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1.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802650

RESUMO

As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.


Assuntos
Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Receptores Fc/química , Receptores Fc/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacocinética , COVID-19/tratamento farmacológico , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Receptores Fc/imunologia , Distribuição Tecidual/imunologia
2.
mBio ; 12(2)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879594

RESUMO

Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. We found that anti-S1 and anti-RBD antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from nonhospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation, whereas higher ADCP was associated with lower systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 specific antibodies as potential contributors to COVID-19 severity. Understanding these qualitative features of natural and vaccine-induced antibodies will be important in achieving optimal efficacy and safety of SARS-CoV-2 vaccines and/or COVID-19 therapeutics.IMPORTANCE A state of hyperinflammation and increased complement activation has been associated with coronavirus disease 2019 (COVID-19) severity. However, the pathophysiological mechanisms that contribute to this phenomenon remain mostly unknown. Our data point to a qualitative, rather than quantitative, difference in SARS-CoV-2-specific antibodies' ability to elicit Fc-mediated innate immune functions as a potential contributor to COVID-19 severity and associated inflammation. These data highlight the need for further studies to understand these qualitative features and their potential contribution to COVID-19 severity. This understanding could be essential to develop antibody-based COVID-19 therapeutics and SARS-CoV-2 vaccines with an optimal balance between efficacy and safety.


Assuntos
Anticorpos Antivirais , COVID-19/imunologia , Imunidade Inata , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Citotoxicidade Celular Dependente de Anticorpos , Biomarcadores/sangue , COVID-19/etiologia , COVID-19/virologia , Estudos de Casos e Controles , Estudos de Coortes , Ativação do Complemento , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Inflamação/sangue , Inflamação/etiologia , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Fagocitose , Receptores Fc/imunologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/imunologia
3.
JCI Insight ; 6(1)2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33427208

RESUMO

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross-SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc variants, no protection was observed after administration of WT IgG1 in mice or hamsters. Conversely, the functionally enhanced Fc variant resulted in increased pathology in both the mouse and hamster models, causing weight loss in mice and enhanced viral replication and weight loss in the more susceptible hamster model, highlighting the pathological functions of Fc-enhancing mutations. These data point to the critical need for strategic Fc engineering for the treatment of SARS-CoV-2 infection.


Assuntos
Anticorpos Neutralizantes/farmacologia , COVID-19/imunologia , Imunidade Inata/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulina G/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Anticorpos Monoclonais , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , Cricetinae , Reações Cruzadas , Epitopos , Humanos , Imunidade Inata/imunologia , Imunoglobulina G/genética , Imunoglobulina G/uso terapêutico , Mesocricetus , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Engenharia de Proteínas , Receptores Fc/imunologia , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/imunologia , Células THP-1 , Carga Viral/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos
4.
Scand J Immunol ; 93(2): e13017, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33351196

RESUMO

The neonatal Fc receptor (FcRn) was first recognized for its role in transfer of maternal IgG to the foetus or newborn, providing passive immunity early in life. However, it has become clear that the receptor is versatile, widely expressed and plays an indispensable role in both immunological and non-immunological processes throughout life. The receptor rescues immunoglobulin G (IgG) and albumin from intracellular degradation and shuttles the ligands across polarized cell barriers, in all cases via a pH-dependent binding-and-release mechanism. These processes secure distribution and high levels of both IgG and albumin throughout the body. At mucosal sites, FcRn transports IgG across polarized epithelial cells where it retrieves IgG in complex with luminal antigens that is delivered to tissue-localized immune cells. In dendritic cells (DCs), FcRn orchestrates processing of IgG-opsonized immune complexes (ICs) in concert with classical Fcγ receptors, which results in antigen presentation and cross-presentation of antigenic peptides on MHC class II and I to CD4+ and CD8+ T cells, respectively. Hence, FcRn regulates transport of the ligands within and across different types of cells, but also processing of IgG-ICs by immune cells. As such, the receptor is involved in immune surveillance and protection against infections. In this brief review, we highlight how FcRn expressed by hematopoietic and non-hematopoietic cells contributes to immune regulation at mucosal barriers-biology that can be utilized in development of biologics and subunit vaccines for non-invasive delivery.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Membrana Mucosa/imunologia , Receptores Fc/imunologia , Animais , Apresentação do Antígeno/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunoglobulina G/imunologia , Fatores Imunológicos/imunologia
5.
PLoS One ; 15(9): e0239595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970735

