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1.
Medicine (Baltimore) ; 99(30): e21151, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791688

RESUMO

BACKGROUND: The introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) into clinical practice has dramatically improve the clinical outcomes of individuals with rheumatoid arthritis (RA). However, bDMARDs are associated with high costs, which has resulted in restricted treatment access and a burden on medical insurance finances. Although biosimilars offer cost-saving, their effectiveness and safety must be established in Post-Marketing Surveillance (PMS). Infliximab (IFX), a chimeric monoclonal antibody to TNF-alpha, is the first bDMARD; its biosimilar, CT-P13, is the first biosimilar DMARD approved for RA treatment in Japan. We will evaluate whether switching from originator IFX to CT-P13 is not inferior for maintaining non-clinical relapse to continued treatment with originator IFX in RA patients achieving clinical remission. METHODS/DESIGN: This study is an interventional, multicenter, open-label, single-arm against historical control and noninferiority clinical trial with a 24-week follow-up. Eighty RA patients who are treated by originator IFX for ≥24 weeks and are achieving clinical remission will be included. Patients will be switched to CT-P13 with the unchanged dosing regimen. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the ratio of patients who experience a nonclinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of many biomarkers such as cytokines and chemokines. DISCUSSION: The study results are expected to show the noninferiority of switching to CT-P13 over the continuation of originator IFX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices but also MSUS to accurately and objectively evaluate disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will explore whether parameters at baseline can predict a nonclinical relapse after switching from originator IFX to CT-P13 by integrating multilateral assessments, i.e., clinical disease activity indices, MSUS findings, and serum biomarkers. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on October 11, 2019 as jRCTs071190030.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Quimiocinas/sangue , Infliximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Biomarcadores/sangue , Substituição de Medicamentos , Estudos de Equivalência como Asunto , Humanos , Japão , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Índice de Gravidade de Doença , Ultrassonografia , Adulto Jovem
2.
Nat Commun ; 11(1): 3459, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651360

RESUMO

Hepatic amebiasis, predominantly occurring in men, is a focal destruction of the liver due to the invading protozoan Entamoeba histolytica. Classical monocytes as well as testosterone are identified to have important functions for the development of hepatic amebiasis in mice, but a link between testosterone and monocytes has not been identified. Here we show that testosterone treatment induces proinflammatory responses in human and mouse classical monocytes. When treated with 5α-dihydrotestosterone, a strong androgen receptor ligand, human classical monocytes increase CXCL1 production in the presence of Entamoeba histolytica antigens. Moreover, plasma testosterone levels of individuals undergoing transgender procedure correlate positively with the TNF and CXCL1 secretion from their cultured peripheral blood mononuclear cells following lipopolysaccharide stimulation. Finally, testosterone substitution of castrated male mice increases the frequency of TNF/CXCL1-producing classical monocytes during hepatic amebiasis, supporting the hypothesis that the effects of androgens may contribute to an increased risk of developing monocyte-mediated pathologies.


Assuntos
Androgênios/farmacologia , Quimiocina CXCL1/metabolismo , Animais , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Di-Hidrotestosterona/farmacologia , Entamoeba histolytica/química , Voluntários Saudáveis , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
3.
J Oral Rehabil ; 47(9): 1150-1160, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32609901

RESUMO

BACKGROUND: Degenerative joint disease (DJD) of the temporomandibular joints (TMJs) in adolescents and young adults is closely associated with disc displacement without reduction (DDw/oR). OBJECTIVE: This study aimed to determine the pathogenesis of early-stage TMJ DJD induced by DDw/oR. METHODS: 31 female subjects aged 12-30 years were enrolled, comprising 12 patients with DDw/oR without DJD, 13 with DDw/oR and early-stage DJD, and 6 healthy volunteers. The synovial fluid samples of the subjects were screened for 27 inflammatory-related cytokines using multiple cytokine array. Significantly increased cytokines and a key regulator of osteoclastogenesis "receptor activator of nuclear factor-κB ligand" (RANKL) were further determined by sandwich immunoassay. These factors were also assessed for the possible pathophysiologic actions on RAW264.7 cell proliferation, migration, osteoclastogenesis and bone-resorbing activity using Cell Counting Kit-8, Transwell system, tartrate-resistant acid phosphatase staining and osteo assay plates. RESULTS: Macrophage-derived inflammatory protein-1 beta (MIP-1ß) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to vary significantly in relation to the controls. In contrast to an unchanged concentration of RANKL, a strong increase in the level of RANTES was detected in subjects with DDw/oR and early-stage DJD. MIP-1ß concentrations were only elevated in subjects with DDw/oR without DJD. Functionally, both MIP-1ß and RANTES could enhance macrophage migration in a concentration-dependent manner, while only RANTES exhibited a promoting effect on osteoclast formation and bone-resorbing activity. CONCLUSIONS: Chemokine RANTES was significantly upregulated and might be a key regulator of osteoclastogenesis contributing to DDw/oR-induced early-stage TMJ DJD.


