RESUMO
Effective treatment and immunoprophylaxis of viral respiratory infections with neutralizing monoclonal antibodies (mAbs) require maintaining inhibitory concentrations of mAbs at the airway surface. While engineered mAbs with increased affinity to the neonatal Fc receptor (FcRn) are increasingly employed, little is known how increased affinity of Fc to FcRn influences basal-to-apical transepithelial transport (transcytosis) of mAbs across the airway epithelium. To investigate this, we utilized a model of well-differentiated human airway epithelium (WD-HAE) that exhibited robust FcRn expression, and measured the transepithelial transport of a mAb against SARS-CoV-2 Spike protein (CR3022) with either wildtype IgG1-Fc or Fc modified with YTE or LS mutations known to increase affinity for FcRn. Despite the marked differences in the affinity of these CR3022 variants for FcRn, we did not find substantial differences in basal-to-apical transport reflective of systemic dosing, or apical-to-basal transport reflective of inhaled dosing, compared to the transport of wildtype IgG1-Fc. These results suggest increasing FcRn affinity may only have limited influence over transcytosis rates of systemically dosed mAbs across the human airway epithelium over short time scales. Over longer time scales, the elevated circulating levels of mAbs with greater FcRn affinity, due to more effective FcRn-mediated recycling, may better resupply mAb into the respiratory tract, leading to more effective extended immunoprophylaxis.
Assuntos
Anticorpos Monoclonais , Antígenos de Histocompatibilidade Classe I , Imunoglobulina G , Receptores Fc , Mucosa Respiratória , Transcitose , Humanos , Receptores Fc/metabolismo , Receptores Fc/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoglobulina G/imunologia , Anticorpos Monoclonais/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/prevenção & controleRESUMO
Sepsis is an infection-induced systemic inflammatory response syndrome. Immune regulation plays a crucial role in sepsis. We looked into the link between immune effector-related proteins and sepsis in this study by using both univariate and multivariate Mendelian randomization (MR) analyses. We accessed and collected data from the Integrative Epidemiology Unit's Open About Sepsis genome-wide association study database. The 6 immune effector-associated proteins each contained 10,534,735 single-nucleotide polymorphisms from 3301 samples. Using the weighted median, MR-Egger, simplex, inverse-variance weighting, and weighted mode methods, univariate MR then investigated the link between complement factor H-related protein-5 (CFHR5), Fc epsilon receptor II (FCER2), granzyme B (GZMB), major histocompatibility complex, class II, DQ alpha (HLA-DQA2), mannose-binding lectin 2 (MBL2), or myeloperoxidase (MPO) and sepsis. In the inverse-variance weighted results, the P values of all 6 immune effector-related proteins were <0.05, suggesting a possible causal relationship between them and sepsis. MBL2 (odds ratio [OR]â =â 1.046) was a risk factor for sepsis, while the other proteins (FCER2: ORâ =â 0.922; GZMB: ORâ =â 0.908; CFHR5: ORâ =â 0.858; HLA-DQA2: ORâ =â 0.896; MPO: ORâ =â 0.875) were safety factors. By revealing a causal link between sepsis and CFHR5, FCER2, GZMB, HLA-DQA2, MBL2, or MPO, our study offers an essential resource for additional investigations on the subject.
Assuntos
Estudo de Associação Genômica Ampla , Lectina de Ligação a Manose , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Sepse , Humanos , Sepse/genética , Sepse/imunologia , Lectina de Ligação a Manose/genética , Granzimas/genética , Peroxidase/genética , Peroxidase/imunologia , Fatores de Risco , Predisposição Genética para Doença , Receptores Fc/genéticaRESUMO
Prenatal administration of monoclonal antibodies (mAbs) is a strategy that could be exploited to prevent viral infections during pregnancy and early life. To reach protective levels in fetuses, mAbs must be transported across the placenta, a selective barrier that actively and specifically promotes the transfer of antibodies (Abs) into the fetus through the neonatal Fc receptor (FcRn). Because FcRn also regulates Ab half-life, Fc mutations like the M428L/N434S, commonly known as LS mutations, and others have been developed to enhance binding affinity to FcRn and improve drug pharmacokinetics. We hypothesized that these FcRn-enhancing mutations could similarly affect the delivery of therapeutic Abs to the fetus. To test this hypothesis, we measured the transplacental transfer of leronlimab, an anti-CCR5 mAb, in clinical development for preventing HIV infections, using pregnant rhesus macaques to model in utero mAb transfer. We also generated a stabilized and FcRn-enhanced form of leronlimab, termed leronlimab-PLS. Leronlimab-PLS maintained higher levels within the maternal compartment while also reaching higher mAb levels in the fetus and newborn circulation. Further, a single dose of leronlimab-PLS led to complete CCR5 receptor occupancy in mothers and newborns for almost a month after birth. These findings support the optimization of FcRn interactions in mAb therapies designed for administration during pregnancy.