RESUMO

Immunotherapy checkpoint inhibitors, such as antibodies targeting PD-1 and CTLA-4, have demonstrated the potential of harnessing the immune system to treat cancer. However, despite encouraging results particularly with respect to survival, only a minority of patients benefit from these therapies. In clinical studies aimed at understanding changes in the immune system following immunotherapy treatment, ICOS (Inducible T cell CO-Stimulator) was shown to be significantly up-regulated on CD4+ T cells and this was associated with clinical activity, indicating that ICOS stimulatory activity may be beneficial in the treatment of solid tumors. In this report, we describe the generation of specific, species cross-reactive, agonist antibodies to ICOS, including the humanized clinical candidate, JTX-2011 (vopratelimab). Preclinical studies suggest that the ICOS stimulating antibodies require Fc receptor cross-linking for optimal agonistic activity. Notably, the ICOS antibodies do not exhibit superagonist properties but rather require T cell receptor (TCR)-mediated upregulation of ICOS for agonist activity. Treatment with the ICOS antibodies results in robust anti-tumor benefit and long-term protection in preclinical syngeneic mouse tumor models. Additional benefit is observed when the ICOS antibodies are administered in combination with anti-PD-1 and anti-CTLA-4 therapies. Based on the preclinical data, JTX-2011 is currently being developed in the clinical setting for the treatment of solid tumors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Apresentação Cruzada , Imunoterapia/métodos , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Neoplasias Experimentais/terapia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais Humanizados/imunologia , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Feminino , Humanos , Células Jurkat , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Receptores Fc/imunologia
6.
Nat Commun ; 11(1): 4421, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887891

RESUMO

Receptor usage that determines cell tropism and drives viral classification closely correlates with the virus structure. Enterovirus B (EV-B) consists of several subgroups according to receptor usage, among which echovirus 30 (E30), a leading causative agent for human aseptic meningitis, utilizes FcRn as an uncoating receptor. However, receptors for many EVs remain unknown. Here we analyzed the atomic structures of E30 mature virion, empty- and A-particles, which reveals serotype-specific epitopes and striking conformational differences between the subgroups within EV-Bs. Of these, the VP1 BC loop markedly distinguishes E30 from other EV-Bs, indicative of a role as a structural marker for EV-B. By obtaining cryo-electron microscopy structures of E30 in complex with its receptor FcRn and CD55 and comparing its homologs, we deciphered the underlying molecular basis for receptor recognition. Together with experimentally derived viral receptor identifications, we developed a structure-based in silico algorithm to inform a rational prediction for EV receptor usage.


Assuntos
Complexo Antígeno-Anticorpo/ultraestrutura , Enterovirus Humano B/ultraestrutura , Antígenos Virais/ultraestrutura , Antígenos CD55/imunologia , Microscopia Crioeletrônica , Enterovirus Humano B/imunologia , Epitopos/ultraestrutura , Humanos , Receptores Fc/imunologia , Vírion/ultraestrutura
7.
Nat Commun ; 11(1): 4419, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887892

RESUMO

Echovirus 30 (E30), a serotype of Enterovirus B (EV-B), recently emerged as a major causative agent of aseptic meningitis worldwide. E30 is particularly devastating in the neonatal population and currently no vaccine or antiviral therapy is available. Here we characterize two highly potent E30-specific monoclonal antibodies, 6C5 and 4B10, which efficiently block binding of the virus to its attachment receptor CD55 and uncoating receptor FcRn. Combinations of 6C5 and 4B10 augment the sum of their individual anti-viral activities. High-resolution structures of E30-6C5-Fab and E30-4B10-Fab define the location and nature of epitopes targeted by the antibodies. 6C5 and 4B10 engage the capsid loci at the north rim of the canyon and in-canyon, respectively. Notably, these regions exhibit antigenic variability across EV-Bs, highlighting challenges in development of broad-spectrum antibodies. Our structures of these neutralizing antibodies of E30 are instructive for development of vaccines and therapeutics against EV-B infections.


