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1.
Phytomedicine ; 68: 153149, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32032836

RESUMO

BACKGROUND: Mast cells (MCs) are crucial effectors in allergic disorders by secreting inflammatory mediators. The Mas-related G-protein-coupled receptor X2 (Mrgprx2) was shown to have a key role in IgE-independent allergic reactions. Therefore, potential drug candidates that directly target Mrgprx2 could be used to treat pseudo-allergic diseases. Shikonin, an active ingredient derived from Lithospermum erythrorhizon Sieb. et Zucc has been used for its anti-inflammatory properties since ancient China. PURPOSE: To investigate the inhibitory effects of Shikonin on IgE-independent allergy both in vitro and in vivo, as well as the mechanism underlying its effects. METHODS/STUDY DESIGNS: The anti-anaphylactoid activity of Shikonin was evaluated in PCA and systemic anaphylaxis models, Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of PLCγ-PKC-IP3 signaling pathway. The analytical method of surface plasmon resonance was employed to study the interaction between Shikonin and potential target protein Mrgprx2. RESULTS: Shikonin can suppress compound 48/80 (C48/80)-induced PCA, active systemic anaphylaxis, and MCs degranulation in mice in a dose-dependent manner. In addition, Shikonin reduced C48/80-induced calcium flux and suppressed LAD2 cell degranulation via PLCγ-PKC-IP3 signaling pathway. Moreover, Shikonin was found to inhibit C48/80-induced Mrgprx2 expression in HEK cells, displaying specific interactions with the Mrgprx2 protein. CONCLUSION: Shikonin could be a potential antagonist of Mrgprx2, thereby inhibiting pseudo-allergic reactions through Ca2+ mobilization.


Assuntos
Anafilaxia/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Naftoquinonas/farmacologia , Proteínas do Tecido Nervoso/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Receptores de Neuropeptídeos/imunologia , Anafilaxia/induzido quimicamente , Animais , Cálcio/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Hipersensibilidade/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL , Naftoquinonas/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Fosfolipase C gama/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/metabolismo , Secretagogos/toxicidade , p-Metoxi-N-metilfenetilamina/toxicidade
2.
Immunity ; 52(2): 404-416.e5, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32049054

RESUMO

Mast cells are rare tissue-resident cells of importance to human allergies. To understand the structural basis of principle mast cell functions, we analyzed the proteome of primary human and mouse mast cells by quantitative mass spectrometry. We identified a mast-cell-specific proteome signature, indicative of a unique lineage, only distantly related to other immune cell types, including innate immune cells. Proteome comparison between human and mouse suggested evolutionary conservation of core mast cell functions. In addition to specific proteases and proteins associated with degranulation and proteoglycan biosynthesis, mast cells expressed proteins potentially involved in interactions with neurons and neurotransmitter metabolism, including cell adhesion molecules, ion channels, and G protein coupled receptors. Toward targeted cell ablation in severe allergic diseases, we used MRGPRX2 for mast cell depletion in human skin biopsies. These proteome analyses suggest a unique role of mast cells in the immune system, probably intertwined with the nervous system.


Assuntos
Mastócitos/citologia , Mastócitos/imunologia , Animais , Biomarcadores/metabolismo , Degranulação Celular , Linhagem da Célula , Células Cultivadas , Tecido Conjuntivo/imunologia , Humanos , Imunoterapia , Mastócitos/metabolismo , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/metabolismo , Neuroimunomodulação , Proteoglicanas/biossíntese , Proteoma , Receptores Acoplados a Proteínas-G/imunologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/imunologia , Receptores de Neuropeptídeos/metabolismo , Pele/imunologia
3.
Nat Commun ; 11(1): 283, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941907

RESUMO

Chimeric antigen receptor (CAR)-expressing T cells targeting B-cell maturation antigen (BCMA) have activity against multiple myeloma, but improvements in anti-BCMA CARs are needed. We demonstrated recipient anti-CAR T-cell responses against a murine single-chain variable fragment (scFv) used clinically in anti-BCMA CARs. To bypass potential anti-CAR immunogenicity and to reduce CAR binding domain size, here we designed CARs with antigen-recognition domains consisting of only a fully human heavy-chain variable domain without a light-chain domain. A CAR designated FHVH33-CD8BBZ contains a fully human heavy-chain variable domain (FHVH) plus 4-1BB and CD3ζ domains. T cells expressing FHVH33-CD8BBZ exhibit similar cytokine release, degranulation, and mouse tumor eradication as a CAR that is identical except for substitution of a scFv for FHVH33. Inclusion of 4-1BB is critical for reducing activation-induced cell death and promoting survival of T cells expressing FHVH33-containing CARs. Our results indicate that heavy-chain-only anti-BCMA CARs are suitable for evaluation in a clinical trial.


