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1.
Front Immunol ; 12: 550236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025634

RESUMO

Purpose: Agonistic ß2-adrenergic receptor autoantibodies (ß2-agAAbs) were recently observed in sera of patients with ocular hypertension (OHT), primary (POAG), and secondary open-angle glaucoma (SOAG), yet not in healthy controls (HCs). It was the aim of the present study to investigate the presence of ß2-agAAb in aqueous humor (AH) samples of OAG patients and to correlate these with the corresponding ß2-agAAb serum data. Material and Methods: Thirty-nine patients (21 male, 18 female) were recruited from the Department of Ophthalmology, University of Erlangen-Nürnberg: twenty-one POAG, 18 SOAG. Aqueous humor samples were collected during minimal invasive glaucoma surgery. Serum and AH samples were analyzed for ß2-agAAb by a bioassay quantifying the beating rate of cultured cardiomyocyte (cut-off: 2 U). Results: Thirty-six of 39 (92.3%) and 34 of 39 (87.2%) of OAG patients showed a ß2-agAAb in their sera and AH samples, respectively. All ß2-agAAb AH-positive OAG patients were also seropositive. We also observed a ß2-agAAb seropositivity in 95 and 89% of patients with POAG and SOAG, respectively. Beta2-agAAbs were seen in 86% (POAG) and 78% (SOAG) of AH samples. The ß2-agAAb adrenergic activity was increased in the AH of patients with POAG (6.5 ± 1.5 U) when compared with those with SOAG (4.1 ± 1.1 U; p = 0.004). Serum ß2-agAAb adrenergic activity did not differ between the cohorts [POAG (4.5 ± 1.5 U); SOAG (4.6 ± 2.1 U; p=0.458)]. No correlation of the beating rates were observed between serum and AH samples for group and subgroup analyses. Conclusion: The detection of ß2-agAAb in systemic and local circulations supports the hypothesis of a direct functional impact of these agAAbs on ocular G-protein coupled receptors. The high prevalence of ß2-agAAb in serum and AH samples of patients with POAG or SOAG suggests a common role of these AAbs in the etiopathogenesis of glaucoma, independent of open-angle glaucoma subtype.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/imunologia , Humor Aquoso/imunologia , Autoanticorpos/imunologia , Glaucoma de Ângulo Aberto/imunologia , Receptores Adrenérgicos beta 2/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Humor Aquoso/fisiologia , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Células Cultivadas , Feminino , Glaucoma de Ângulo Aberto/sangue , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Ratos Sprague-Dawley
2.
Acta Biochim Biophys Sin (Shanghai) ; 53(6): 784-795, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33928341

RESUMO

Autoantibody against the angiotensin II type I receptor (AT1-AA) has been found in the serum of patients with diabetes mellitus (DM). However, it remains unclear whether AT1-AA induces ß-cell apoptosis and participates in the development of DM. In this study, an AT1-AA-positive rat model was set up by active immunization, and AT1-AA IgG was purified. INS-1 cells were treated with AT1-AA, and cell viability, apoptosis, and autophagy-related proteins were detected by Cell Counting Kit-8 assay, flow cytometry, and western blot analysis, respectively. Results showed that existence of AT1-AA impaired the islet function and increased the apoptosis of pancreatic islet cells in rats, and the autophagy level in rat pancreatic islet tissues tended to increase gradually with the prolongation of immunization time. AT1-AA markedly reduced INS-1 cell viability, promoted cell apoptosis, and decreased insulin secretion in vitro. In addition, the autophagy level was gradually increased along with the prolongation of AT1-AA treatment time. Meanwhile, it was determined that treatment with autophagy inhibitor 3-methyladenine and angiotensin II type 1 receptor (AT1R) blocker telmisartan could improve insulin secretion and apoptosis in vitro and in vivo. In conclusion, it is deduced that upregulation of autophagy contributed to the AT1-AA-induced ß-cell apoptosis and islet dysfunction, and AT1R mediated the signal transduction.