Assuntos
Líquido Sinovial , Transtornos da Articulação Temporomandibular , Adolescente , Adulto , Quimiocina CCL5 , Quimiocinas , Criança , Feminino , Humanos , Osteoclastos , Ligante RANK , Linfócitos T , Articulação Temporomandibular , Adulto Jovem
4.
BMC Infect Dis ; 20(1): 505, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32660552

RESUMO

BACKGROUND: Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10-20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM. METHODS: BALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi. RESULTS: Analysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX. CONCLUSIONS: Treatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.


Assuntos
Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Doxiciclina/uso terapêutico , Meningite Meningocócica/tratamento farmacológico , Neisseria meningitidis Sorogrupo C , Animais , Antibacterianos/administração & dosagem , Carga Bacteriana/efeitos dos fármacos , Ceftriaxona/administração & dosagem , Hemorragia Cerebral/tratamento farmacológico , Quimiocinas/análise , Quimiocinas/metabolismo , Modelos Animais de Doenças , Doxiciclina/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/metabolismo , Meningite Meningocócica/mortalidade , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Resultado do Tratamento
5.
Viruses ; 12(6)2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599823

RESUMO

The respiratory Influenza A Viruses (IAVs) and emerging zoonotic viruses such as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pose a significant threat to human health. To accelerate our understanding of the host-pathogen response to respiratory viruses, the use of more complex in vitro systems such as normal human bronchial epithelial (NHBE) cell culture models has gained prominence as an alternative to animal models. NHBE cells were differentiated under air-liquid interface (ALI) conditions to form an in vitro pseudostratified epithelium. The responses of well-differentiated (wd) NHBE cells were examined following infection with the 2009 pandemic Influenza A/H1N1pdm09 strain or following challenge with the dsRNA mimic, poly(I:C). At 30 h postinfection with H1N1pdm09, the integrity of the airway epithelium was severely impaired and apical junction complex damage was exhibited by the disassembly of zona occludens-1 (ZO-1) from the cell cytoskeleton. wdNHBE cells produced an innate immune response to IAV-infection with increased transcription of pro- and anti-inflammatory cytokines and chemokines and the antiviral viperin but reduced expression of the mucin-encoding MUC5B, which may impair mucociliary clearance. Poly(I:C) produced similar responses to IAV, with the exception of MUC5B expression which was more than 3-fold higher than for control cells. This study demonstrates that wdNHBE cells are an appropriate ex-vivo model system to investigate the pathogenesis of respiratory viruses.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/virologia , Mucosa Respiratória/citologia , Mucosa Respiratória/virologia , Animais , Brônquios/citologia , Brônquios/virologia , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Cães , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/epidemiologia , Junções Intercelulares , Células Madin Darby de Rim Canino , Modelos Biológicos , Mucina-5AC/metabolismo , Pandemias , Cultura de Vírus
6.
Front Immunol ; 11: 1636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670298

RESUMO

The current pandemic of coronavirus disease 19 (COVID-19) has affected millions of individuals and caused thousands of deaths worldwide. The pathophysiology of the disease is complex and mostly unknown. Therefore, identifying the molecular mechanisms that promote progression of the disease is critical to overcome this pandemic. To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. Here, we provide novel perspectives on the pathophysiology of COVID-19 using robust functional approaches to analyze public transcriptome datasets. In addition, we compared the transcriptional signature of COVID-19 patients with individuals infected with SARS-CoV-1 and Influenza A (IAV) viruses. We identified a core transcriptional signature induced by the respiratory viruses in peripheral leukocytes, whereas the absence of significant type I interferon/antiviral responses characterized SARS-CoV-2 infection. We also identified the higher expression of genes involved in metabolic pathways including heme biosynthesis, oxidative phosphorylation and tryptophan metabolism. A BTM-driven meta-analysis of bronchoalveolar lavage fluid (BALF) from COVID-19 patients showed significant enrichment for neutrophils and chemokines, which were also significant in data from lung tissue of one deceased COVID-19 patient. Importantly, our results indicate higher expression of genes related to oxidative phosphorylation both in peripheral mononuclear leukocytes and BALF, suggesting a critical role for mitochondrial activity during SARS-CoV-2 infection. Collectively, these data point for immunopathological features and targets that can be therapeutically exploited to control COVID-19.