Assuntos
Cadeias Pesadas de Imunoglobulinas/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Antígeno de Maturação de Linfócitos B/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular , Células Cultivadas , Humanos , Leucócitos Mononucleares/imunologia , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Domínios Proteicos/genética , Domínios Proteicos/imunologia , Engenharia de Proteínas , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/imunologia , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/metabolismo
4.
Anticancer Res ; 39(11): 5919-5925, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704816

RESUMO

BACKGROUND/AIM: The aim of the current study was to investigate the synergistic efficacy of Robo1 bichimeric antigen receptor-natural killer cell (BiCAR-NK) immunotherapy and 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model. MATERIALS AND METHODS: The orthotopic pancreatic tumor model was established with human pancreatic cancer BxPC-3 cells expressing red fluorescent protein. The mice were treated with 125I seed implantation alone or the combination of 125I seeds with Robo1-specific CAR-NK cells. To assess tumor inhibition, in vivo fluorescence imaging was conducted. 7 Tesla magnetic resonance (7T-MR) scanning was applied to measure the changes in the metabolic profiles of tumor tissues. RESULTS: Tumor size was significantly reduced in the 125I and 125I +CAR-NK treated group compared to the untreated group (p<0.05). The 125I seed +CAR-NK treated group showed significantly higher tumor reduction than 125I seed treatment alone (p<0.05). T1 diffusion weighted imaging (T1DWI) sequence showed that the tumors of the 125I +BiCAR-NK treated group had a significantly higher grey scale value than the tumors from the untreated control and the group treated with 125I seed alone (p<0.05). CONCLUSION: Robo1 specific CAR-NK immunotherapy enhances efficacy of 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model.


Assuntos
Braquiterapia/métodos , Imunoterapia , Radioisótopos do Iodo/uso terapêutico , Células Matadoras Naturais/imunologia , Proteínas do Tecido Nervoso/imunologia , Neoplasias Pancreáticas/terapia , Receptores de Antígenos/imunologia , Receptores Imunológicos/imunologia , Animais , Apoptose , Proliferação de Células , Citotoxicidade Imunológica/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Pan Afr Med J ; 33: 281, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31692829

RESUMO

Paraneoplastic neurologic degeneration (PND) is characterized by acute and subacute onset neurological syndrome associated with active or with subclinical cancer. It is rare but early diagnosis can improve the neurological and carcinological prognosis. Among the PNDs it is possible to distinguish subacute cerebellar degeneration often associated with gynecological or breast cancer. We report the case of a 50-year old female patient on follow-up for ovarian adenocarcinoma treated with surgery and whose recurrence was detected due to anti-Yo antibody-positive subacute cerebellar degeneration.


Assuntos
Adenocarcinoma/diagnóstico , Neoplasias Ovarianas/diagnóstico , Degeneração Paraneoplásica Cerebelar/diagnóstico , Adenocarcinoma/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Proteínas do Tecido Nervoso/imunologia , Neoplasias Ovarianas/patologia , Degeneração Paraneoplásica Cerebelar/imunologia , Prognóstico
6.
Neurology ; 93(20): e1873-e1880, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31624089