Assuntos
Apoptose/efeitos dos fármacos , Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Células Secretoras de Insulina/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Adenina/análogos & derivados , Adenina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Apoptose/imunologia , Autoanticorpos/isolamento & purificação , Autofagia/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Imunização/métodos , Imunoglobulina G/isolamento & purificação , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/imunologia , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Telmisartan/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
3.
Q J Nucl Med Mol Imaging ; 65(2): 91-101, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33565846

RESUMO

Hyperthyroidism is a clinical condition characterized by inappropriately high synthesis and secretion of thyroid hormones by the thyroid gland. It has multiple aetiologies, manifestations and potential therapies. Graves' disease is the most common form of hyperthyroidism, due to the production of autoantibodies against thyrotropin receptor, capable of over-stimulating thyroid function. A reliable diagnosis of hyperthyroidism can be established on clinical grounds, followed by the evaluation of serum thyroid function tests (thyrotropin first and then free thyroxine, adding the measurement of free triiodothyronine in selected specific situations). The recent guidelines of both the American and European Thyroid Associations have strongly recommended the measurement of thyrotropin receptor autoantibodies for the accurate diagnosis and management of Graves' disease. If autoantibody test is negative, a radioiodine uptake should be performed. Considering the most recent laboratory improvements, binding assays can be considered the best first solution for the measurement of thyrotropin receptor autoantibodies in diagnosis and management of overt cases of Graves' disease. In fact, they have a satisfactory clinical sensitivity and specificity (97.4% and 99.2%, respectively) being performed in clinical laboratories on automated platforms together with the other thyroid function tests. In this setting, the bioassays should be reserved for fine and complex diagnoses and for particular clinical conditions where it is essential to document the transition from stimulating to blocking activity or vice versa (e.g. pregnancy and post-partum, related thyroid eye disease, Hashimoto's thyroiditis with extrathyroidal manifestations, unusual cases after LT4 therapy for hypothyroidism or after antithyroid drug treatment for Graves' disease). Undoubtedly, technological advances will help improve laboratory diagnostics of hyperthyroidism. Nevertheless, despite future progress, the dialogue between clinicians and laboratory will continue to be crucial for an adequate knowledge and interpretation of the laboratory tests and, therefore, for an accurate diagnosis and correct management of the patient.


Assuntos
Antitireóideos/imunologia , Autoanticorpos/imunologia , Hipertireoidismo/diagnóstico , Receptores da Tireotropina/imunologia , Animais , Antitireóideos/farmacologia , Autoanticorpos/farmacologia , Técnicas Biossensoriais , Linhagem Celular , Humanos , Hipertireoidismo/tratamento farmacológico , Radioisótopos do Iodo/química , Ligação Proteica , Sensibilidade e Especificidade , Glândula Tireoide
4.
Artigo em Inglês | MEDLINE | ID: mdl-33622675

RESUMO

OBJECTIVE: To evaluate the outcomes of immunosuppressive therapy (IST) discontinuation in patients with neuromyelitis optica spectrum disorder (NMOSD) after a sustained remission period. METHODS: We retrospectively reviewed the medical records of 17 patients with antiaquaporin-4 antibody-positive NMOSD who discontinued IST after a relapse-free period of ≥3 years. RESULTS: IST was discontinued at a median age of 40 years (interquartile range [IQR], 32-51) after a median relapse-free period of 62 months (IQR, 52-73). Among the 17 enrolled patients, 14 (82%) relapsed at a median interval of 6 months (IQR, 4-34) after IST discontinuation, 3 (18%) of whom experienced severe attacks; notably, all 3 of these patients had a history of severe attack before IST. These 3 patients received steroids, followed by plasma exchange for acute treatment, but 2 exhibited poor recovery and significant disability worsening at 6 months after relapse. CONCLUSIONS: IST discontinuation may increase the risk of relapse in seropositive patients with NMOSD even after 5 years of remission. Given the potentially devastating consequence of a single attack of NMOSD, caution is advised with IST discontinuation, particularly in patients with severe attack before IST.


Assuntos
Aquaporina 4/imunologia , Autoanticorpos/farmacologia , Imunossupressão , Neuromielite Óptica/terapia , Adulto , Autoanticorpos/imunologia , Humanos , Imunossupressão/métodos , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Troca Plasmática/métodos , Recidiva , Estudos Retrospectivos , Resultado do Tratamento
5.
Exp Biol Med (Maywood) ; 246(7): 790-795, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33430618

RESUMO

The association between the presence of anti-interferon-γ autoantibodies and the onset of immunodeficiency with intracellular infections has been clearly established. No standard regimen to control the production of these pathogenic autoantibodies, apart from antimicrobial therapy to eliminate infections, contributes to the medical burden of this syndrome, which sometimes has a fatal outcome. In this review, we summarize the findings on anti-interferon-γ autoantibodies to facilitate further research and to provide guidance for treatment strategies.