Assuntos
Anticorpos Neutralizantes/ultraestrutura , Complexo Antígeno-Anticorpo/ultraestrutura , Proteínas do Capsídeo/imunologia , Enterovirus Humano B/imunologia , Animais , Anticorpos Monoclonais/ultraestrutura , Antígenos Virais , Antígenos CD55/imunologia , Microscopia Crioeletrônica , Epitopos/ultraestrutura , Humanos , Meningite Asséptica/virologia , Camundongos , Receptores Fc/imunologia , Sorogrupo
9.
Mol Immunol ; 127: 79-86, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32947169

RESUMO

Immunoglobulin G (IgG) antibodies are important for protection against pathogens and exert effector functions through binding to IgG-Fc receptors (FcγRs) on myeloid and natural killer cells, resulting in destruction of opsonized target cells. Despite interspecies differences, IgG subclasses and FcγRs show substantial similarities and functional conservation between mammals. Accordingly, binding of human IgG (hIgG) to mouse FcγRs (mFcγRs) has been utilized to study effector functions of hIgG in mice. In other applications, such as immunostaining with mouse IgG monoclonal antibodies (mAbs), these cross-reactivities are undesired and prone to misinterpretation. Despite this drawback, the binding of mouse IgG (mIgG) subclasses to human FcγR (hFcγR) classes has never been fully documented. Here, we report detailed and quantifiable characterization of binding affinities for all mIgG subclasses to hFcγRs, including functional polymorphic variants. mIgG subclasses show the strongest binding to hFcγRIa, with relative affinities mIgG2a = mIgG2c > mIgG3 >> mIgG2b, and no binding by mIgG1. hFcγRIIa/b showed general low reactivities to all mIgG (mIgG1> mIgG2a/c > mIgG2b), with no reactivity to mIgG3. A particularly high affinity was observed for mIgG1 to the hFcγRIIa-R131 polymorphic variant. hFcγRIIIa showed lower binding (mIgG2a/c > mIgG3), slightly favouring binding to the hFcγRIIIa-V158 over the F158 polymorphic variant. No binding was observed of mIgG to hFcγRIIIb. Deglycosylation of mIgG1 did not abrogate binding to hFcγRIIa-R131, nor did deglycosylation of mIgG2a/c and mIgG3 prevent hFcγRIa binding. Importantly, deglycosylation of the least cross-reactive mIgG subclass, mIgG2b, abrogated reactivity to all hFcγRs. Together, these data document for the first time the full spectrum of cross-reactivities of mouse IgG to human FcγRs.


Assuntos
Anticorpos/imunologia , Reações Cruzadas/imunologia , Imunoglobulina G/imunologia , Receptores Fc/imunologia , Animais , Proteínas de Bactérias/metabolismo , Sequência Conservada , Glicosídeo Hidrolases/metabolismo , Glicosilação , Humanos , Imunoglobulina G/química , Camundongos , Polissacarídeos/metabolismo , Ligação Proteica , Especificidade da Espécie
10.
EBioMedicine ; 55: 102768, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32344202

RESUMO

The pandemic spread of a novel coronavirus - SARS coronavirus-2 (SARS-CoV-2) as a cause of acute respiratory illness, named Covid-19, is placing the healthcare systems of many countries under unprecedented stress. Global economies are also spiraling towards a recession in fear of this new life-threatening disease. Vaccines that prevent SARS-CoV-2 infection and therapeutics that reduces the risk of severe Covid-19 are thus urgently needed. A rapid method to derive antiviral treatment for Covid-19 is the use of convalescent plasma derived hyperimmune globulin. However, both hyperimmune globulin and vaccine development face a common hurdle - the risk of antibody-mediated disease enhancement. The goal of this review is to examine the body of evidence supporting the hypothesis of immune enhancement that could be pertinent to Covid-19. We also discuss how this risk could be mitigated so that both hyperimmune globulin and vaccines could be rapidly translated to overcome the current global health crisis.