RESUMO

OBJECTIVE: To define the clinicopathologic features of amphiphysin-immunoglobulin G (IgG)-mediated neuropathy. METHODS: Patients examined at our institution from January 1, 1995, to September 30, 2018, with amphiphysin-IgG by indirect immunofluorescence and Western blot, were reviewed. Their phenotypes were compared to cases of coexisting collapsin response-mediator protein-5 (CRMP5)-IgG or anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity. Improvement in modified Rankin Scale (mRS) (≥1) on follow-up was considered a favorable outcome. Amphiphysin RNA expression was assessed in healthy nerves. RESULTS: Fifty-three amphiphysin-IgG-positive cases were identified. Of 33 (60%) patients with neuropathy, 21 had amphiphysin-IgG alone, and 12 had coexisting autoantibodies (ANNA1-IgG, n = 8; CRMP5-IgG, n = 2; ANNA1-IgG and CRMP5-IgG, n = 2). The neuropathies in isolated amphiphysin-IgG autoimmunity included polyradiculoneuropathy (62%), diffuse sensory neuronopathy (35%), and facial neuropathy with gastroparesis (3%). Among these, pain (80%), breast cancer (63%), and CNS (57%) involvements commonly coexisted, and neuropathy frequently prompted breast cancer diagnosis (76%). Stiff-person spectrum disorder was the most common CNS accompaniment (45%). Nerve biopsies showed axonal loss (n = 6/6), subperineurial edema (n = 4/6), and CD4 predominant inflammation (n = 2/6). Median mRS score at last follow-up was 3.5; 58% of patients were immunotherapy-responsive. Patients with amphiphysin-IgG alone had more favorable immunotherapy response than patients with CRMP5-IgG polyneuropathy (n = 45) (44% vs 16%, p = 0.028, odds ratio 4.2, 95% confidence interval 1.1 to 15.5). Only 1/9 (11%) patients with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had immunotherapy response. RNA amphiphysin expression occurred at low levels in nerve. CONCLUSION: Amphiphysin-IgG autoimmune neuropathy has a recognizable phenotype, is frequently immune responsive, and can prompt early diagnosis of breast cancer.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Proteínas do Tecido Nervoso/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antinucleares/imunologia , Doenças Autoimunes do Sistema Nervoso/epidemiologia , Doenças Autoimunes do Sistema Nervoso/patologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Biópsia , Neoplasias da Mama/epidemiologia , Comorbidade , Doenças do Nervo Facial/epidemiologia , Doenças do Nervo Facial/imunologia , Doenças do Nervo Facial/patologia , Doenças do Nervo Facial/fisiopatologia , Feminino , Humanos , Hidrolases/imunologia , Imunoglobulina G/imunologia , Masculino , Proteínas Associadas aos Microtúbulos/imunologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Dor , Nervos Periféricos/imunologia , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Polirradiculoneuropatia/epidemiologia , Polirradiculoneuropatia/imunologia , Polirradiculoneuropatia/patologia , Polirradiculoneuropatia/fisiopatologia , Rigidez Muscular Espasmódica/epidemiologia , Síndrome
7.
Nat Commun ; 10(1): 4408, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562318

RESUMO

Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.


Assuntos
Colite/imunologia , Receptores ErbB/imunologia , Helmintíase/imunologia , Mucosa Intestinal/imunologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/imunologia , Fator Trefoil-3/imunologia , Animais , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/metabolismo , Sulfato de Dextrana , Receptores ErbB/genética , Receptores ErbB/metabolismo , Células Caliciformes/imunologia , Células Caliciformes/metabolismo , Células Caliciformes/parasitologia , Células HEK293 , Helmintíase/metabolismo , Helmintíase/parasitologia , Helmintos/imunologia , Helmintos/fisiologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitologia , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Organofosfonatos , Fator Trefoil-3/genética , Fator Trefoil-3/metabolismo , Células U937
8.
Int J Mol Sci ; 20(18)2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540204

RESUMO

The detection of neuronal surface protein autoantibody-related disorders has contributed to several changes in our understanding of central nervous system autoimmunity. The clinical presentation of these disorders may be associated (or not) with tumors, and often patients develop an inexplicable onset of epilepsy, catatonic or autistic features, or memory and cognitive dysfunctions. The autoantigens in such cases have critical roles in synaptic transmission and plasticity, memory function, and process learning. For months, patients with such antibodies may be comatose or encephalopathic and yet completely recover with palliative care and immunotherapies. This paper reviews several targets of neuronal antibodies as biomarkers in seizure disorders, focusing mainly on autoantibodies, which target the extracellular domains of membrane proteins, namely leucine-rich glioma-inactivated-1 (LGI1), contactin-associated protein-like 2 (CASPR2), the N-methyl-D-aspartate receptor (NMDAR), γ-aminobutyric acid receptor-B (GABABR), the glycine receptor (GlyR), and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). In order to restore health status, limit hospitalization, and optimize results, testing these antibodies should be done locally, using internationally certified procedures for a precise and rapid diagnosis, with the possibility of initiating therapy as soon as possible.