Assuntos
Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Síndromes de Imunodeficiência/imunologia , Interferon gama/imunologia , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Infecções/imunologia , Ligação Proteica/imunologia
6.
Toxicol Appl Pharmacol ; 410: 115364, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33290778

RESUMO

Semaphorin (Sema) 3A and Sema 4A are immunomodulatory molecules with a common receptor, neuropilin-1 (NRP-1), on the immune cells. Sema 3A binds to NRP-1 and inhibits T cell activation and inflammation, while Sema 4A binds to NRP-1 and promotes T cell activation and inflammation. These molecules are associated closely with the regulation of protein kinase B (AKT)/nuclear factor-kappaB (NF-κB) signaling, which are poorly understood in arsenic toxicity. The present study explored the role of Sema 3A or Sema 4A in arsenic-induced hepatotoxicity in mice. Arsenic exposure induced hepatic injury and resulted in the activations of p-AKT2, NF-κB p65, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, downregulation of Sema 3A, and upregulation of Sema 4A or NRP-1. Interestingly, intervention with anti-Sema 4A antibody showed the mitigation of arsenic-induced hepatotoxicity, accompanied by the downregulation of Sema 4A, rebound of Sema 3A, and upregulation of NRP-1. And, the inflammatory signaling p-AKT2 or NF-κB p65, and NLRP3 inflammasome showed a downregulation compared with arsenic treatment group. In contrast, anti-Sema 3A antibody intervention did not show the significant effect in the histopathological features compared with arsenic treatment group. In conclusion, the anti-Sema 4A antibody antagonizes arsenic-induced hepatotoxicity in mice and may be involved in the inhibitions of AKT2/NF-κB and NLRP3 inflammatory signaling mediated synergistically by Sema 4A or Sema 3A and their receptor NRP-1.


Assuntos
Arsênio/toxicidade , Autoanticorpos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Semaforinas/antagonistas & inibidores , Animais , Autoanticorpos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Relação Dose-Resposta a Droga , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Semaforinas/metabolismo
7.
Life Sci ; 258: 118217, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768575

RESUMO

AIMS: Astrocytes expressing the aquaporin-4 (AQP4) water channel are pathogenic, disease specific immunoglobulins (IgG) found in neuromyelitis optica spectrum disorder (NMOSD), referred to as NMO-IgG, which targets astrocytic AQP4. The interleukin-6 (IL-6) signaling when astrocytes were exposed to NMO-IgG present in the serum of NMOSD patients was evaluated. MAIN METHODS: Serum or human-IgG from NMOSD or healthy controls were exposed to astrocytes. The selectivity and immuno-pathological consequences of Ig binding to surface epitopes were measured by confocal microscopy. Astrocytes were exposed to medium, IL-6, soluble IL-6 receptor (sIL-6R), IL-6 + sIL-6R (IL-6/R), NMO-IgG or control-IgG, NMO-IgG + IL-6/R. The expression of key proteins in IL-6 signaling pathway, IL-6 cytokine and mRNA levels were evaluated by western blotting, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. KEY FINDINGS: Serum or NMO-IgG from NMOSD patients both induced the rapid downregulation of AQP4 expression on the surface of astrocytes. Stimulation of astrocytes with NMO-IgG, IL-6/R, and NMO-IgG + IL-6/R resulted in the enhancement of IL-6 mRNA expression. Meanwhile, the exogenous addition of NMO-IgG elicited an inflammatory transcriptional response that involved signaling through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. Inhibition of the IL-6/JAK/STAT3 pathway with the JAK1/2 specific inhibitor, AZD1480, reversed the associated increase of IL-6. SIGNIFICANCE: Our findings suggest that NMO-IgG can stimulate the astrocytic JAK1/2/STAT3-dependent inflammatory response, which represents one of the important events in NMO pathogenesis. Inhibition of the JAK1/2 signaling pathway may be a novel promising therapy for NMOSD.


Assuntos
Astrócitos/metabolismo , Imunoglobulina G/sangue , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neuromielite Óptica/sangue , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Animais , Astrócitos/efeitos dos fármacos , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Células Cultivadas , Feminino , Humanos , Imunoglobulina G/farmacologia , Interleucina-6/agonistas , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Fator de Transcrição STAT3/agonistas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Adulto Jovem
8.
Circ Res ; 127(9): e232-e249, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32811295

