ; 4(5)2019 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-31533998

RESUMEN

Dengue is caused by infection with any one of four dengue viruses (DENV); the risk of severe disease appears to be enhanced by the cross-reactive or subneutralizing levels of antibody from a prior DENV infection. These antibodies opsonize DENV entry through the activating Fc gamma receptors (FcγR), instead of infection through canonical receptor-mediated endocytosis, to result in higher levels of DENV replication. However, whether the enhanced replication is solely due to more efficient FcγR-mediated DENV entry or is also through FcγR-mediated alteration of the host transcriptome response to favor DENV infection remains unclear. Indeed, more efficient viral entry through activation of the FcγR can result in an increased viral antigenic load within target cells and confound direct comparisons of the host transcriptome response under antibody-dependent and antibody-independent conditions. Herein, we show that, despite controlling for the viral antigenic load in primary monocytes, the antibody-dependent and non-antibody-dependent routes of DENV entry induce transcriptome responses that are remarkably different. Notably, antibody-dependent DENV entry upregulated DENV host dependency factors associated with RNA splicing, mitochondrial respiratory chain complexes, and vesicle trafficking. Additionally, supporting findings from other studies, antibody-dependent DENV entry impeded the downregulation of ribosomal genes caused by canonical receptor-mediated endocytosis to increase viral translation. Collectively, our findings support the notion that antibody-dependent DENV entry alters host responses that support the viral life cycle and that host responses to DENV need to be defined in the context of its entry pathway.IMPORTANCE Dengue virus is the most prevalent mosquito-borne viral infection globally, resulting in variable manifestations ranging from asymptomatic viremia to life-threatening shock and multiorgan failure. Previous studies have indicated that the risk of severe dengue in humans can be increased by a specific range of preexisting anti-dengue virus antibody titers, a phenomenon termed antibody-dependent enhancement. There is hence a need to understand how antibodies augment dengue virus infection compared to the alternative canonical receptor-mediated viral entry route. Herein, we show that, besides facilitating viral uptake, antibody-mediated entry increases the expression of early host dependency factors to promote viral infection; these factors include RNA splicing, mitochondrial respiratory chain complexes, vesicle trafficking, and ribosomal genes. These findings will enhance our understanding of how differences in entry pathways can affect host responses and offer opportunities to design therapeutics that can specifically inhibit antibody-dependent enhancement of dengue virus infection.


Asunto(s)
Anticuerpos Antivirales/inmunología , Virus del Dengue/fisiología , Interacciones Microbiota-Huesped , Receptores de IgG/inmunología , Internalización del Virus , Acrecentamiento Dependiente de Anticuerpo , Antígenos Virales/inmunología , Línea Celular , Células Cultivadas , Dengue/virología , Humanos , Monocitos/inmunología , Monocitos/virología , Análisis de Secuencia de ARN , Transcriptoma , Replicación Viral
13.
Mol Immunol ; 114: 629-642, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31542608

RESUMEN

Neutrophils are essential to the pathogenesis of many inflammatory diseases. In the autoantibody-mediated K/BxN model of inflammatory arthritis, the alternative pathway (AP) of complement and Fc gamma receptors (FcγRs) are required for disease development while the classical pathway is dispensable. The reason for this differential requirement is unknown. We show that within minutes of K/BxN serum injection complement activation (CA) is detected on circulating neutrophils, as evidenced by cell surface C3 fragment deposition. CA requires the AP factor B and FcγRs but not C4, implying that engagement of FcγRs by autoantibody or immune complexes directly triggers AP C3 convertase assembly. The absence of C5 does not prevent CA on neutrophils but diminishes the upregulation of adhesion molecules. In vivo two-photon microscopy reveals that CA on neutrophils is critical for neutrophil extravasation and generation of C5a at the site of inflammation. C5a stimulates the release of neutrophil proteases, which contribute to the degradation of VE-cadherin, an adherens junction protein that regulates endothelial barrier integrity. C5a receptor antagonism blocks the extracellular release of neutrophil proteases, suppressing VE-cadherin degradation and neutrophil transendothelial migration in vivo. These results elucidate the AP-dependent intravascular neutrophil-endothelial interactions that initiate the inflammatory cascade in this disease model but may be generalizable to neutrophil extravasation in other inflammatory processes.