Assuntos
Autoanticorpos/metabolismo , Proteínas do Tecido Nervoso/imunologia , Convulsões/diagnóstico , Biomarcadores/metabolismo , Diagnóstico Precoce , Feminino , Humanos , Imunomodulação , Masculino , Convulsões/imunologia , Convulsões/terapia
9.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(3): 344-350, 2019 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-31282328

RESUMO

Objective To explore the clinical characteristics of autoimmune disease with dual seropositive antibodies of leucine-rich glioma inactivated 1(LGI1)and contactin-associated protein 2(Caspr2).Methods The clinical data of seven patients with dual seropositive LGI1 and Caspr2 antibodies who were admitted to the Neurology Department of Peking Union Medical College Hospital from July 2014 to December 2017 were retrospectively analyzed.Results Central,peripheral and autonomic nervous systems were all involved in the seven cases;100%(7/7)presented with insomnia,myokymia,neuropahic pain and hyperhydrosis;71%(5/7)showed memory decline or psychiatric and behavioral symptoms;57%(4/7)had urinary hesitation or constipation;and 43%(3/7)had seizure.Electromyography showed 100%(6/6) of the patients had prolonged afterdischarges following normal M waves and/or abnormal spontaneous firing.Electroencephalography revealed slow waves or basic rhythm slowing in 71%(5/7)of patients.Electrocardiography showed sinus tachycardia,axis deviation,and prolonged QT intervals in 71%(5/7)of patients.One patient died from arrhythmia before immunotherapy.One died from pulmonary infection after immunotherapy.Improvement with immunotherapy was documented in the other five cases.No relapse was noted during the 1-2-year follow-up.Conclusions Autoimmune disease with dual seropositive antibodies of LGI1 and Caspr2 can diffusely affect the central,peripheral,and autonomic nervous systems.The possibility of this disease should be considered in patients with acute and subacute onset of neuropsychiatric symptoms,especially in patients with accompanying insomnia,myokymia,and hyperhydrosis.


Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Proteínas/imunologia , Humanos , Estudos Retrospectivos
10.
Fish Shellfish Immunol ; 92: 680-689, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271837

RESUMO

The Notch signaling pathway is known to regulate innate immunity by influencing macrophage function and interacting with the Toll-like receptor (TLR) signaling pathway. However, the comprehensive role of the Notch signaling pathway in the innate immune response remains unknown. To assess the function of Notch1a in immunity, we examined the innate immune responses to Vibrio parahaemolyticus strain Vp13 of wild-type (WT) and notch1a-/- zebrafish larvae generated using the clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system. The median lethal dose (LD50) of V. parahaemolyticus was significantly lower in notch1a-/- larvae than in WT larvae 3 days post fertilization (dpf). Transcriptome data analysis revealed 359 significantly differentially expressed genes (DEGs), including 246 significantly down-regulated genes and 113 significantly up-regulated genes, in WT infected groups compared with WT control groups. In contrast, 986 significantly DEGs were found in notch1a-/- infected groups compared with notch1a-/- control groups, of which 82 genes were significantly down-regulated and 904 genes were significantly up-regulated. These DEGs belonged to the tumor necrosis factor (TNF), complement, nuclear factor kappa B (NF-κB), cathepsin, interleukin (IL), chemokine, serpin peptidase inhibitor, matrix metallopeptidase, innate immune cells, pattern recognition receptor (PRR), and other cytokine families. Our results indicate that Notch1a plays roles in inhibiting many immunity-related genes and could comprehensively mediate the innate immune response by regulating TLRs, nucleotide-binding-oligomerization-domain-like receptors (NLRs), lectins, complement, ILs, chemokines, TNF, cathepsin, and serpin. Further studies are required to understand the specific mechanism of Notch1a in innate immunity.