Assuntos
Betacoronavirus/imunologia , Quimiocinas/sangue , Infecções por Coronavirus/imunologia , Interferon Tipo I/sangue , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Infecções por Coronavirus/patologia , Perfilação da Expressão Gênica , Humanos , Inflamação/virologia , Influenza Humana/imunologia , Interferon Tipo I/imunologia , Neutrófilos/citologia , Fosforilação Oxidativa , Pandemias , Pneumonia Viral/patologia , Transcriptoma/genética
7.
Korean J Parasitol ; 58(3): 217-227, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32615735

RESUMO

Trichomonas vaginalis causes inflammation of the prostate and has been detected in tissues of prostate cancers (PCa), prostatitis and benign prostatic hyperplasia. Obesity is a risk factor for PCa and causes a chronic subclinical inflammation. This chronic inflammation further exacerbates adipose tissue inflammation as results of migration and activation of macrophages. Macrophages are the most abundant immune cells in the PCa microenvironment. M2 macrophages, known as Tumor-Associated Macrophages, are involved in increasing cancer malignancy. In this study, conditioned medium (TCM) of PCa cells infected with live trichomonads contained chemokines that stimulated migration of the mouse preadipocytes (3T3-L1 cells). Conditioned medium of adipocytes incubated with TCM (ATCM) contained Th2 cytokines (IL-4, IL-13). Macrophage migration was stimulated by ATCM. In macrophages treated with ATCM, expression of M2 markers increased, while M1 markers decreased. Therefore, it is suggested that ATCM induces polarization of M0 to M2 macrophages. In addition, conditioned medium from the macrophages incubated with ATCM stimulates the proliferation and invasiveness of PCa. Our findings suggest that interaction between inflamed PCa treated with T. vaginalis and adipocytes causes M2 macrophage polarization, so contributing to the progression of PCa.


Assuntos
Adipócitos/imunologia , Macrófagos/imunologia , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/parasitologia , Trichomonas vaginalis , Animais , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Quimiocinas/imunologia , Inflamação , Masculino , Camundongos , Obesidade , Neoplasias da Próstata/patologia , Fatores de Risco
8.
PLoS Negl Trop Dis ; 14(6): e0008414, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574175

RESUMO

Chemokine receptor type 3 (CXCR3) plays an important role in CD8+ T cells migration during intracellular infections, such as Trypanosoma cruzi. In addition to chemotaxis, CXCR3 receptor has been described as important to the interaction between antigen-presenting cells and effector cells. We hypothesized that CXCR3 is fundamental to T. cruzi-specific CD8+ T cell activation, migration and effector function. Anti-CXCR3 neutralizing antibody administration to acutely T. cruzi-infected mice decreased the number of specific CD8+ T cells in the spleen, and those cells had impaired in activation and cytokine production but unaltered proliferative response. In addition, anti-CXCR3-treated mice showed decreased frequency of CD8+ T cells in the heart and numbers of plasmacytoid dendritic cells in spleen and lymph node. As CD8+ T cells interacted with plasmacytoid dendritic cells during infection by T. cruzi, we suggest that anti-CXCR3 treatment lowers the quantity of plasmacytoid dendritic cells, which may contribute to impair the prime of CD8+ T cells. Understanding which molecules and mechanisms guide CD8+ T cell activation and migration might be a key to vaccine development against Chagas disease as those cells play an important role in T. cruzi infection control.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Quimiocinas/metabolismo , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Receptores CXCR3/metabolismo , Trypanosoma cruzi/imunologia , Animais , Movimento Celular , Doença de Chagas/parasitologia , Citoplasma/metabolismo , Citoplasma/parasitologia , Modelos Animais de Doenças , Feminino , Coração , Controle de Infecções , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia
9.
mSphere ; 5(3)2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581077