Asunto(s)
Adhesión Celular/inmunología , Activación de Complemento/inmunología , Complemento C5a/inmunología , Células Endoteliales de la Vena Umbilical Humana/inmunología , Neutrófilos/inmunología , Animales , Complejo Antígeno-Anticuerpo/inmunología , Autoanticuerpos/inmunología , Células Cultivadas , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Receptores de IgG/inmunología
14.
PLoS One ; 14(9): e0222999, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31560714

RESUMEN

Immunotherapy shows a promise for treating glioblastoma (GBM), the most malignant and immunosuppressive glioma. The mesenchymal phenotype of cancer cells was frequently reported to be associated with their induction of immunosuppression within the cancer microenvironment. Overexpressed insulin-like growth factor binding protein 2 (IGFBP2) promotes GBM cell migration and invasion, and contributes to glioma progression and cancer recurrence and poor survival in GBM. However, whether IGFBP2 can induce immunosuppression in GBM was not reported yet. Thus, the study applied a syngeneic mouse GBM model, human GBM samples, and cancer-immune cell co-culture experiments to investigate the effect of IGFBP2 on GBM exposed immune cells and its association with the mesenchymal induction. We found that IGFBP2 promoted the mesenchymal feature of GBM cells. The inhibition of IGFBP2 relieved immunosuppression by increasing CD8+ T and CD19+ B cells and decreasing CD163+ M2 macrophages. Further, the IGFBP2-promoted immunosuppression was associated with its induction of the mesenchymal feature of GBM cells and the inhibitory phosphorylated FcγRIIB of GBM exposed immune cells. Blocking IGFBP2 suppressed tumor growth and improved survival of tumor bearing mice in the mouse GBM model. These findings support the notion that targeting the IGFBP2 may present an effective immunotherapeutic strategy for mesenchymal GBMs.


Asunto(s)
Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Receptores de IgG/metabolismo , Escape del Tumor/inmunología , Animales , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Línea Celular Tumoral/trasplante , Movimiento Celular , Proliferación Celular , Técnicas de Cocultivo , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/inmunología , Técnicas de Silenciamiento del Gen , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/inmunología , Estimación de Kaplan-Meier , Ratones , Fosforilación/inmunología , Receptores de IgG/inmunología , Análisis de Matrices Tisulares , Microambiente Tumoral/inmunología
15.
Expert Opin Biol Ther ; 19(12): 1229-1232, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31510805

RESUMEN

Introduction: ADCC by natural killer (NK) cells is a key mechanism for several clinically successful tumor-targeting therapeutic antibodies. Most patients, however, have limited responses to this therapy and/or develop resistance. NK cells exclusively recognize IgG by their low-affinity FcγR CD16A.Areas covered: We describe in this editorial a novel recombinant FcγR that consists of CD64, the only high affinity IgG receptor, and the transmembrane and cytoplasmic regions of CD16A, a potent activating receptor. CD64/16A was expressed in engineered iPSCs that were differentiated into NK cells (referred to as iNK cells).Expert opinion: iNK-CD64/16A cells in combination with therapeutic antibodies provide a universal tumor antigen targeting approach and potential off-the-shelf cell therapy to treat various malignancies.


Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Células Asesinas Naturales/inmunología , Receptores de IgG/inmunología , Humanos , Neoplasias/terapia
16.
J Clin Invest ; 129(9): 3492-3498, 2019 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-31478910

RESUMEN

IgG antibodies are secreted from B cells and bind to a variety of pathogens to control infections as well as contribute to inflammatory diseases. Many of the functions of IgGs are mediated through Fcγ receptors (FcγRs), which transduce interactions with immune complexes, leading to a variety of cellular outcomes depending on the FcγRs and cell types engaged. Which FcγRs and cell types will be engaged during an immune response depends on the structure of Fc domains within immune complexes that are formed when IgGs bind to cognate antigen(s). Recent studies have revealed an unexpected degree of structural variability in IgG Fc domains among people, driven primarily by differences in IgG subclasses and N-linked glycosylation of the CH2 domain. This translates, in turn, to functional immune diversification through type I and type II FcγR-mediated cellular functions. For example, Fc domain sialylation triggers conformational changes of IgG1 that enable interactions with type II FcγRs; these receptors mediate cellular functions including antiinflammatory activity or definition of thresholds for B cell selection based on B cell receptor affinity. Similarly, presence or absence of a core fucose alters type I FcγR binding of IgG1 by modulating the Fc's affinity for FcγRIIIa, thereby altering its proinflammatory activity. How heterogeneity in IgG Fc domains contributes to human immune diversity is now being elucidated, including impacts on vaccine responses and susceptibility to disease and its sequelae during infections. Here, we discuss how Fc structures arising from sialylation and fucosylation impact immunity, focusing on responses to vaccination and infection. We also review work defining individual differences in Fc glycosylation, regulation of Fc glycosylation, and clinical implications of these pathways.