Assuntos
Feto , Antígenos de Histocompatibilidade Classe I , Macaca mulatta , Receptores CCR5 , Receptores Fc , Animais , Gravidez , Receptores Fc/genética , Receptores Fc/imunologia , Receptores Fc/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Feto/imunologia , Receptores CCR5/genética , Receptores CCR5/imunologia , Animais Recém-Nascidos , Humanos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/genética , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Troca Materno-Fetal/imunologia , Mutação , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/genética , Antagonistas dos Receptores CCR5/farmacologia , Anticorpos Monoclonais Humanizados/imunologiaRESUMO
Schistosomiasis, a highly prevalent parasitic disease, affects more than 200 million people worldwide. Current diagnostics based on parasite egg detection in stool detect infection only at a late stage, and current antibody-based tests cannot distinguish past from current infection. Here, we developed and used a multiplexed antibody profiling platform to obtain a comprehensive repertoire of antihelminth humoral profiles including isotype, subclass, Fc receptor (FcR) binding, and glycosylation profiles of antigen-specific antibodies. Using Essential Regression (ER) and SLIDE, interpretable machine learning methods, we identified latent factors (context-specific groups) that move beyond biomarkers and provide insights into the pathophysiology of different stages of schistosome infection. By comparing profiles of infected and healthy individuals, we identified modules with unique humoral signatures of active disease, including hallmark signatures of parasitic infection such as elevated immunoglobulin G4 (IgG4). However, we also captured previously uncharacterized humoral responses including elevated FcR binding and specific antibody glycoforms in patients with active infection, helping distinguish them from those without active infection but with equivalent antibody titers. This signature was validated in an independent cohort. Our approach also uncovered two distinct endotypes, nonpatent infection and prior infection, in those who were not actively infected. Higher amounts of IgG1 and FcR1/FcR3A binding were also found to be likely protective of the transition from nonpatent to active infection. Overall, we unveiled markers for antibody-based diagnostics and latent factors underlying the pathogenesis of schistosome infection. Our results suggest that selective antigen targeting could be useful in early detection, thus controlling infection severity.
Assuntos
Biomarcadores , Aprendizado de Máquina , Esquistossomose , Humanos , Esquistossomose/imunologia , Esquistossomose/diagnóstico , Esquistossomose/sangue , Esquistossomose/parasitologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Imunidade Humoral , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Glicosilação , Animais , Anticorpos Anti-Helmínticos/sangue , Anticorpos Anti-Helmínticos/imunologia , Receptores Fc/metabolismo , Feminino , AdultoRESUMO
BACKGROUND: Our study aims to investigate the mechanisms through which Fc receptor-like A (FCRLA) promotes renal cell carcinoma (RCC) and to examine its significance in relation to tumor immune infiltration. MATERIALS AND METHODS: The correlation between FCRLA and data clinically related to RCC was explored using The Cancer Genome Atlas (TCGA), then validated using Gene Expression Omnibus (GEO) gene chip data. Enrichment and protein-protein interaction (PPI) network analyses were performed for FCRLA and its co-expressed genes. FCRLA was knocked down in RCC cell lines to evaluate its impact on biological behavior. Then the potential downstream regulators of FCRLA were determined by western blotting, and rescue experiments were performed for verification. The relevance between FCRLA and various immune cells was analyzed through GSEA, TIMER, and GEPIA tools. TIDE and ESTIMATE algorithms were used to predict the effect of FCRLA in immunotherapy. RESULTS: Fc receptor-like A was associated with clinical and T stages and could predict the M stage (AUC = 0.692) and 1-3- and 5-year survival rates (AUC = 0.823, 0.834, and 0.862) of RCC patients. Higher expression of FCLRA predicted an unfavorable overall survival (OS) in TCGA-RCC and GSE167573 datasets (p = 0.03, p = 0.04). FCRLA promoted the malignant biological behavior of RCC cells through the pERK1/2/-MMP2 pathway and was associated with tumor immune microenvironment in RCC. CONCLUSION: Fc receptor-like A is positively correlated with poor outcomes in RCC patients and plays an oncogenic role in RCC through the pERK1/2-MMP2 pathway. Patients with RCC might benefit from immunotherapy targeting FCRLA.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Feminino , Humanos , Masculino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Prognóstico , Mapas de Interação de Proteínas , Receptores Fc/genética , Receptores Fc/metabolismo , Microambiente Tumoral/imunologiaRESUMO