RESUMO

RATIONALE: After myocardial infarction, neutrophils rapidly and massively infiltrate the heart, where they promote both tissue healing and damage. OBJECTIVE: To characterize the dynamics of circulating and cardiac neutrophil diversity after infarction. METHODS AND RESULTS: We employed single-cell transcriptomics combined with cell surface epitope detection by sequencing to investigate temporal neutrophil diversity in the blood and heart after murine myocardial infarction. At day 1, 3, and 5 after infarction, cardiac Ly6G+ (lymphocyte antigen 6G) neutrophils could be delineated into 6 distinct clusters with specific time-dependent patterning and proportions. At day 1, neutrophils were characterized by a gene expression profile proximal to bone marrow neutrophils (Cd177, Lcn2, Fpr1), and putative activity of transcriptional regulators involved in hypoxic response (Hif1a) and emergency granulopoiesis (Cebpb). At 3 and 5 days, 2 major subsets of Siglecfhi (enriched for eg, Icam1 and Tnf) and Siglecflow (Slpi, Ifitm1) neutrophils were found. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis in blood and heart revealed that while circulating neutrophils undergo a process of aging characterized by loss of surface CD62L and upregulation of Cxcr4, heart infiltrating neutrophils acquired a unique SiglecFhi signature. SiglecFhi neutrophils were absent from the bone marrow and spleen, indicating local acquisition of the SiglecFhi signature. Reducing the influx of blood neutrophils by anti-Ly6G treatment increased proportions of cardiac SiglecFhi neutrophils, suggesting accumulation of locally aged neutrophils. Computational analysis of ligand/receptor interactions revealed putative pathways mediating neutrophil to macrophage communication in the myocardium. Finally, SiglecFhi neutrophils were also found in atherosclerotic vessels, revealing that they arise across distinct contexts of cardiovascular inflammation. CONCLUSIONS: Altogether, our data provide a time-resolved census of neutrophil diversity and gene expression dynamics in the mouse blood and ischemic heart at the single-cell level, and reveal a process of local tissue specification of neutrophils in the ischemic heart characterized by the acquisition of a SiglecFhi signature.


Assuntos
Infarto do Miocárdio , Infiltração de Neutrófilos , Neutrófilos/citologia , Neutrófilos/fisiologia , Animais , Antígenos Ly/imunologia , Doenças da Aorta/patologia , Aterosclerose/patologia , Autoanticorpos/farmacologia , Células da Medula Óssea , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Comunicação Celular , Senescência Celular , Mapeamento de Epitopos/métodos , Adesões Focais , Proteínas Ligadas por GPI/metabolismo , Perfilação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoantígenos/metabolismo , Antígenos Comuns de Leucócito , Lipocalina-2/metabolismo , Macrófagos/fisiologia , Camundongos , Infarto do Miocárdio/sangue , Neutrófilos/metabolismo , Especificidade de Órgãos , Receptores de Superfície Celular/metabolismo , Receptores de Formil Peptídeo/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Baço/citologia , Fatores de Tempo
9.
Emerg Top Life Sci ; 4(2): 169-173, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32633322

RESUMO

Preclinical evidence indicates that prion diseases can respond favorably to passive immunotherapy. However, certain antibodies to the cellular prion protein PrPC can be toxic. Comprehensive studies of structure-function relationships have revealed that the flexible amino-terminal tail of PrPC is instrumental for mediating prion toxicity. In a first-in-human study, an anti-prion antibody has been recently administered to patients diagnosed with sporadic Creutzfeldt-Jakob's disease, the most prevalent human prion disease. Moreover, large-scale serosurveys have mapped the prevalence of naturally occurring human anti-prion autoantibodies in health and disease. Here, we provide a perspective on the limitations and opportunities of therapeutic anti-prion antibodies.


Assuntos
Autoanticorpos/química , Autoanticorpos/farmacologia , Doenças Priônicas/tratamento farmacológico , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Imunoterapia , Proteínas PrPC/imunologia , Príons/metabolismo , Conformação Proteica , Relação Estrutura-Atividade
10.
Cell Death Dis ; 11(6): 432, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514012

RESUMO

Vascular remodeling can be caused by angiotensin II type 1 receptor (AT1R) autoantibody (AT1-AA), although the related mechanism remains unknown. Angiotensin II type 2 receptor (AT2R) plays multiple roles in vascular remodeling through cross-talk with AT1R in the cytoplasm. Here, we aimed to explore the role and mechanism of AT2R in AT1-AA-induced vascular smooth muscle cell (VSMC) migration, which is a key event in vascular remodeling. In vitro and in vivo, we found that AT2R can promote VSMC migration in AT1-AA-induced vascular remodeling. Moreover, AT2R expression was upregulated via Klf-5/IRF-1-mediated transcriptional and circErbB4/miR-29a-5p-mediated posttranscriptional mechanisms in response to AT1-AA. Our data provide a molecular basis for AT1-AA-induced AT2R expression by transcription factors, namely, a circular RNA and a microRNA, and showed that AT2R participated in AT1-AA-induced VSMC migration during the development of vascular remodeling. AT2R may be a potential target for the treatment of AT1-AA-induced vascular diseases.