RESUMO

COVID-19 is often related to hyperinflammation that drives lung or multiorgan injury. The immunopathological mechanisms that cause excessive inflammation are under investigation and constantly updated. Here, a gene network approach was used on recently published data sets to identify possible COVID-19 inflammatory mechanisms and bioactive genes. First, network analysis of putative SARS-CoV-2 cellular receptors led to the mining of a neutrophil-response signature and relevant inflammatory genes. Second, analysis of RNA-seq data sets of lung cells infected with SARS-CoV-2 revealed that infected cells expressed neutrophil-attracting chemokines. Third, analysis of RNA-seq data sets of bronchoalveolar lavage fluid cells from COVID-19 patients identified upregulation of neutrophil genes and chemokines. Different inflammatory genes mined here, including TNFR, IL-8, CXCR1, CXCR2, ADAM10, GPR84, MME, ANPEP, and LAP3, might be druggable targets in efforts to limit SARS-CoV-2 inflammation in severe clinical cases. The possible role of neutrophils in COVID-19 inflammation needs to be studied further.


Assuntos
Betacoronavirus/imunologia , Quimiocinas/imunologia , Infecções por Coronavirus/imunologia , Inflamação/patologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Quimiocinas/genética , Infecções por Coronavirus/patologia , Humanos , Inflamação/imunologia , Pneumopatias/imunologia , Pneumopatias/patologia , Infiltração de Neutrófilos/imunologia , Pandemias , Pneumonia Viral/patologia , Receptores Virais/genética
10.
Nat Commun ; 11(1): 3033, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561830

RESUMO

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.


Assuntos
Peptídeos Opioides/química , Receptores CXCR/metabolismo , Analgésicos Opioides/química , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Quimiocinas/metabolismo , Humanos , Ligantes , Sistema de Sinalização das MAP Quinases , Masculino , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais , Relação Estrutura-Atividade , beta-Arrestina 1/metabolismo
11.
PLoS One ; 15(6): e0234525, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32542038

RESUMO

Our purpose was to evaluate the concentrations of vitreous cytokines in patients with rhegmatogenous retinal detachment (RRD). We hypothesized that patients with macula on RRD have lower levels of cytokines compared to patients with macula off RRD and proliferative vitreoretinopathy (PVR). Vitreous fluids were collected during 23G pars plana vitrectomy from 58 eyes of 58 patients. Indication for vitrectomy included macula off and macula on RRD, PVR, and idiopathic epiretinal membrane (ERM). A multiplex chemiluminescent immunoassay was performed to measure the concentrations of 48 cytokines, chemokines, and growth factors. Levels of HGF, IL-6, IL-8, IL-16, IFN-gamma, MCP-1, and MIF were significantly higher in all groups of retinal detachment compared to ERM. Levels of CTACK, eotaxin, G-CSF, IP-10, MIG, SCF, SCGF-beta, SDF-1alpha were significantly higher in PVR compared to macula on RRD and ERM. Levels of IL-1ra, IL-5, IL-9, M-CSF, MIP-1alpha, and TRIAL were significantly higher in PVR compared to macula on RRD. Our results indicate that the position of macula lutea and the presence of PVR significantly influence vitreous cytokine expression. The detected proteins may serve as biomarkers to estimate the possibility of PVR formation and may help to invent personalized therapeutic strategies to slow down or prevent PVR.


Assuntos
Macula Lutea/metabolismo , Descolamento Retiniano/genética , Vitreorretinopatia Proliferativa/genética , Descolamento do Vítreo/genética , Idoso , Quimiocinas/classificação , Quimiocinas/genética , Citocinas/classificação , Citocinas/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/classificação , Peptídeos e Proteínas de Sinalização Intercelular/genética , Macula Lutea/patologia , Masculino , Pessoa de Meia-Idade , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologia , Vitreorretinopatia Proliferativa/metabolismo , Vitreorretinopatia Proliferativa/patologia , Descolamento do Vítreo/metabolismo , Descolamento do Vítreo/patologia
12.
Autoimmun Rev ; 19(8): 102592, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32561462