CD177 plays an important role in the proliferation and differentiation of myeloid lineage cells including neutrophils, myelocytes, promyelocytes, megakaryocytes, and early erythroblasts in bone marrow. CD177 deficiency is a common phenotype in humans. Our previous studies revealed genetic mechanisms of human CD177 deficiency and expression variations. Up to now, immune functions of CD177 remain undefined. In the current study, we revealed human IgG as a ligand for CD177 by using flow cytometry, bead-rosette formation, and surface plasmon resonance (SPR) assays. In addition, we show that CD177 variants affect the binding capacity of CD177 for human IgG. Furthermore, we show that the CD177 genetic variants significantly affect antibody-dependent cell-mediated cytotoxicity (ADCC) function. The demonstration of CD177 as a functional IgG Fc-receptor may provide new insights into CD177 immune function and genetic mechanism underlying CD177 as biomarkers for human diseases.
Assuntos
Proteínas Ligadas por GPI , Imunoglobulina G , Humanos , Imunoglobulina G/imunologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Receptores de IgG/genética , Receptores de IgG/metabolismo , Isoantígenos/imunologia , Isoantígenos/genética , Variação Genética , Receptores Fc/metabolismo , Receptores Fc/genética , Ligação ProteicaRESUMO
Chemotherapy-induced thrombocytopenia (CIT) is a common challenge of cancer therapy and can lead to chemotherapy dose reduction, delay, and/or discontinuation, affecting relative dose intensity, and possibly adversely impacting cancer care. Besides changing anticancer regimens, standard management of CIT has been limited to platelet transfusions and supportive care. Use of the thrombopoietin receptor agonist romiplostim, already approved for use in immune thrombocytopenia, has shown promising signs of efficacy in CIT. In a phase 2 prospective randomized study of solid tumor patients with platelet counts <100 × 109/L for ≥4 weeks due to CIT, weekly romiplostim corrected the platelet count to >100 × 109/L in 93% (14/15) of patients within 3 weeks versus 12.5% (1/8) of untreated patients (p < 0.001). Including patients treated with romiplostim in an additional single-arm cohort, 85% (44/52) of all romiplostim-treated patients responded with platelet count correction within 3 weeks. Several retrospective studies of CIT have also shown responses to weekly romiplostim, with the largest study finding that poor response to romiplostim was predicted by tumor invasion of the bone marrow (odds ratio, 0.029; 95% CI: 0.0046-0.18; p < 0.001), prior pelvic irradiation (odds ratio, 0.078; 95% CI: 0.0062-0.98; p = 0.048), and prior temozolomide treatment (odds ratio 0.24; 95% CI: 0.061-0.96; p = 0.043). Elsewhere, lower baseline TPO levels were predictive of romiplostim response (p = 0.036). No new safety signals have emerged from romiplostim CIT studies. Recent treatment guidelines, including those from the National Comprehensive Cancer Network, now support consideration of romiplostim use in CIT. Data are expected from two ongoing phase 3 romiplostim CIT trials.
Assuntos
Antineoplásicos , Receptores Fc , Proteínas Recombinantes de Fusão , Trombocitopenia , Trombopoetina , Humanos , Receptores Fc/uso terapêutico , Trombopoetina/uso terapêutico , Trombopoetina/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Trombocitopenia/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Contagem de Plaquetas , Receptores de Trombopoetina/agonistas , Resultado do TratamentoRESUMO
PURPOSE: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood-brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP/PS1 TG mice using 89Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7 days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated. PROCEDURES: AduH310A-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with 89Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled AduH310A-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP/PS1 TG mice and wild-type animals as controls. RESULTS: Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [89Zr]Zr-AduH310A-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [89Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [89Zr]Zr-AduH310A-8D3. CONCLUSIONS: Although a faster blood clearance of AduH310A-8D3 was observed, it was concluded that no beneficial effects for 89Zr-immuno-PET imaging of brain uptake were obtained.