Assuntos
Autoanticorpos/farmacologia , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Receptor Tipo 2 de Angiotensina/biossíntese , Animais , Movimento Celular/fisiologia , Células HEK293 , Humanos , Fator Regulador 1 de Interferon/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso Vascular/citologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptor ErbB-4/metabolismo , Transfecção
11.
Ann Neurol ; 88(3): 544-561, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32588476

RESUMO

OBJECTIVE: Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. METHODS: A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. RESULTS: Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues 29 A to 62 G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. INTERPRETATION: Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561.


Assuntos
Autoanticorpos/imunologia , Encefalomielite/imunologia , Rigidez Muscular/imunologia , Receptores de Glicina/metabolismo , Rigidez Muscular Espasmódica/imunologia , Adulto , Idoso , Animais , Autoanticorpos/farmacologia , Autoantígenos/imunologia , Comportamento Animal/efeitos dos fármacos , Encefalomielite/metabolismo , Epitopos de Linfócito B/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rigidez Muscular/metabolismo , Receptores de Glicina/imunologia , Rigidez Muscular Espasmódica/metabolismo , Peixe-Zebra
12.
Ann Neurol ; 88(3): 603-613, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32583480

RESUMO

OBJECTIVE: The aim was to demonstrate that antibodies from patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis alter the levels of dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) and cause psychotic-like features in mice. METHODS: Cultured rat hippocampal neurons were treated with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, and the effects on clusters of D1R and D2R were quantified. In vivo studies included 71 C57BL/6J mice that were chronically infused with CSF from patients or controls through ventricular catheters connected to subcutaneous osmotic pumps. Prepulse inhibition of the acoustic startling reflex (PPI; a marker of psychotic-like behavior), memory, locomotor activity, and the density of cell-surface and synaptic D1R, D2R, and NMDAR clusters were examined at different time points using reported techniques. RESULTS: In cultured neurons, CSF from patients, but not from controls, caused a significant decrease of cell-surface D1R and an increase of D2R clusters. In mice, CSF from patients caused a significant decrease of synaptic and total cell-surface D1R clusters and an increase of D2R clusters associated with a decrease of PPI. These effects were accompanied by memory impairment and a reduction of surface NMDARs, as reported in this model. The psychotic-like features, memory impairment, and changes in levels of D1R, D2R, and NMDAR progressively improved several days after the infusion of CSF from patients stopped. INTERPRETATION: In addition to memory deficits and reduction of NMDARs, CSF antibodies from patients with anti-NMDAR encephalitis cause reversible psychotic-like features accompanied by changes (D1R decrease, D2R increase) in cell-surface dopamine receptor clusters. ANN NEUROL 2020 ANN NEUROL 2020;88:603-613.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/imunologia , Autoanticorpos/farmacologia , Neurônios/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Adolescente , Adulto , Animais , Encefalite Antirreceptor de N-Metil-D-Aspartato/líquido cefalorraquidiano , Encefalite Antirreceptor de N-Metil-D-Aspartato/metabolismo , Autoanticorpos/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Transtornos Psicóticos , Ratos , Ratos Wistar , Receptores Dopaminérgicos/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Adulto Jovem
13.
Mult Scler Relat Disord ; 37: 101420, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32172994

RESUMO

Immunoglobulin G (IgG) autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG) have recently been associated with autoimmune CNS demyelination. We present the case of a 35-year-old patient who was seronegative for MOG-IgG (as confirmed by means of three independent immunoassays) during two corticosteroid-responsive attacks of brainstem encephalitis and optic neuritis, respectively, but turned positive for MOG-IgG under treatment with interferon-beta (IFN-beta), which was commenced 6 months after onset of the first attack. MOG-IgG serum levels declined after therapy was switched to glatiramer acetate. The fact that seroconversion was first observed under treatment with IFN-beta is in accordance with previous evidence suggesting a role of IFN-beta in disease exacerbation in antibody-mediated disorders.