Assuntos
Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Imunidade Inata/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Receptor Notch1/genética , Receptor Notch1/imunologia , Transdução de Sinais/imunologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/imunologia , Peixe-Zebra/genética , Peixe-Zebra/imunologia , Animais , Doenças dos Peixes/imunologia , Vibrioses/imunologia , Vibrioses/veterinária , Vibrio parahaemolyticus/fisiologia
11.
Fish Shellfish Immunol ; 93: 559-566, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31330256

RESUMO

Shrimps like other arthropods rely on innate immune system, and may have some form of adaptive immunity in defending against pathogens. Phagocytosis is one of the oldest cellular processes, serving as a development process, a feeding mechanism and especially as a key defense reaction in innate immunity of all multicellular organisms. It is confirmed that crustacean hyperglycemic hormone (CHH) is one of the most important neuropeptides produced by Neuro-endocrine Immune (NEI) regulatory network, which undertakes important roles in various biological processes, especially in immune function and stress response. In this study, the recombinant Litopenaeus vannamei CHH (rLvCHH) was obtained from a bacterial expression system and the intracellular signaling pathways involved in the mechanism of phagocytosis after rLvCHH injection was investigated. The results showed that the contents of adenylyl cyclase (AC), phospholipase C (PLC) and calmodulin (CaM) in hemocytes were increased significantly after rLvCHH injection. Furthermore, the mRNA expression levels of NF-kB family members (relish and dorsal) and phagocytosis-related proteins in hemocytes were basically overexpressed after rLvCHH stimulation, while the expression level of NF-kB repressing factor (NKRF) gene was down-regulated significantly. Eventually, the total hemocyte count and phagocytic activity of hemocyte were dramatically enhanced within 3 h. Collectively, these results indicate that shrimps L. vannamei could carry out a simple but 'smart' NEI regulation through the action of neuroendocrine factors, which could couple with their receptors and trigger the downstream signaling pathways during the phagocytic responses of hemocytes.


Assuntos
Proteínas de Artrópodes/imunologia , Hemócitos/imunologia , Imunidade Inata/genética , Hormônios de Invertebrado/imunologia , Proteínas do Tecido Nervoso/imunologia , Penaeidae/genética , Penaeidae/imunologia , Fagocitose/imunologia , Animais , Proteínas de Artrópodes/genética , Relação Dose-Resposta a Droga , Hormônios de Invertebrado/genética , Proteínas do Tecido Nervoso/genética , Distribuição Aleatória , Transdução de Sinais/imunologia
12.
Immunohorizons ; 3(2): 71-87, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31236543

RESUMO

We previously reported that neuroimmune semaphorin (Sema) 4A regulates the severity of experimental allergic asthma and increases regulatory T (Treg) cell numbers in vivo; however, the mechanisms of Sema4A action remain unknown. It was also reported that Sema4A controls murine Treg cell function and survival acting through neuropilin 1 (NRP-1) receptor. To clarify Sema4A action on human T cells, we employed T cell lines (HuT78 and HuT102), human PBMCs, and CD4+ T cells in phenotypic and functional assays. We found that HuT78 demonstrated a T effector-like phenotype (CD4+CD25lowFoxp3-), whereas HuT102 expressed a Treg-like phenotype (CD4+CD25hi Foxp3+). Neither cell line expressed NRP-1. HuT102 cells expressed Sema4A counter receptor Plexin B1, whereas HuT78 cells were Sema4A+. All human peripheral blood CD4+ T cells, including Treg cells, expressed PlexinB1 and lacked both NRP-1 and -2. However, NRP-1 and Sema4A were detected on CD3negativeCD4intermediate human monocytes. Culture of HuT cells with soluble Sema4A led to an upregulation of CD25 and Foxp3 markers on HuT102 cells. Addition of Sema4A increased the relative numbers of CD4+CD25+Foxp3+ cells in PBMCs and CD4+ T cells, which were NRP-1negative but PlexinB1+, suggesting the role of this receptor in Treg cell stability. The inclusion of anti-PlexinB1 blocking Ab in cultures before recombinant Sema4A addition significantly decreased Treg cell numbers as compared with cultures with recombinant Sema4A alone. Sema4A was as effective as TGF-ß in inducible Treg cell induction from CD4+CD25depleted cells but did not enhance Treg cell suppressive activity in vitro. These results suggest strategies for the development of new Sema4A-based therapeutic measures to combat allergic inflammatory diseases. ImmunoHorizons, 2019, 3: 71-87.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforinas/metabolismo , Semaforinas/farmacologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Anticorpos , Asma/imunologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Proteínas do Tecido Nervoso/imunologia , Neuropilina-1/metabolismo , Fenótipo , Receptores de Superfície Celular/imunologia , Fator de Crescimento Transformador beta/metabolismo
13.
Rinsho Shinkeigaku ; 59(7): 442-447, 2019 Jul 31.
Artigo em Japonês | MEDLINE | ID: mdl-31243254