Assuntos
Peptídeos beta-Amiloides , Barreira Hematoencefálica , Encéfalo , Mutação , Tomografia por Emissão de Pósitrons , Radioisótopos , Zircônio , Animais , Zircônio/química , Barreira Hematoencefálica/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos/química , Peptídeos beta-Amiloides/metabolismo , Receptores Fc/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Distribuição Tecidual , Camundongos Transgênicos , Camundongos , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/farmacocinética , Células CHO , Cricetulus , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/química , HumanosRESUMO
BACKGROUND: In early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti-neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels. METHODS: In an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks' gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks' gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%). RESULTS: Live birth at 32 weeks' gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks' gestation or later and one fetus before fetal loss at 22 weeks and 5 days' gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity. CONCLUSIONS: Nipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.).
Assuntos
Anticorpos Monoclonais Humanizados , Eritroblastose Fetal , Hidropisia Fetal , Imunoglobulina G , Isoanticorpos , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Transfusão de Sangue Intrauterina/efeitos adversos , Eritroblastose Fetal/sangue , Eritroblastose Fetal/imunologia , Eritroblastose Fetal/terapia , Idade Gestacional , Antígenos de Histocompatibilidade Classe I , Imunoglobulina G/imunologia , Isoanticorpos/sangue , Isoanticorpos/imunologia , Nascido Vivo , Receptores Fc/antagonistas & inibidores , Receptores Fc/sangue , Receptores Fc/imunologia , Infusões Intravenosas , Hidropisia Fetal/imunologia , Hidropisia Fetal/prevenção & controle , Anemia/imunologia , Anemia/prevenção & controleRESUMO
Bovine neutrophils possess a particular set of receptors for immunoglobulins. They have been shown to express a distinctive receptor for IgG2, and it has long been known that they interact poorly with IgG1 but that they can use IgM antibodies as opsonins. We show that the binding of labeled IgM was inhibited by unlabeled IgM but not by IgA, suggesting that bovine neutrophils express a specific IgM receptor. The binding of non-aggregated IgM is strong at 4 °C, but shedding occurs at 37 °C. We designed anti-peptide antibodies based on the sequence of the FcµR, the newly described receptor for IgM. These antibodies bound to bovine neutrophils at 4 °C. At 37 °C, labeling was lost, but the loss was inhibited by pretreatment with cytochalasin D, indicating internalization of the receptor after cross-linking by antibodies. Neutrophils that had internalized the receptor were no longer able to bind IgM. Eosinophils showed a low level of FcµR expression. FcµR expression by neutrophils was not increased by stimulation with Toll-like receptor agonists or the complement anaphylatoxin C5a, and decreased by TNF-α. Exposure of neutrophils to IFN-γ for 18 h increased FcµR expression without augmenting the binding of IgG1 or IgG2. We confirmed that bovine neutrophils can use IgM to phagocytose and kill bacteria without the help of Complement. Neutrophils that have migrated into the lumen of inflamed lactating mammary glands expressed the FcµR. These results indicate that bovine neutrophils express an IgM receptor, the FcµR, which is functional to contribute to the opsonophagocytosis of bacteria at inflammatory sites. Expression of the FcµR by neutrophils gives IgM a particular importance for the immune defense in the bovine species.