Assuntos
Anticorpos Antivirais/efeitos adversos , Infecções por Coronavirus/imunologia , Pandemias , Pneumonia Viral/imunologia , Vacinas Virais/imunologia , Internalização do Vírus , Animais , Anticorpos Antivirais/imunologia , Ensaios Clínicos Fase I como Assunto , Convalescença , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Células Dendríticas/virologia , Saúde Global , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunização Passiva , Macrófagos/virologia , Modelos Animais , Monócitos/virologia , Pandemias/prevenção & controle , Plasma , Plasmaferese , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Receptores Fc/imunologia , Pesquisa Médica Translacional
11.
Immunol Cell Biol ; 98(4): 305-317, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32142167

RESUMO

Antibody-dependent complement activity is associated not only with autoimmune morbidity, but also with antitumor efficacy. In infectious disease, both recombinant monoclonal antibodies and polyclonal antibodies generated in natural adaptive responses can mediate complement activity to protective, therapeutic or disease-enhancing effect. Recent advances have contributed to the structural resolution of molecular complexes involved in antibody-mediated complement activation, defining the avid nature of participating interactions and pointing to how antibody isotype, subclass, hinge flexibility, glycosylation state, amino acid sequence and the contextual nature of the cognate antigen/epitope are all factors that can determine complement activity through impact on antibody multimerization and subsequent recruitment of complement component 1q. Beyond the efficiency of activation, complement activation products interact with various cell types that mediate immune adherence, trafficking, immune education and innate functions. Similarly, depending on the anatomical location and extent of activation, complement can support homeostatic restoration or be leveraged by pathogens or neoplasms to enhance infection or promote tumorigenic microenvironments, respectively. Advances in means to suppress complement activation by intravenous immunoglobulin (IVIG), IVIG mimetics and complement-intervening antibodies represent proven and promising exploratory therapeutic strategies, while antibody engineering has likewise offered frameworks to enhance, eliminate or isolate complement activation to interrogate in vivo mechanisms of action. Such strategies promise to support the optimization of antibody-based drugs that are able to tackle emerging and difficult-to-treat diseases by improving our understanding of the synergistic and antagonistic relationships between antibody mechanisms mediated by Fc receptors, direct binding and the products of complement activation.


Assuntos
Anticorpos Monoclonais/imunologia , Doenças Transmissíveis/imunologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Neoplasias/imunologia , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/metabolismo , Antígenos/imunologia , Antígenos/metabolismo , Autoanticorpos/efeitos adversos , Autoanticorpos/imunologia , Engenharia Biomédica , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/patologia , Doenças Transmissíveis/virologia , Complemento C1q/química , Complemento C1q/imunologia , Complemento C1q/metabolismo , Proteínas do Sistema Complemento/química , Proteínas do Sistema Complemento/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/química , Imunoglobulina G/imunologia , Imunoglobulina G/ultraestrutura , Neoplasias/patologia , Receptores Fc/imunologia , Receptores Fc/metabolismo
12.
Mol Immunol ; 121: 1-6, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135400

RESUMO

The transglutaminase 2 (TG2) is one of the enigmatic enzymes with important functional diversity. It plays an important role in several pathologies such as celiac disease (CD). In patients with active CD, the abnormal retrotranscytosis of IgA/gliadin complexes is mediated by Transferrin Receptor 1 (TfR1). This triad association takes also place in IgA nephropathy (IgA-N). IgA-N is characterized by the formation of nephrotoxic complexes of IgA1 and soluble CD89 (sCD89). These complexes are abnormally deposited in the kidney. Using a humanized mouse model of IgA-N (α1KI-CD89Tg), we showed that IgA1-sCD89 complexes engender mesangial cell activation and proliferation with TfR1 and TG2 up-regulation, associated with IgA-N features. This TG2-TfR1 interaction enhances mesangial IgA1 deposition promoting inflammation. Humanized α1KI-CD89Tg mice deficient for TG2 show a decrease in TfR1 expression in kidney leading to reduced IgA1-sCD89 deposits and an improvement in IgA-N features. Moreover, TG2 is active and overexpressed in the intestine of IgA-N mice and gliadin participates to this renal pathology. In kidney as in intestine, the TG2 has a crucial role in the cooperation between TfR1-IgA and a central role in the pathogenic amplification.