Assuntos
Autoanticorpos/farmacologia , Imunomodulação/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/terapia , Soroconversão/fisiologia , Adulto , Aquaporina 4/imunologia , Autoanticorpos/sangue , Encefalite/complicações , Encefalite/tratamento farmacológico , Humanos , Imunoglobulina G/sangue , Neuromielite Óptica/complicações , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/tratamento farmacológico , Neurite Óptica/diagnóstico , Neurite Óptica/imunologia , Soroconversão/efeitos dos fármacos
14.
Immunohorizons ; 4(2): 108-118, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32086320

RESUMO

Atherosclerosis prevalence is increased in chronic obstructive pulmonary disease (COPD) patients, independent of other risk factors. The etiology of the excess vascular disease in COPD is unknown, although it is presumably related to an underlying (if cryptic) systemic immune response. Autoantibodies with specificity for glucose-regulated protein 78 (GRP78), a multifunctional component of the unfolded protein response, are common in COPD patients and linked to comorbidities of this lung disease. We hypothesized anti-GRP78 autoreactivity might also be a risk factor for atherosclerosis in COPD patients. Carotid intima-medial thickness (cIMT) was measured in 144 current and former smokers by ultrasound. Concentrations of circulating IgG autoantibodies against full-length GRP78, determined by ELISA, were greater among subjects with abnormally increased cIMT (p < 0.01). Plasma levels of autoantibodies against a singular GRP78 peptide segment, amino acids 246-260 (anti-GRP78aa 246-260), were even more highly correlated with cIMT, especially among males with greater than or equal to moderate COPD (r s = 0.62, p = 0.001). Anti-GRP78aa 246-260 concentrations were independent of CRP, IL-6, and TNF-α levels. GRP78 autoantigen expression was upregulated among human aortic endothelial cells (HAECs) stressed by incubation with tunicamycin (an unfolded protein response inducer) or exposure to culture media flow disturbances. Autoantibodies against GRP78aa 246-260, isolated from patient plasma by immunoprecipitation, induced HAEC production of proatherosclerotic mediators, including IL-8. In conclusion, anti-GRP78 autoantibodies are highly associated with carotid atherosclerosis in COPD patients and exert atherogenic effects on HAECs. These data implicate Ag-specific autoimmunity in the pathogenesis of atherosclerosis among COPD patients and raise possibilities that directed autoantibody reduction might ameliorate vascular disease in this high-risk population.


Assuntos
Autoanticorpos/sangue , Doenças das Artérias Carótidas/imunologia , Proteínas de Choque Térmico/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Adulto , Idoso , Sequência de Aminoácidos , Autoanticorpos/farmacologia , Biomarcadores/sangue , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/epidemiologia , Doenças das Artérias Carótidas/patologia , Espessura Intima-Media Carotídea , Comorbidade , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Risco
15.
Ann Neurol ; 87(5): 670-676, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32052483

RESUMO

OBJECTIVE: Antibodies against neuronal N-methyl-D-aspartate receptors (NMDARs) in patients with anti-NMDAR encephalitis alter neuronal synaptic function and plasticity, but the effects on other cells of the nervous system are unknown. METHODS: Cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis (preabsorbed or not with GluN1) and a human NMDAR-specific monoclonal antibody (SSM5) derived from plasma cells of a patient, along the corresponding controls, were used in the studies. To evaluate the activity of oligodendrocyte NMDARs and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in vitro after exposure to patients' CSF antibodies or SSM5, we used a functional assay based on cytosolic Ca2+ imaging. Expression of the glucose transporter (GLUT1) in oligodendrocytes was assessed by immunocytochemistry. RESULTS: NMDAR agonist responses were robustly reduced after preincubation of oligodendrocytes with patients' CSF or SSM5 but remained largely unaltered with the corresponding controls. These effects were NMDAR specific, as patients' CSF did not alter responses to AMPA receptor agonists and was abrogated by preabsorption of CSF with HEK cells expressing GluN1 subunit. Patients' CSF also reduced oligodendrocyte expression of glucose transporter GLUT1 induced by NMDAR activity. INTERPRETATION: Antibodies from patients with anti-NMDAR encephalitis specifically alter the function of NMDARs in oligodendrocytes, causing a decrease of expression of GLUT1. Considering that normal GLUT1 expression in oligodendrocytes and myelin is needed to metabolically support axonal function, the findings suggest a link between antibody-mediated dysfunction of NMDARs in oligodendrocytes and the white matter alterations reported in patients with this disorder. ANN NEUROL 2020;87:670-676.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/metabolismo , Autoanticorpos/imunologia , Oligodendroglia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Adolescente , Adulto , Animais , Encefalite Antirreceptor de N-Metil-D-Aspartato/imunologia , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/farmacologia , Autoantígenos/imunologia , Células Cultivadas , Criança , Feminino , Transportador de Glucose Tipo 1/biossíntese , Humanos , Masculino , Oligodendroglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/imunologia , Adulto Jovem
16.
Ann Neurol ; 87(3): 405-418, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900946

RESUMO

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. METHODS: We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. RESULTS: Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. INTERPRETATION: Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.