RESUMO

A 69-year-old man presented with a history of personality change for several years. He was admitted to our hospital due to partial seizure. A cerebrospinal fluid test and an electroencephalogram showed no specific abnormalities, but brain magnetic resonance imaging revealed abnormal findings in the right temporal pole, bilateral amygdala to hippocampus, and insular cortex. He was diagnosed with limbic encephalitis accompanied by partial seizure, and received infusion of an antiepileptic agent and acyclovir. Additional examinations for malignancy and autoimmune disease were performed, and neck CT and MRI revealed a neck tumor. Neck lymph node biopsy suggested lymph node metastasis of a neuroendocrine neoplasm derived from other organs. He did not want aggressive treatment involving surgical resection and chemotherapy, and thus, conservative treatment was chosen by an otorhinolaryngologist and immunotherapy was not used. After discharge, the neck tumor grew gradually. To manage the focal mass effect, chemotherapy and surgical resection followed by chemoradiotherapy were performed by the otorhinolaryngologist on days 244 and 325 of the disease course, respectively. Histology of resected tissues disclosed neck neuroendocrine carcinoma derived from a submandibular gland. His personality change improved temporarily after surgical resection, but then worsened again with regrowth of the tumor. He died on day 723. After death, a blood test revealed the presence of anti-amphiphysin antibody. This case suggests that neck neuroendocrine carcinoma can induce paraneoplastic limbic encephalitis, and in such cases, early surgical resection of the neck tumor with suspected lymph node metastasis is necessary both to control symptoms associated with encephalitis and to exclude carcinoma derived from the neck itself.


Assuntos
Carcinoma Neuroendócrino/complicações , Encefalite Límbica/etiologia , Neoplasias da Glândula Submandibular/complicações , Idoso , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Terapia Combinada , Evolução Fatal , Humanos , Metástase Linfática , Proteínas do Tecido Nervoso/imunologia , Neoplasias da Glândula Submandibular/diagnóstico , Neoplasias da Glândula Submandibular/patologia , Neoplasias da Glândula Submandibular/terapia
16.
Graefes Arch Clin Exp Ophthalmol ; 257(8): 1759-1764, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31119427

RESUMO

PURPOSE: To explore the presence of serum anti-retinal antibodies (ARAs) in the Chinese patients with presumed autoimmune retinopathy (AIR). METHODS: Twenty-three Chinese patients with presumed AIR, disease controls including 40 RP patients, 22 bilateral uveitis patients, 18 acute zonal outer occult retinopathy (AZOOR) patients, and 30 healthy donors were included. Serum samples of all the subjects were obtained and analyzed for the presence of four ARAs including recoverin, α-enolase, carbonic anhydraseII (CAII), and collapsin response-mediated protein (CRMP)-5 by Western bolt assay. RESULTS: ARAs were present in the serum of either presumed AIR patients, disease control, or healthy donors. One or more ARAs were present in the 78.2% of presumed AIR while they were indicated in the 35.0% of RP patients (p < 0.01) and 33.3% of healthy donors (p < 0.01). The prevalence of ARAs in the bilateral uveitis and AZOOR was 63.3% and 100% respectively. Positive rate of α-enolase antibody present in the presumed AIR, disease control, and healthy donors was 73.9%, 47.5%, and 33.3% respectively. Positive rate of CAII antibody present above groups was 52.1%, 50%, and 33.3% respectively. Recoverin antibody seemed to be specifically present in the serum of patients with cancer-associated retinopathy. CONCLUSION: Presence of serum ARAs including recoverin, α-enolase, CAII, or CRMP-5 in the Chinese patients with presumed AIR occurred significantly more often than RP patients and healthy donors. Seropositivity of ARAs had diagnostic value for the presumed AIR but mere presence was not sufficient for the diagnosis due to identification of them in the healthy controls and other retinal diseases.


Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Retina/imunologia , Doenças Retinianas/imunologia , Adulto , Idoso , Doenças Autoimunes/sangue , Doenças Autoimunes/epidemiologia , Western Blotting , Anidrase Carbônica II/sangue , Anidrase Carbônica II/imunologia , China/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/imunologia , Fosfopiruvato Hidratase/sangue , Fosfopiruvato Hidratase/imunologia , Prevalência , Recoverina/sangue , Recoverina/imunologia , Doenças Retinianas/sangue , Doenças Retinianas/epidemiologia , Estudos Retrospectivos
17.
Pharmacol Biochem Behav ; 181: 101-109, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31054945

RESUMO

While insulin secreted from pancreas plays a pivotal role in the control of glucose homeostasis, it also interacts with hypothalamic sites and negatively influences the energy balance. The present study was undertaken to reveal the functional interaction between cocaine- and amphetamine-regulated transcript (CART), a well-known anorexic peptide, and insulin within the framework of hypothalamus in the regulation of feeding behavior and body weight. Insulin was administered daily by intracerebroventricular (icv) route, alone or in combination with CART (icv) for a period of seven days. Immediately thereafter, preweighed food was offered to the animals at the commencement of the dark phase. The food intake and body weight were measured daily just prior to next injection. Furthermore, brains of insulin-treated rats were processed for the immunohistochemical analysis of CART-containing elements in the hypothalamus. Treatment with insulin (6 mU, icv) for a period of 7 days caused a significant decrease in food intake and body weight as compared to control. Concomitant administration of CART (0.5 µg, icv) potentiated insulin-induced anorexia and weight loss. Insulin administration resulted in a significant increase in CART immunoreactivity in the hypothalamic arcuate, paraventricular, dorsomedial and ventromedial nuclei. We suggest that increased CART contents in the hypothalamus may be causally linked with anorexia and weight loss induced by insulin.


Assuntos
Peso Corporal/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Insulina/farmacologia , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/farmacologia , Neuropeptídeos/imunologia , Neuropeptídeos/farmacologia , Animais , Anorexia/induzido quimicamente , Anticorpos Monoclonais/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/imunologia , Imuno-Histoquímica , Insulina/administração & dosagem , Masculino , Proteínas do Tecido Nervoso/administração & dosagem , Neuropeptídeos/administração & dosagem , Fotoperíodo , Ratos , Ratos Sprague-Dawley , Perda de Peso/efeitos dos fármacos
18.
J Immunol ; 202(9): 2546-2557, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867238

RESUMO

Reactive oxygen species (ROS) are not only toxic substances inducing oxidative stress but also play a role as a second messenger in signal transduction through various receptors. Previously, B cell activation was shown to involve prolonged ROS production induced by ligation of BCR. However, the mechanisms for ROS production and ROS-mediated activation in B cells are still poorly understood. In this study, we demonstrate that BCR ligation induces biphasic ROS production in both mouse spleen B cells and the mouse B cell line BAL17; transient and modest ROS production is followed by sustained and robust ROS production at 2-6 h after BCR ligation. ROS production in the late phase but not in the early phase augments activation of signaling pathways, such as the NF-κB and PI3K pathways, and is essential for B cell proliferation. ROS production in the late phase appears to be mediated by NADPH oxidases (NOXes) because prolonged ROS production is inhibited by various NOX inhibitors, including the specific inhibitor VAS2870. BCR ligation-induced ROS production is also inhibited by CRISPR/Cas9-mediated deletion of either the Cyba gene encoding p22phox, the regulator of NOX1-4 required for their activation, or NOX3, whereas ROS production is not affected by double deficiency of the DUOXA1 and DUOXA2 genes essential for the activation of the NOX isoforms DUOX1 and DUOX2. These results indicate that NOXes play a crucial role in sustained but not early BCR signaling and suggest an essential role of NOX-dependent sustained BCR signaling in B cell activation.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , NADPH Oxidases/imunologia , Espécies Reativas de Oxigênio/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais/imunologia , Animais , Linfócitos B/citologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , NADPH Oxidases/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais/genética
19.
Nature ; 568(7751): 249-253, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30894749