RESUMO

INTRODUCTION: The aim of this narrative review is to provide an overview of the literature on the possible immunologic pathophysiology of psychiatric manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: A systematic search on PubMed was conducted. English studies with full text availability that investigated the correlation between blood-brain barrier (BBB) dysfunction, intrathecal synthesis of antibodies, antibodies, cytokines, chemokines, metalloproteinases, complement and psychiatric NPSLE manifestations in adults were included. RESULTS: Both transient BBB-dysfunction with consequent access of antibodies to the cerebrospinal fluid (CSF) and intrathecal synthesis of antibodies could occur in psychiatric NPSLE. Anti-phospholipid antibodies, anti-NMDA antibodies and anti-ribosomal protein p antibodies seem to mediate concentration dependent neuronal dysfunction. Interferon-α may induce microglial engulfment of neurons, direct neuronal damage and production of cytokines and chemokines in psychiatric NPSLE. Several cytokines, chemokines and matrix metalloproteinase-9 may contribute to the pathophysiology of psychiatric NPSLE by attracting and activating Th1-cells and B-cells. DISCUSSION: This potential pathophysiology may help understand NPSLE and may have implications for the diagnostic management and therapy of psychiatric NPSLE. However, the presented pathophysiological model is based on correlations between potential immunologic etiologies and psychiatric NPSLE that remain questionable. More research on this topic is necessary to further elucidate the pathophysiology of NPSLE.


Assuntos
Anticorpos , Barreira Hematoencefálica , Citocinas , Lúpus Eritematoso Sistêmico , Transtornos Mentais , Anticorpos/imunologia , Barreira Hematoencefálica/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Transtornos Mentais/etiologia , Transtornos Mentais/imunologia
13.
Nat Commun ; 11(1): 3177, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576819

RESUMO

Vascular permeability and plasma leakage are immune-pathologies of severe dengue virus (DENV) infection, but the mechanisms underlying the exacerbated inflammation during DENV pathogenesis are unclear. Here, we demonstrate that TLR2, together with its co-receptors CD14 and TLR6, is an innate sensor of DENV particles inducing inflammatory cytokine expression and impairing vascular integrity in vitro. Blocking TLR2 prior to DENV infection in vitro abrogates NF-κB activation while CD14 and TLR6 block has a moderate effect. Moreover, TLR2 block prior to DENV infection of peripheral blood mononuclear cells prevents activation of human vascular endothelium, suggesting a potential role of the TLR2-responses in vascular integrity. TLR2 expression on CD14 + + classical monocytes isolated in an acute phase from DENV-infected pediatric patients correlates with severe disease development. Altogether, these data identify a role for TLR2 in DENV infection and provide insights into the complex interaction between the virus and innate receptors that may underlie disease pathogenesis.


Assuntos
Vírus da Dengue/metabolismo , Dengue/imunologia , Monócitos/metabolismo , Receptor 2 Toll-Like/metabolismo , Permeabilidade Capilar , Quimiocinas/metabolismo , Criança , Pré-Escolar , Citocinas/metabolismo , Dengue/virologia , Endotélio Vascular/metabolismo , Feminino , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Inflamação , Leucócitos Mononucleares/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , NF-kappa B/metabolismo , Receptores de IgG/metabolismo , Índice de Gravidade de Doença , Receptor 6 Toll-Like
14.
Nat Commun ; 11(1): 3187, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581235

RESUMO

The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNß infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNß. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.


Assuntos
Imunoterapia Adotiva , Interferon beta/metabolismo , Vírus Oncolíticos/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Terapia Combinada , Feminino , Interferon beta/genética , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Baço/imunologia
15.
Rev Assoc Med Bras (1992) ; 66(3): 300-306, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32520149

RESUMO

OBJECTIVES: To compare the serum concentrations of adipokines resistin and chemerin in children and adolescents with eutrophic and overweight and to evaluate their relationship with anthropometric, biochemical, and blood pressure variables. METHODS: a cross-sectional epidemiological study was conducted with 234 students enrolled in public elementary schools in the city of Juiz de Fora / MG. Anthropometric evaluation, biochemistry, and blood pressure measurement were performed. Statistical analyzes included the Student-t or Mann-Whitney tests, Pearson or Spearman correlation, used according to the distribution of the variables, and linear regression analysis, by means of the evaluation of the effect of the independent variables on the serum levels of chemerin and resistin, adjusted for age and sex. For the data analysis, SPSS® software version 21.0 and STATA® version 10.1 were used, assuming a significance level of 5%. RESULTS: the concentrations of chemerin were higher in eutrophic individuals than in those with excess weight (p> 0.05). In contrast, levels of resistin were higher in the young with excess weight than in the eutrophic ones (p <0.05). In the multiple linear regression analysis, the levels of chemerin were associated with the values of resistin, systolic, and diastolic blood pressure. Resistance levels maintained association only with BMI and chemerin values. CONCLUSION: the adipokines analyzed presented a distinct profile in the groups of children and adolescents with eutrophic and overweight.