Assuntos
Anticorpos Monoclonais/farmacologia , Autoanticorpos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Neurônios/fisiologia , Proteínas ADAM/efeitos dos fármacos , Idoso , Animais , Anticorpos Monoclonais/líquido cefalorraquidiano , Autoanticorpos/líquido cefalorraquidiano , Região CA3 Hipocampal/fisiologia , Células Cultivadas , Encefalite/líquido cefalorraquidiano , Encefalite/imunologia , Feminino , Doença de Hashimoto/líquido cefalorraquidiano , Doença de Hashimoto/imunologia , Humanos , Isotipos de Imunoglobulinas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/efeitos dos fármacos , Ratos , Transmissão Sináptica/efeitos dos fármacos
17.
Clin Immunol ; 212: 108346, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31954803

RESUMO

Previous studies showed that circulating autoantibodies against M2 muscarinic receptors (anti-M2R Ab) are associated with decreased cardiac parasympathetic modulation in patients with chronic Chagas disease (CD). Here we investigated whether the exposure of M2R to such antibodies could impair agonist-induced receptor activation, leading to the inhibition of associated signaling pathways. Preincubation of M2R-expressing HEK 293T cells with serum IgG fractions from chagasic patients with cardiovascular dysautonomia, followed by the addition of carbachol, resulted in the attenuation of agonist-induced Gi protein activation and arrestin-2 recruitment. These effects were not mimicked by the corresponding Fab fractions, suggesting that they occur through receptor crosslinking. IgG autoantibodies did not enhance M2R/arrestin interaction or promote M2R internalization, suggesting that their inhibitory effects are not likely a result of short-term receptor regulation. Rather, these immunoglobulins could function as negative allosteric modulators of acetylcholine-mediated responses, thereby contributing to the development of parasympathetic dysfunction in patients with CD.


Assuntos
Autoanticorpos/imunologia , Doenças do Sistema Nervoso Autônomo/imunologia , Doença de Chagas/imunologia , Receptor Muscarínico M2/imunologia , Adulto , Idoso , Regulação Alostérica , Autoanticorpos/metabolismo , Autoanticorpos/farmacologia , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/metabolismo , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Carbacol/farmacologia , Doença de Chagas/complicações , Doença de Chagas/metabolismo , Doença de Chagas/fisiopatologia , Agonistas Colinérgicos/farmacologia , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Receptor Muscarínico M2/efeitos dos fármacos , Receptor Muscarínico M2/metabolismo , beta-Arrestina 1/metabolismo
18.
Behav Brain Res ; 379: 112397, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31790783

RESUMO

Multiple lines of evidence suggest a link between depression and osteoporosis in elderly people. Receptor activator of nuclear factor-κB ligand (RANKL) plays a role in the pathology of osteoporosis, and anti-RANKL antibody has been used in the treatment of osteoporosis. In this study, we investigated whether anti-mouse RANKL antibody could attenuate depression-like phenotypes, inflammatory bone markers and bone mineral density (BMD) in male susceptible mice after chronic social defeat stress (CSDS). We measured plasma levels of inflammatory bone markers, including osteoprotegerin (OPG), RANKL, and osteopontin. A single intravenous injection of anti-RANKL (2 mg/kg) elicited rapid antidepressant effects in CSDS susceptible mice. Furthermore, anti-RANKL significantly improved the increased plasma levels of RANKL and decreased OPG/RANKL ratio in CSDS susceptible mice. Moreover, anti-RANKL significantly attenuated the decreased BMD in CSDS susceptible mice. Interestingly, there is a positive correlation between anhedonia-like behavior and OPG/RANKL ratio in mice. These findings demonstrate that anti-RANKL may have beneficial effects in depression-like phenotype and abnormalities in bone functions of CSDS susceptible mice. It is, therefore, likely that anti-human RANKL antibody (i.e., Denosumab) would be a potential therapeutic drug for depression and osteoporosis.