RESUMO

The non-canonical NF-κB signalling cascade is essential for lymphoid organogenesis, B cell maturation, osteoclast differentiation, and inflammation in mammals1,2; dysfunction of this system is associated with human diseases, including immunological disorders and cancer3-6. Although expression of NF-κB-inducing kinase (NIK, also known as MAP3K14) is the rate-limiting step in non-canonical NF-κB pathway activation2,7, the mechanisms by which transcriptional responses are regulated remain largely unknown. Here we show that the sine oculis homeobox (SIX) homologue family transcription factors SIX1 and SIX2 are integral components of the non-canonical NF-κB signalling cascade. The developmentally silenced SIX proteins are reactivated in differentiated macrophages by NIK-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 target a subset of inflammatory gene promoters and directly inhibit the trans-activation function of the transcription factors RELA and RELB in a negative feedback circuit. In support of a physiologically pivotal role for SIX proteins in host immunity, a human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS/P53-driven non-small-cell lung carcinomas from inflammatory cell death induced by SMAC-mimetic chemotherapeutic agents (small-molecule activators of the non-canonical NF-κB pathway). Our findings identify a NIK-SIX signalling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.


Assuntos
Proteínas de Homeodomínio/metabolismo , Inflamação/metabolismo , NF-kappa B/deficiência , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Fibroblastos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Proteínas de Homeodomínio/imunologia , Humanos , Inflamação/genética , Listeria monocytogenes/imunologia , Masculino , Camundongos , NF-kappa B/genética , Proteínas do Tecido Nervoso/imunologia , Regiões Promotoras Genéticas , Shigella flexneri/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelB/metabolismo
20.
J Immunol ; 202(8): 2210-2219, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30824481

RESUMO

The aim of this study was to test whether autoantibodies against neurologic surface Ags are found in nonneurologic autoimmune diseases, indicating a broader loss of tolerance. Patient and matched healthy donor (HD) sera were derived from four large cohorts: 1) rheumatoid arthritis (RA) (n = 194, HD n = 64), 2) type 1 diabetes (T1D) (n = 200, HD n = 200), 3) systemic lupus erythematosus (SLE) (n = 200, HD n = 67; neuro-SLE n = 49, HD n = 33), and 4) a control cohort of neurologic autoimmunity (relapsing-remitting multiple sclerosis [MS] n = 110, HD n = 110; primary progressive MS n = 9; secondary progressive MS n = 10; neuromyelitis optica spectrum disorders n = 15; and other neurologic disorders n = 26). Screening of 1287 unique serum samples against four neurologic surface Ags (myelin oligodendrocyte glycoprotein, aquaporin 4, acetylcholine receptor, and muscle-specific kinase) was performed with live cell-based immunofluorescence assays using flow cytometry. Positive samples identified in the screening were further validated using autoantibody titer quantification by serial dilutions or radioimmunoassay. Autoantibodies against neurologic surface Ags were not observed in RA and T1D patients, whereas SLE patients harbored such autoantibodies in rare cases (2/200, 1%). Within the CNS autoimmunity control cohort, autoantibodies against aquaporin 4 and high-titer Abs against myelin oligodendrocyte glycoprotein were, as expected, specific for neuromyelitis optica spectrum disorders. We conclude that neurologic autoantibodies do not cross disease barriers in RA and T1D. The finding of mildly increased neurologic autoantibodies in SLE may be consistent with a broader loss of B cell tolerance in this form of systemic autoimmunity.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Proteínas do Tecido Nervoso/imunologia , Doenças Autoimunes/patologia , Linfócitos B/patologia , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade
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