Assuntos
Adiponectina/sangue , Quimiocinas/sangue , Sobrepeso/sangue , Resistina/sangue , Adipocinas , Adolescente , Antropometria , Criança , Estudos Transversais , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Sobrepeso/complicações , Sobrepeso/metabolismo
16.
J Infect Dis ; 222(5): 734-745, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32563187

RESUMO

Clinical manifestations of coronavirus disease 2019 (COVID-19) vary from asymptomatic virus shedding, nonspecific pharyngitis, to pneumonia with silent hypoxia and respiratory failure. Dendritic cells and macrophages are sentinel cells for innate and adaptive immunity that affect the pathogenesis of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The interplay between SARS-CoV-2 and these cell types remains unknown. We investigated infection and host responses of monocyte-derived dendritic cells (moDCs) and macrophages (MDMs) infected by SARS-CoV-2. MoDCs and MDMs were permissive to SARS-CoV-2 infection and protein expression but did not support productive virus replication. Importantly, SARS-CoV-2 launched an attenuated interferon response in both cell types and triggered significant proinflammatory cytokine/chemokine expression in MDMs but not moDCs. Investigations suggested that this attenuated immune response to SARS-CoV-2 in moDCs was associated with viral antagonism of STAT1 phosphorylation. These findings may explain the mild and insidious course of COVID-19 until late deterioration.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Células Dendríticas/imunologia , Interferons/imunologia , Monócitos/imunologia , Pneumonia Viral/imunologia , Fator de Transcrição STAT1/antagonistas & inibidores , Imunidade Adaptativa , Animais , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/metabolismo , Quimiocinas/metabolismo , Chlorocebus aethiops , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Humanos , Macrófagos/imunologia , Macrófagos/virologia , Monócitos/virologia , Pandemias , Fosforilação , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/metabolismo , Células Vero , Replicação Viral/fisiologia , Eliminação de Partículas Virais
17.
J Infect Dis ; 222(5): 746-754, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32563194

RESUMO

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We investigated the serum cytokine and chemokine levels in asymptomatic, mild, moderate, severe, and convalescent SARS-CoV-2-infected cases. Proinflammatory cytokine and chemokine production induced by SARS-CoV-2 were observed not only in symptomatic patients but also in asymptomatic cases, and returned to normal after recovery. IL-6, IL-7, IL-10, IL-18, G-CSF, M-CSF, MCP-1, MCP-3, IP-10, MIG, and MIP-1α were found to be associated with the severity of COVID-19. Moreover, a set of cytokine and chemokine profiles were significantly higher in SARS-CoV-2-infected male than female patients. The serum levels of MCP-1, G-CSF, and VEGF were weakly and positively correlated with viral titers. We suggest that combinatorial analysis of serum cytokines and chemokines with clinical classification may contribute to evaluation of the severity of COVID-19 and optimize the therapeutic strategies.


Assuntos
Quimiocinas/sangue , Infecções por Coronavirus/sangue , Citocinas/sangue , Pneumonia Viral/sangue , Adulto , Betacoronavirus/isolamento & purificação , Quimiocina CCL2/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Fator A de Crescimento do Endotélio Vascular/sangue , Carga Viral
18.
Cell ; 181(5): 1036-1045.e9, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: covidwho-72372

RESUMO

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Vírus de RNA/imunologia , Animais , Células Cultivadas , Quimiocinas/genética , Quimiocinas/imunologia , Infecções por Coronavirus/genética , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Inflamação/virologia , Interferons/genética , Interferons/imunologia , Pandemias , Pneumonia Viral/genética , Vírus de RNA/classificação , Transcrição Genética
19.
Nat Commun ; 11(1): 2361, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398640

RESUMO

The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14+Sirpα+ population of monocyte-derived dendritic cells (CD14+moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14+moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25+Foxp3+ Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14+moDC, the generation of Tregs, and thereby the establishment of central tolerance.


Assuntos
Colite/imunologia , Células Dendríticas/imunologia , Células Epiteliais/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Transferência Adotiva , Animais , Apresentação do Antígeno , Autoantígenos/imunologia , Separação Celular , Quimiocinas/imunologia , Quimiocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Citometria de Fluxo , Receptores de Lipopolissacarídeos/metabolismo , Camundongos , Receptores Imunológicos/metabolismo , Tolerância a Antígenos Próprios , Análise de Sequência de RNA , Transdução de Sinais/imunologia , Análise de Célula Única , Linfócitos T Reguladores/transplante , Timo/citologia , Receptores Toll-Like/metabolismo , Regulação para Cima
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