Assuntos
Autoanticorpos/farmacologia , Densidade Óssea/efeitos dos fármacos , Depressão/tratamento farmacológico , Osteíte/tratamento farmacológico , Osteopontina/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoprotegerina/efeitos dos fármacos , Ligante RANK/imunologia , Derrota Social , Estresse Psicológico/imunologia , Animais , Autoanticorpos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteíte/sangue , Osteopontina/sangue , Osteoporose/sangue , Osteoprotegerina/sangue , Fenótipo , Ligante RANK/sangue
19.
Lupus ; 28(14): 1663-1668, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31701800

RESUMO

Platelet activation and decrease in platelet count characterize the development of the most feared form of antiphospholipid syndrome (APS), i.e. catastrophic APS (CAPS). We aimed to assess if immuno-affinity purified anti-ß2-glycoprotein I (aß2GPI) antibodies enhance platelet activation inducing a significant flow obstruction in a platelet function analyzer (PFA). Affinity purified aß2GPI antibodies were obtained from 13 triple positive patients with a strong lupus anticoagulant (LA) and high titers of IgG anticardiolipin antibodies (aCL) and IgG aß2GPI. Platelet activation stimulated by adenosine diphosphate (ADP) in the presence or absence of aß2GPI was measured by the expression of P-selectin on platelet surface using flow cytometry. P-selectin expression remained close to baseline when normal whole blood was incubated with aß2GPI alone. When stimulated using aß2GPI combined with ADP, P-selectin expression (28.42 ± 5.15% vs. 20.98 ± 3.94%, p = 0.0076) was significantly higher than ADP alone. Closure time of normal whole blood passed through the PFA was significantly shorter using affinity purified aß2GPI than control IgG both in Col/ADP (160.1 ± 62.1 s vs. 218.6 ± 43.8 s; p = 0.021) and Col/EPI cartridges (149.5 ± 26.7 s vs. 186.9 ± 45.5 s; p = 0.030). Thus, platelet activation is enhanced by aß2GPI antibodies with a consequent premature closure in a PFA, possibly resembling that in microcirculation in patients with CAPS.


Assuntos
Síndrome Antifosfolipídica/sangue , Autoanticorpos/farmacologia , Selectina-P/metabolismo , Ativação Plaquetária , Trombose/etiologia , beta 2-Glicoproteína I/imunologia , Adulto , Anticorpos Anticardiolipina/sangue , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/imunologia , Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Inibidor de Coagulação do Lúpus , Masculino , Pessoa de Meia-Idade , Selectina-P/genética , Trombose/sangue , Trombose/imunologia , beta 2-Glicoproteína I/farmacologia
20.
Brain ; 142(11): 3398-3410, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31591639

RESUMO

Chloride-permeable glycine receptors have an important role in fast inhibitory neurotransmission in the spinal cord and brainstem. Human immunoglobulin G (IgG) autoantibodies to glycine receptors are found in a substantial proportion of patients with progressive encephalomyelitis with rigidity and myoclonus, and less frequently in other variants of stiff person syndrome. Demonstrating a pathogenic role of glycine receptor autoantibodies would help justify the use of immunomodulatory therapies and provide insight into the mechanisms involved. Here, purified IgGs from four patients with progressive encephalomyelitis with rigidity and myoclonus or stiff person syndrome, and glycine receptor autoantibodies, were observed to disrupt profoundly glycinergic neurotransmission. In whole-cell patch clamp recordings from cultured rat spinal motor neurons, glycinergic synaptic currents were almost completely abolished following incubation in patient IgGs. Most human autoantibodies targeting other CNS neurotransmitter receptors, such as N-methyl-d-aspartate (NMDA) receptors, affect whole cell currents only after several hours incubation and this effect has been shown to be the result of antibody-mediated crosslinking and internalization of receptors. By contrast, we observed substantial reductions in glycinergic currents with all four patient IgG preparations with 15 min of exposure to patient IgGs. Moreover, monovalent Fab fragments generated from the purified IgG of three of four patients also profoundly reduced glycinergic currents compared with control Fab-IgG. We conclude that human glycine receptor autoantibodies disrupt glycinergic neurotransmission, and also suggest that the pathogenic mechanisms include direct antagonistic actions on glycine receptors.


Assuntos
Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/imunologia , Receptores de Glicina/antagonistas & inibidores , Transmissão Sináptica/imunologia , Idoso , Animais , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Imunoglobulina G/genética , Masculino , Pessoa de Meia-Idade , Neurônios Motores/efeitos dos fármacos , Técnicas de Patch-Clamp , Gravidez , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia , Rigidez Muscular Espasmódica/imunologia , Sinapses/efeitos dos fármacos
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