Asunto(s)
Linfocitos B/inmunología , Fucosa/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunoglobulina G/inmunología , Animales , Complejo Antígeno-Anticuerpo/inmunología , Glicosilación , Humanos , Receptores de IgG/inmunología
17.
J Clin Invest ; 129(9): 3952-3962, 2019 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-31424423

RESUMEN

Sialyl Lewis A (sLeA, also known as CA19-9), a tetrasaccharide selectively and highly expressed on advanced adenocarcinomas including colon, stomach, and pancreatic cancers, has long been considered as an attractive target for active and passive vaccination. While progress in antibodies targeting tumor-associated protein antigens resulted in an impressive array of therapeutics for cancer treatment, similar progress in exploiting tumor-associated carbohydrate antigens, such as sLeA, has been hampered by the lack of a detailed understanding of the singular characteristics of these antigens. We have addressed this issue by analyzing antibodies derived from patients immunized with an sLeA/KLH vaccine. These antibodies were engineered to mediate tumor clearance in vivo in preclinical models through Fc-FcγR interactions. However, in contrast to protein antigens in which hFcγRIIIA engagement was both necessary and sufficient to mediate tumor clearance in both preclinical and clinical settings, a similar selective dependence was not seen for anti-sLeA antibodies. Thus, re-engineering the Fc portion of sLeA-targeting antibodies to broadly enhance their affinity for activating FcγRs led to an enhanced therapeutic effect. These findings will facilitate the development of more efficient anticancer therapies and further advance this promising class of therapeutic antibodies into clinical use.


Asunto(s)
Anticuerpos Antineoplásicos , Antígeno CA-19-9/inmunología , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/inmunología , Receptores de IgG/inmunología , Animales , Anticuerpos Antineoplásicos/inmunología , Anticuerpos Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Ratones , Ratones Transgénicos , Neoplasias Experimentales/patología
18.
Blood ; 134(17): 1430-1440, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31383641

RESUMEN

Antibodies that bind CD47 on tumor cells and prevent interaction with SIRPα on phagocytes are active against multiple cancer types including T-cell lymphoma (TCL). Here we demonstrate that surface CD47 is heterogeneously expressed across primary TCLs, whereas major histocompatibility complex (MHC) class I, which can also suppress phagocytosis, is ubiquitous. Multiple monoclonal antibodies (mAbs) that block CD47-SIRPα interaction promoted phagocytosis of TCL cells, which was enhanced by cotreatment with antibodies targeting MHC class I. Expression levels of surface CD47 and genes that modulate CD47 pyroglutamation did not correlate with the extent of phagocytosis induced by CD47 blockade in TCL lines. In vivo treatment of multiple human TCL patient-derived xenografts or an immunocompetent murine TCL model with a short course of anti-CD47 mAb markedly reduced lymphoma burden and extended survival. Depletion of macrophages reduced efficacy in vivo, whereas depletion of neutrophils had no effect. F(ab')2-only fragments of anti-CD47 antibodies failed to induce phagocytosis by human macrophages, indicating a requirement for Fc-Fcγ receptor interactions. In contrast, F(ab')2-only fragments increased phagocytosis by murine macrophages independent of SLAMF7-Mac-1 interaction. Full-length anti-CD47 mAbs also induced phagocytosis by Fcγ receptor-deficient murine macrophages. An immunoglobulin G1 anti-CD47 mAb induced phagocytosis and natural killer cell-mediated cytotoxicity of TCL cells that was augmented by cotreatment with mogamulizumab, an anti-CCR4 mAb, or a mAb blocking MHC class I. These studies help explain the disparate activity of monotherapy with agents that block CD47 in murine models compared with patients. They also have direct translational implications for the deployment of anti-CD47 mAbs alone or in combination.