Assuntos
Antígenos CD/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Gliadina/imunologia , Glomerulonefrite por IGA/imunologia , Imunoglobulina A/metabolismo , Receptores da Transferrina/metabolismo , Transglutaminases/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Doença Celíaca/imunologia , Doença Celíaca/patologia , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/imunologia , Gliadina/metabolismo , Humanos , Imunoglobulina A/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Células Mesangiais/imunologia , Células Mesangiais/patologia , Camundongos , Camundongos Transgênicos , Receptores Fc/genética , Receptores Fc/imunologia , Receptores Fc/metabolismo , Receptores da Transferrina/imunologia , Transglutaminases/genética , Transglutaminases/imunologia , Regulação para Cima/imunologia
14.
Immunol Cell Biol ; 98(4): 264-275, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32003072

RESUMO

Many parasitic infections stimulate antibody responses in their mammalian hosts. The ability of these antibodies to protect against disease varies markedly. Research has revealed that functional properties of antibodies determine their role in protection against parasites. Investigations of antibodies against Plasmodium spp. have demonstrated a variety of functional activities, ranging from invasion inhibition and parasite growth inhibition to antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity. These activities have been demonstrated with a large variety of parasite molecules at multiple life cycle stages, highlighting the importance of functional antibody responses in malaria. Other parasitic infections have not yet been investigated in similar detail, but these mechanisms are likely to operate in nonmalarial parasitic infections as well. In this report, we review data on the role of functional antibody responses in protection from parasitic infections, highlighting discoveries in malaria, a parasite for which our knowledge base is the most advanced.


Assuntos
Anticorpos Antiprotozoários/imunologia , Malária/imunologia , Parasitos/imunologia , Doenças Parasitárias/imunologia , Plasmodium/imunologia , Animais , Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Proteínas do Sistema Complemento/imunologia , Eritrócitos/imunologia , Eritrócitos/parasitologia , Humanos , Malária/parasitologia , Fagocitose/imunologia , Receptores Fc/imunologia , Esquizontes/imunologia , Esporozoítos/imunologia
15.
Nature ; 577(7791): 543-548, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915378

RESUMO

Although maternal antibodies protect newborn babies from infection1,2, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice that lack the capacity to produce IgG are protected from infection with the enteric pathogen enterotoxigenic Escherichia coli by maternal natural IgG antibodies against the maternal microbiota when antibodies are delivered either across the placenta or through breast milk. By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that IgG derived from breast milk was crucial for protection against mucosal disease induced by enterotoxigenic E. coli. IgG also provides protection against systemic infection by E. coli. Pups used the neonatal Fc receptor to transfer IgG from milk into serum. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by enterotoxigenic E. coli and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers protection against enterotoxigenic E. coli in pups. This role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defence mechanism against infection in neonates.


Assuntos
Anticorpos/imunologia , Escherichia coli Enterotoxigênica/imunologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/prevenção & controle , Imunidade Materno-Adquirida/imunologia , Recém-Nascido/imunologia , Microbiota/imunologia , Leite Humano/imunologia , Animais , Anticorpos/sangue , Anticorpos/metabolismo , Aleitamento Materno , Reações Cruzadas/imunologia , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Masculino , Camundongos , Mães , Pantoea/imunologia , Receptores Fc/imunologia , Receptores Fc/metabolismo , Simbiose/imunologia
16.
Viruses ; 12(1)2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936476

RESUMO

Porcine deltacoronavirus (PDCoV) is a porcine enteropathogenic coronavirus that causes watery diarrhea, vomiting, and frequently death in piglets, causing serious economic losses to the pig industry. The strain CHN-JS-2017 was isolated and identified by cytopathology, immunofluorescence assays, transmission electron microscopy, and sequence analysis. A nucleotide sequence alignment showed that the whole genome of CHN-JS-2017 is 97.4%-99.6% identical to other PDCoV strains. The pathogenicity of the CHN-JS-2017 strain was investigated in orally inoculated five-day-old piglets; the piglets developed acute, watery diarrhea, but all recovered and survived. CHN-JS-2017 infection-induced microscopic lesions were observed, and viral antigens were detected mainly by immunohistochemical staining in the small intestine. The neonatal Fc receptor (FcRn) and polymeric immunoglobulin receptor (pIgR) are crucial immunoglobulin (Ig) receptors for the transcytosis ofimmunoglobulin G (IgG), IgA, or IgM. Importantly, CHN-JS-2017 infected five-day-old piglets could significantly down-regulate the expression of FcRn, pIgR, and nuclear factor-kappa B (NF-κB)in the intestinal mucosa. Note that the level of FcRn mRNA in the intestinal mucosa of normal piglets is positively correlated with pIgR and NF-κB. At the same time, the expressions of FcRn, pIgR, and NF-κB mRNA are also positively correlated in infected piglets. These results may help explain the immunological and pathological changes associated with porcine deltacorononirus infection.