Assuntos
Imunoglobulina M , Neutrófilos , Animais , Bovinos , Imunoglobulina M/metabolismo , Imunoglobulina M/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fagocitose , Receptores Imunológicos/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/genética , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Receptores Fc/metabolismo , Receptores Fc/imunologia , Receptores Fc/genética , Células CultivadasRESUMO
Immunity acquired by vaccination following infection, termed hybrid immunity, has been shown to confer enhanced protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by enhancing the breadth and potency of immune responses. Here, we assess Fc-mediated humoral profiles in hybrid immunity and their association with age and vaccine type. Participants are divided into three groups: infection only, vaccination only, and vaccination following infection (i.e., hybrid immunity). Using systems serology, we profile humoral immune responses against spikes and subdomains of SARS-CoV-2 variants. We find that hybrid immunity is characterized by superior Fc receptor binding and natural killer (NK) cell-, neutrophil-, and complement-activating antibodies, which is higher than what can be expected from the sum of the vaccination and infection. These differences between hybrid immunity and vaccine-induced immunity are more pronounced in aged adults, especially for immunoglobulin (Ig)G1, IgG2, and Fcγ receptor-binding antibodies. Our findings suggest that vaccination strategies that aim to mimic hybrid immunity should consider age as an important modifier.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Imunidade Humoral , SARS-CoV-2 , Vacinação , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Adulto , Pessoa de Meia-Idade , Imunidade Humoral/imunologia , Idoso , Feminino , Masculino , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Fatores Etários , Receptores Fc/imunologia , Receptores Fc/metabolismo , Células Matadoras Naturais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Receptores de IgG/metabolismo , Receptores de IgG/imunologia , Adulto Jovem , Fragmentos Fc das Imunoglobulinas/imunologia , Neutrófilos/imunologiaRESUMO
Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor-induced MG. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.
Assuntos
Autoanticorpos , Miastenia Gravis , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Miastenia Gravis/patologia , Humanos , Autoanticorpos/imunologia , Receptores Colinérgicos/imunologia , Timoma/imunologia , Timoma/patologia , Timoma/terapia , Antígenos de Histocompatibilidade Classe I/imunologia , Receptores Fc/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidoresRESUMO
Thrombopoietin receptor agonists (TPO-Ras; romiplostim/eltrombopag/avatrombopag) have demonstrated high efficacy rates (59-88%) and a good safety profile in clinical trials with adult patients with immune thrombocytopenia (ITP). Similar efficacy and safety results have been observed with romiplostim and eltrombopag in paediatric cohorts. Continuous treatment with TPO-RAs has shown durable responses with long-term use, up to 3 years. The effect of TPO-RAs was generally considered transient, as platelet counts tended to drop to baseline values after a short period of time (about 2 weeks), unless treatment was maintained. Several groups have reported successful discontinuation of TPO-RAs without the need for concomitant treatments. This is referred to as sustained remission off treatment (SROT). Both short- and medium-term treatment with TPO-RAs may reduce costs to our healthcare systems and, more importantly, may reduce the potential side effects that may be associated with continuous TPO-RA treatment. The issue of tapering and discontinuation of TPO-RAs in paediatric patients with ITP has received little attention to date. Given that paediatric ITP has much higher rates of spontaneous remission than ITP in adults, we consider that the possibility of SROT of TPO-RAs in paediatric patients with ITP is a neglected but very relevant issue in this subtype of the disease.
Assuntos
Benzoatos , Hidrazinas , Púrpura Trombocitopênica Idiopática , Pirazóis , Receptores de Trombopoetina , Proteínas Recombinantes de Fusão , Tiazóis , Trombopoetina , Criança , Humanos , Benzoatos/uso terapêutico , Esquema de Medicação , Hidrazinas/uso terapêutico , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Indução de Remissão , Tiazóis/uso terapêutico , Tiofenos , Trombopoetina/uso terapêutico , Resultado do TratamentoRESUMO
Variable number tandem repeat (VNTR) polymorphisms of the human neonatal IgG Fc receptor α-chain gene (FCGRT) are known to influence the expression levels of FCGRT and IgG in serum. Monkeys are considered to be a relevant biological model for studying the effects of immunobiological drugs. The study determined the functional VNTR polymorphisms of the FCGRT gene in 109 male rhesus macaques from the nursery of the Kurchatov Complex of Medical Primatology. PCR amplification of samples was carried out followed by electrophoretic separation of DNA fragments in a 2% agarose gel. Individual DNA amplification products were sequenced (according to Sanger system) in forward and reverse directions to confirm the specificity. The genotyping showed that the VNTR polymorphism of the FCGRT gene in the studied population of rhesus macaques is presented by 9 variants. The frequency of the VNTR5 allele associated with lower IgG levels was 14.2%, and the most common one was the VNTR7 allele (25.2%). We also identified alleles that have not been previously reported: VNTR3, VNTR4, VNTR6, VNTR8, and VNTR9. The study allows to consider rhesus macaques as a potential model for studying the immunological response depending on the genetic VNTR variant of FCGRT.