Asunto(s)
Antígenos de Diferenciación/inmunología , Antineoplásicos Inmunológicos/farmacología , Antígeno CD47/inmunología , Linfoma de Células T/tratamiento farmacológico , Receptores de IgG/inmunología , Receptores Inmunológicos/inmunología , Animales , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno CD47/antagonistas & inhibidores , Línea Celular Tumoral , Humanos , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Ratones , Receptores Fc/inmunología
19.
Int Arch Allergy Immunol ; 180(2): 91-102, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31401630

RESUMEN

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and mast cells. METHODS: The affinity of AK002 for Siglec-8 and CD16 was determined by biolayer interferometry. Ex vivo activity of AK002 on human eosinophils from blood and dissociated human tissue was tested in apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. The in vivo activity of a murine precursor of AK002 (mAK002) was tested in a passive systemic anaphylaxis (PSA) humanized mouse model. RESULTS: AK002 bound selectively to mast cells, eosinophils and, at a lower level, to basophils in human blood and tissue and not to other cell types examined. AK002 induced apoptosis of interleukin-5-activated blood eosinophils and demonstrated potent ADCC activity against blood eosinophils in the presence of natural killer cells. AK002 also significantly reduced eosinophils in dissociated human lung tissue. Furthermore, mAK002 prevented PSA in humanized mice through mast cell inhibition. CONCLUSION: AK002 selectively evokes potent apoptotic and ADCC activity against eosinophils and prevents systemic anaphylaxis through mast cell inhibition.


Asunto(s)
Anafilaxia/prevención & control , Anticuerpos Monoclonales Humanizados/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos B/inmunología , Eosinófilos/inmunología , Lectinas/inmunología , Mastocitos/inmunología , Anafilaxia/inmunología , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Basófilos/inmunología , Humanos , Ratones , Ácido N-Acetilneuramínico/inmunología , Receptores de IgG/inmunología
20.
Artículo en Inglés | MEDLINE | ID: mdl-31316920

RESUMEN

Toxoplasma gondii is a prevalent parasite of mammals and birds including up to 30% of humans world-wide. Primary infection of immunocompetent hosts leads to a robust cell-mediated immune response, which controls but does not clear the infection, thus enabling long-term parasite persistence in brain and muscle tissues. Chronic toxoplasmosis in mice is associated with resistance to heterologous pathogens and this has been related to increased numbers of inflammatory monocytes. Here we have analyzed whether chronic T. gondii infection impacts the subset distribution and the phenotype of peripheral human monocytes in vivo and their responses to parasite infection in vitro. CD14+ monocytes from T. gondii-seropositive blood donors expressed significantly less FcγRIII (CD16) than those from seronegative controls, but they did not show a shift in the distribution of classical, intermediate and non-classical monocyte subpopulations. Percentages of CD62L+ and CD64+ monocytes were however decreased and increased, respectively, in chronically infected individuals as compared to naïve controls. Infection of monocyte-enriched PBMCs from both seropositive and seronegative individuals with T. gondii led to an increase of CD14+CD16- classical monocytes and a decrease of CD14+CD16+ double positive monocytes. Remarkably, after in vitro parasite infection, expression of the chemokine receptor CCR2 was severely impaired in monocytes from both, individuals with chronic toxoplasmosis and seronegative controls. In contrast, only monocytes from chronically infected humans but not those from controls dose-dependently up-regulated HLA-DR, DP, DQ expression following in vitro infection. Furthermore, monocyte-enriched PBMCs from seropositive individuals up-regulated IL-12 mRNA more vigorously after in vitro infection than cells from naïve controls. Collectively, our results establish that infection of humans with T. gondii exerts long-term effects on the phenotype and responsiveness of blood monocytes. This may have important implications for innate immune responses to T. gondii and unrelated pathogens.


Asunto(s)
Monocitos/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Enfermedad Crónica , Humanos , Inmunidad Innata , Interleucina-12/metabolismo , Selectina L , Receptores de Lipopolisacáridos , Ratones , Monocitos/metabolismo , Receptores CCR2 , Receptores de IgG/inmunología , Toxoplasma/patogenicidad
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