Assuntos
Infecções por Coronavirus/veterinária , Coronavirus/classificação , Antígenos de Histocompatibilidade Classe I/imunologia , Mucosa Intestinal/imunologia , Receptores Fc/imunologia , Receptores de Imunoglobulina Polimérica/imunologia , Doenças dos Suínos/virologia , Animais , Antígenos Virais/análise , Coronavirus/isolamento & purificação , Infecções por Coronavirus/imunologia , Diarreia/veterinária , Diarreia/virologia , Regulação da Expressão Gênica , Mucosa Intestinal/virologia , Intestino Delgado/imunologia , Intestino Delgado/virologia , NF-kappa B/imunologia , Filogenia , RNA Viral/análise , Alinhamento de Sequência , Análise de Sequência de DNA , Suínos , Doenças dos Suínos/imunologia , Eliminação de Partículas Virais
17.
Int Immunol ; 32(2): 89-104, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31713625

RESUMO

Staphylococcus aureus is a main pathogen of osteomyelitis and protein A is a virulence factor with high affinity for IgG. In this study, we investigated whether S. aureus affects the differentiation and bone resorption of osteoclasts through the IgG-binding capacity of protein A. Staphylococcus aureus pre-treated with serum or IgG showed marked enhancement in osteoclastogenesis and bone resorption compared to non-treated S. aureus or a protein A-deficient mutant. Blocking of the Fc receptor and deletion of the Fcγ receptor gene in osteoclast precursor cells showed that enhanced osteoclastogenesis stimulated by S. aureus IgG immune complexes (ICs) was mediated by the Fc receptor on osteoclast precursor cells. In addition, osteoclastogenesis stimulated by S. aureus ICs but not the protein A-deficient mutant was markedly reduced in osteoclast precursor cells of Myd88-knockout mice. Moreover, NFATc1, Syk and NF-κB signals were necessary for osteoclastogenesis stimulated by S. aureus ICs. The results suggest the contribution of a of Toll-like receptor 2 (TLR2)-Myd88 signal to the activity of S. aureus ICs. We further examined the expression of pro-inflammatory cytokines that is known to be enhanced by FcγR-TLR cross-talk. Osteoclasts induced by S. aureus ICs showed higher expression of TNF-α and IL-1ß, and marked stimulation of proton secretion of osteoclasts activated by pro-inflammatory cytokines. Finally, injection of S. aureus, but not the protein A-deficient mutant, exacerbated bone loss in implantation and intra-peritoneal administration mouse models. Our results provide a novel mechanistic aspect of bone loss induced by S. aureus in which ICs and both Fc receptors and TLR pathways are involved.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Diferenciação Celular , Imunoglobulina G/imunologia , Receptores Fc/imunologia , Proteína Estafilocócica A/imunologia , Staphylococcus aureus/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteogênese/efeitos dos fármacos , Ligante RANK/antagonistas & inibidores , Ligante RANK/farmacologia , Receptores Fc/deficiência , Receptores Fc/genética , Proteína Estafilocócica A/genética , Staphylococcus aureus/citologia , Ácidos Teicoicos/farmacologia
18.
Immunol Cell Biol ; 98(4): 276-286, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31785006

RESUMO

Immunoglobulin (Ig) A is the most abundant antibody isotype present at mucosal surfaces and the second most abundant in human serum. In addition to preventing pathogen entry at mucosal surfaces, IgA can control and eradicate bacterial and viral infections through a variety of antibody-mediated innate effector cell mechanisms. The role of mucosal IgA in infection (e.g. neutralization) and in inflammatory homeostasis (e.g. allergy and autoimmunity) has been extensively investigated; by contrast, serum IgA is comparatively understudied. IgA binding to fragment crystallizable alpha receptor plays a dual role in the activation and inhibition of innate effector cell functions. Mounting evidence suggests that serum IgA induces potent effector functions against various bacterial and some viral infections including Neisseria meningitidis and rotavirus. Furthermore, in the era of immunotherapy, serum IgA provides an interesting alternative to classical IgG monoclonal antibodies to treat cancer and infectious pathogens. Here we discuss the role of serum IgA in infectious diseases with reference to bacterial and viral infections and the potential for IgA as a monoclonal antibody therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Transmissíveis/imunologia , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Neoplasias/imunologia , Receptores Fc/fisiologia , Motivos de Aminoácidos/imunologia , Anticorpos Monoclonais/imunologia , Antígenos CD/imunologia , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Humanos , Imunoglobulina A/química , Fragmentos Fc das Imunoglobulinas/fisiologia , Receptores Fc/sangue , Receptores Fc/química , Receptores Fc/imunologia
19.
Front Immunol ; 10: 2865, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867015

RESUMO

Human memory-like NK cells are commonly defined by either a lack of FcεRIγ or gain of NKG2C expression. Here, we investigated the heterogeneity of human CD56dim NK cell subpopulations according to the expression of FcεRIγ and NKG2C in a large cohort (n = 127). Although the frequency of FcεRIγ- and NKG2C+ NK cells positively correlated, the FcεRIγ- and NKG2C+ NK cell populations did not exactly overlap. The FcεRIγ+NKG2C+, FcεRIγ-NKG2C+, and FcεRIγ-NKG2C- NK cell populations were only evident after HCMV infection, but each had distinct characteristics. Among the subpopulations, FcεRIγ-NKG2C+ NK cells exhibited the most restricted killer immunoglobulin-like receptor repertoire, suggesting clonal expansion. Moreover, FcεRIγ-NKG2C+ NK cells exhibited the lowest Ki-67 and highest Bcl-2 expression, indicating the long-lived quiescent memory-like property. Functionally, FcεRIγ-NKG2C+ NK cells had weak natural effector function against K562 but strong effector functions by CD16 engagement, whereas FcεRIγ+NKG2C+ NK cells had strong effector functions in both settings. Anatomically, the FcεRIγ+NKG2C+, FcεRIγ-NKG2C+, and FcεRIγ-NKG2C- NK cell populations were present in multiple human peripheral organs. In conclusion, we demonstrate the heterogeneity of memory-like NK cells stratified by FcεRIγ and NKG2C and suggest both markers be utilized to better define these cells.


Assuntos
Regulação da Expressão Gênica/imunologia , Memória Imunológica , Células Matadoras Naturais/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores Fc/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Células K562 , Células Matadoras Naturais/citologia , Masculino , Pessoa de Meia-Idade
20.
PLoS Pathog ; 15(12): e1008064, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31841557

RESUMO

Broadly neutralizing antibodies (bNAbs) protect against HIV infection in non-human primates and their efficacy may be enhanced through interaction with Fc receptors on immune cells. Antibody isotype is a modulator of this binding with the IgG3 subclass mediating potent Fc effector function and is associated with HIV vaccine efficacy and HIV control. BNAb functions are typically assessed independently of the constant region with which they are naturally expressed. To examine the role of natural isotype in the context of a bNAb lineage we studied CAP256, an HIV-infected individual that mounted a potent V2-specific bNAb response. CAP256 expressed persistently high levels of plasma IgG3 which we found mediated both broad neutralizing activity and potent Fc function. Sequencing of germline DNA and the constant regions of V2-directed bNAbs from this donor revealed the expression of a novel IGHG3 allele as well as IGHG3*17, an allele that produces IgG3 antibodies with increased plasma half-life. Both allelic variants were used to generate CAP256-VRC26.25 and CAP256-VRC26.29 IgG3 bNAbs and these were compared to IgG1 versions. IgG3 variants were shown to have significantly higher phagocytosis and trogocytosis compared to IgG1 versions, which corresponded to increased affinity for FcγRIIa. Neutralization potency was also significantly higher for IgG3 bNAbs, particularly against viruses lacking the N160 glycan. By exchanging hinge regions between subclass variants, we showed that hinge length modulated both neutralization potency and Fc function. This study showed that co-operation between the variable and natural IgG3 constant regions enhanced the polyfunctionality of antibodies, indicating the value of leveraging genetic variation which could be exploited for passive immunity.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Imunoglobulina G/imunologia , Isotipos de Imunoglobulinas/imunologia , Adulto , Feminino , Infecções por HIV/imunologia , Humanos , Receptores Fc/imunologia
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