Assuntos
Alelos , Macaca mulatta , Repetições Minissatélites , Polimorfismo Genético , Animais , Macaca mulatta/genética , Repetições Minissatélites/genética , Polimorfismo Genético/genética , Masculino , Frequência do Gene/genética , Imunoglobulina G/sangue , Imunoglobulina G/genética , Receptores Fc/genética , Genótipo , Antígenos de Histocompatibilidade Classe IRESUMO
Immunoglobulin G (IgG) antibodies that bind their cognate antigen in a pH-dependent manner (acid-switched antibodies) can release their bound antigen for degradation in the acidic environment of endosomes, while the IgGs are rescued by the neonatal Fc receptor (FcRn). Thus, such IgGs can neutralize multiple antigens over time and therefore be used at lower doses than their non-pH-responsive counterparts. Here, we show that light-chain shuffling combined with phage display technology can be used to discover IgG1 antibodies with increased pH-dependent antigen binding properties, using the snake venom toxins, myotoxin II and α-cobratoxin, as examples. We reveal differences in how the selected IgG1s engage their antigens and human FcRn and show how these differences translate into distinct cellular handling properties related to their pH-dependent antigen binding phenotypes and Fc-engineering for improved FcRn binding. Our study showcases the complexity of engineering pH-dependent antigen binding IgG1s and demonstrates the effects on cellular antibody-antigen recycling.
Assuntos
Antígenos de Histocompatibilidade Classe I , Imunoglobulina G , Receptores Fc , Concentração de Íons de Hidrogênio , Imunoglobulina G/metabolismo , Imunoglobulina G/química , Humanos , Receptores Fc/metabolismo , Receptores Fc/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/imunologia , Engenharia de Proteínas/métodos , Ligação Proteica , Cadeias Leves de Imunoglobulina/química , Cadeias Leves de Imunoglobulina/metabolismo , Cadeias Leves de Imunoglobulina/genética , Antígenos/metabolismo , Antígenos/química , Animais , Modelos MolecularesRESUMO
Arteriviruses infect a variety of mammalian hosts, but the receptors used by these viruses to enter cells are poorly understood. We identified the neonatal Fc receptor (FcRn) as an important pro-viral host factor via comparative genome-wide CRISPR-knockout screens with multiple arteriviruses. Using a panel of cell lines and divergent arteriviruses, we demonstrate that FcRn is required for the entry step of arterivirus infection and serves as a molecular barrier to arterivirus cross-species infection. We also show that FcRn synergizes with another known arterivirus entry factor, CD163, to mediate arterivirus entry. Overexpression of FcRn and CD163 sensitizes non-permissive cells to infection and enables the culture of fastidious arteriviruses. Treatment of multiple cell lines with a pre-clinical anti-FcRn monoclonal antibody blocked infection and rescued cells from arterivirus-induced death. Altogether, this study identifies FcRn as a novel pan-arterivirus receptor, with implications for arterivirus emergence, cross-species infection, and host-directed pan-arterivirus countermeasure development.
Assuntos
Antígenos de Histocompatibilidade Classe I , Receptores Fc , Receptores Virais , Receptores Fc/metabolismo , Receptores Fc/genética , Humanos , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Animais , Receptores Virais/metabolismo , Receptores Virais/genética , Linhagem Celular , Internalização do Vírus , Antígenos CD/metabolismo , Antígenos CD/genética , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/genética , Células HEK293RESUMO
INTRODUCTION: Immune thrombocytopenia (ITP) affecting pregnancy is a diagnostic and often a therapeutic challenge. AREAS COVERED: We review the current diagnostic criteria for ITP in pregnancy and the potential utility of laboratory tests. We discuss the impact of ITP on pregnancy outcomes and the effects of pregnancy on patients living with chronic ITP. We describe the criteria for intervention, the evidence supporting first-line treatment approaches and the therapeutic decisions and challenges in cases refractory to steroids and IVIG. We review the evidence supporting the potential use of thrombopoietin receptor agonists for refractory thrombocytopenia. Finally, we describe the diagnostic, prognostic, and treatment approaches to neonatal ITP and considerations regarding breastfeeding. We searched the terms 'immune thrombocytopenia' and 'pregnancy' on PubMed to identify the relevant literature published before 31 December 2023, including within cited references. EXPERT OPINION: Decreased platelet production may play a role in pregnancy-related ITP exacerbation. Putative mechanisms include placental hormones, such as inhibin. Although IVIG and prednisone usually suffice to achieve hemostasis for delivery, second-line agents are sometimes required to allow for neuraxial anesthesia. There is growing evidence supporting the use of romiplostim during pregnancy; however, its risk of venous thromboembolism warrants further evaluation.
Assuntos
Complicações Hematológicas na Gravidez , Púrpura Trombocitopênica Idiopática , Humanos , Gravidez , Feminino , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/terapia , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/terapia , Complicações Hematológicas na Gravidez/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Gerenciamento Clínico , Receptores de Trombopoetina/agonistas , Trombopoetina/uso terapêutico , Resultado da Gravidez , Receptores Fc , Proteínas Recombinantes de FusãoRESUMO
Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB.
Assuntos
Anticorpos Antibacterianos , Fragmentos Fc das Imunoglobulinas , Mycobacterium tuberculosis , Neutrófilos , Tuberculose , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/genética , Neutrófilos/imunologia , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/genética , Tuberculose/imunologia , Tuberculose/microbiologia , Anticorpos Antibacterianos/imunologia , Engenharia de Proteínas , Animais , Receptores Fc/imunologia , Receptores Fc/metabolismo , Receptores Fc/genética , CamundongosRESUMO
Whole virion inactivated vaccine CoronaVac (C) and Spike (S) mRNA BNT162b2 (B) vaccines differ greatly in their ability to elicit neutralizing antibodies but have somewhat comparable effectiveness in protecting from severe COVID-19. We conducted further analyses for a randomized trial (Cobovax study, NCT05057169) of third dose homologous and heterologous booster vaccination, i.e. four interventions CC-C, CC-B, BB-C and BB-B. Here, we assess vaccine immunogenicity beyond neutralizing function, including S and non-S antibodies with Fc receptor (FcR) binding, antibody avidity and T cell specificity to 6 months post-vaccination. Ancestral and Omicron S-specific IgG and FcR binding are significantly higher by BNT162b2 booster than CoronaVac, regardless of first doses. Nucleocapsid (N) antibodies are only increased in homologous boosted CoronaVac participants (CC-C). CoronaVac primed participants have lower baseline S-specific CD4+ IFNγ+ cells, but are significantly increased by either CoronaVac or BNT162b2 boosters. Priming vaccine content defined T cell peptide specificity preference, with S-specific T cells dominating B primed groups and non-S structural peptides contributing more in C primed groups, regardless of booster type. S-specific CD4+ T cell responses, N-specific antibodies, and antibody effector functions via Fc receptor binding may contribute to protection and compensate for less potent neutralizing responses in CoronaVac recipients.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , Vacinas contra COVID-19 , COVID-19 , Receptores Fc , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vacinas de Produtos Inativados , Vacinas de mRNA , Humanos , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , COVID-19/imunologia , Receptores Fc/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Vacina BNT162/imunologia , Vacina BNT162/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de mRNA/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Feminino , Imunização Secundária , Imunogenicidade da Vacina , Adulto , Linfócitos T/imunologia , Masculino , Imunoglobulina G/imunologia , Pessoa de Meia-IdadeRESUMO
Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to this autoimmune disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). We focused on IgA, which is the second-most prevalent isotype in serum and, along with IgG, is deposited in glomeruli in individuals with lupus nephritis. We show that individuals with SLE have serum IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoprotein (Sm/RNP), played a role in IC activation of pDCs. We found that pDCs expressed the IgA-specific Fc receptor, FcαR, and IgA1 autoantibodies synergized with IgG in RNA-containing ICs to generate robust primary blood pDC IFN-α responses in vitro. pDC responses to these ICs required both FcαR and FcγRIIa, showing synergy between these Fc receptors. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. Circulating pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcαR than pDCs from healthy control individuals. Although pDC FcαR expression correlated with the blood IFN-stimulated gene signature in SLE, Toll-like receptor 7 agonists, but not IFN-α, up-regulated pDC FcαR expression in vitro. Together, we show a mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis.