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To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. METHODS: A retrospective observational study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). RESULTS: Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). CONCLUSIONS: Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.
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Encefalite , Infecções por Vírus Epstein-Barr , Masculino , Humanos , Feminino , Autoimunidade , Estudos Retrospectivos , Herpesvirus Humano 4 , Autoanticorpos , Imunoglobulina GRESUMO
Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a newly defined meningoencephalomyelitis. The pathogenesis of GFAP-A is not well understood. The present study measured the expression levels of 200 serological cytokines in GFAP-A patients, NMOSD patients and healthy controls (HCs). The correlations between serum cytokine levels and clinical information in GFAP-A patients were analyzed. A total of 147 serological proteins were differentially expressed in GFAP-A patients compared to HCs, and 33 of these proteins were not observed in NMOSD patients. Serum levels of EG-VEGF negatively correlated with GFAP antibody titers, MIP-3 alpha positively correlated with clinical severity in GFAP-A patients, and LIGHT positively correlated with WBC counts and protein levels in the CSF of GFAP-A patients. These results suggest that GFAP and AQP4 astrocytopathy share some common pathology related to TNF signaling. Serum MIP 3 alpha may be a biomarker to assess clinical severity and a potential target for therapy of autoimmune GFAP astrocytopathy.
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Astrócitos , Doenças Autoimunes , Citocinas , Encefalomielite , Astrócitos/patologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/patologia , Biomarcadores/sangue , Citocinas/sangue , Encefalomielite/diagnóstico , Encefalomielite/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Filamentos IntermediáriosRESUMO
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare and severe inflammatory demyelinating disorder of the central nervous system (CNS), which mainly affects the optic nerves and spinal cord. The aims of this study were to determine whether the expression levels of serological cytokines could distinguish 1) NMOSD from healthy controls (HCs); and 2) NMOSD patients with and without the aquaporin-4 (AQP4) antibody biomarker from each other; and 3) NMOSD patients without the antibody to AQP4 from MS patients. METHODS: The expression levels of 200 proteins in serum from 41 NMOSD (32 with antibodies to AQP4, 9 without antibodies to AQP4), 12 MS patients, and 34 HCs were measured using glass-based antibody arrays. None of the patients received any immunosuppressive treatment. In parallel, the correlation between protein expression in NMOSD/MS patients and clinical traits was determined with Weighted Gene Co-expression Network Analysis (WGCNA). RESULTS: Thirty-nine serological proteins were differentially expressed in NMOSD patients compared to HCs, with 29 of these proteins not observed in MS patients. In addition, the data reveal 15 differentially-expression proteins (DEPs) between AQP4-IgG seronegative and AQP4-IgG seropositive NMOSD patients, and 9 DEPs between NMOSD and MS patients who did not have AQP4-IgG. CONCLUSION: Serological IL-17B is significantly upregulated in both NMOSD and MS patients compared to HCs, and could be a key biomarker of NMOSD and MS. Serological VEGF, MPIF-1 and NrCAM were positively associated with AQP4-IgG titer. We also demonstrate that EGF may be involved in the breakdown of the BBB by downregulating Claudin-5.
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Esclerose Múltipla , Neuromielite Óptica , Aquaporina 4 , Autoanticorpos , Biomarcadores , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Neuromielite Óptica/complicaçõesRESUMO
Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy has been considered a novel central nervous system autoimmune disease characterized by relapse and responsiveness to corticosteroid with a specific GFAP-Immunoglobulin G (IgG) being noted in cerebrospinal fluid. We report the case of a 21-year-old girl presenting with dysuria and weariness, who subsequently developed blurry vision, slight dysphagia, slurred speech, and sensory abnormality. GFAP-IgG was detected in her cerebrospinal fluid. Magnetic resonance imaging using both T2-weighted and contrast-enhanced T1-weighted images revealed a rare finding of lesions distributed mainly in the entire spinal cord rather than typical brain lesions. After treating with corticosteroids, her clinical symptoms were alleviated, and the spinal cord lesion enhancement was reduced. Our observations extend the clinical spectrum of autoimmune GFAP astrocytopathy. We suggest that rare distributed lesions in the entire spinal cord in patients with autoimmune GFAP astrocytopathy cannot be ignored by neurologists. The identification of potential atypical lesions broadens the understanding of autoimmune GFAP astrocytopathy.
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AIM: To detect the nuclear factor kappa B (NF-kappaB) condition in human stage IV gastric carcinoma patients and to explore the correlation between NF-kappaB activation and survival of these patients after chemotherapy. METHODS: Expression of NF-kappaB-p65 was determined by immunohistochemical analysis. Activity of NF-kappaB DNA-binding in carcinoma tissue was detected by electrophoretic mobility shift assay. Kaplan-Meier survival analysis was performed to show the relation between NF-kappaB and progression-free survival (PFS) or overall survival (OS) of the patients. RESULTS: The positive expression rate of NF-kappaB-p65 in 60 gastric cancer tissue samples was 76.7% (46/60). The expression of NF-kappaB-p65 was reduced in adjacent carcinoma and normal tissue samples. Electrophoretic mobility shift assay (EMSA) analysis showed a strong activation of NF-kappaB in cancer tissue samples. A survival difference was found in NF-kappaB-p65 positive and negative patients. NF-kappaB-p65 expression was negative in cancer tissue samples (n=14). PFS was 191.40+/-59.88 d and 152.93+/-16.99 d, respectively, in patients with positive NF-kappaB-p65 expression (n=46) (P=0.4028). The survival time of patients with negative and positive NF-kappaB-p65 expression was 425.16+/-61.61 d and 418.85+/-42.98 d, respectively (P=0.7303). Kaplan-Meier analysis showed no significant difference in PFS or OS. The 46 patient tissue which positive NF-kappaB-p65 expression was found in the tissue samples from the 46 patients whose PFS and OS were 564.89+/-75.94 d and s 352.37+/-41.32 d, respectively (P=0.0165). CONCLUSION: NF-kappaB is activated in gastric carcinoma tissue, which is related to the OS after chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma/química , Carcinoma/tratamento farmacológico , Neoplasias Gástricas/química , Neoplasias Gástricas/tratamento farmacológico , Fator de Transcrição RelA/análise , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma/mortalidade , Carcinoma/patologia , Intervalo Livre de Doença , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Fluoruracila/administração & dosagem , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
AIM: To explore the changes of nuclear factor-kappa B (NF-kappaB) DNA-binding activity, the expression of intercellular adhesion molecule-1 (ICAM-1) regulated by NF-kappaB at various times and to evaluate the effects of pyrrolidine dithiocarbamate (PDTC) on trinitrobenzene sulfonic acid (TNBS)-induced rat colitis. METHODS: TNBS of 0.6 mL was mixed with ethanol of 0.3 mL solution and instilled into the lumen of the rat colon. The rat models were divided into 6 groups, which were killed at 24 h, 3, 7, 14, and 21 d after enema. Colonic inflammation and damage were assessed by macroscopical and histological criteria. Activity of NF-kappaB DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA). Expression of ICAM-1 was detected by in situ hybridization (ISH) and immunohistochemistry (IH). Then various doses of PDTC were injected into rat abdomen 30 min before enema with TNBS/ethanol as pretreatment. The rats were killed 4 h after enema and the colonic inflammation, myeloperoxidase (MPO) activity, malondialdehyde (MDA) level, and DNA-binding activity of NF-kappaB were assessed. Finally, PDTC was injected intraperitoneally after colitis was induced. Changes of morphology were assayed. RESULTS: During the first week, hyperemia, hemorrhage, edema and ulceration of the colonic mucosa appeared with predominant infiltration of leukocytes. Neutrophils, macrophages, lymphocytes infiltrated in mucosa and submucosa 14 d later. Fibroblasts and granuloma-like structures were also obviously seen. The binding activity of NF-kappaB began to increase at 24 h time point and reached a peak at 14 d, then decreased but still was higher than control group at 21 d (P<0.01). Levels of ICAM-1 mRNA and protein significantly elevated at 24 h and the peak was at 21 d. Pretreatment with PDTC could attenuate the development of inflammation but not by reducing NF-kappaB activity. This attenuation of inflammation had a positive relationship with the dose of PDTC. PDTC at the dose of 100 mg/kg had no therapeutic effect after colitis was induced. CONCLUSION: NF-kappaB activation is an important event that may be involved in acute and chronic inflammation development and may contribute to self-protection against early inflammation damage. NF-kappaB also regulates ICAM-1 expression during colonic inflammation. Pretreatment of PDTC may attenuate the inflammation development. But PDTC has no therapeutic effect after the colitis is induced.
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Antioxidantes/farmacologia , Colite/metabolismo , Colite/patologia , NF-kappa B/metabolismo , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Ácido Trinitrobenzenossulfônico , Animais , Colite/induzido quimicamente , Colite/prevenção & controle , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Previous studies have reported that statins can prevent infections, and these findings were ascribed to the anti-inflammatory and immunomodulatory properties of statins. However, the effects of statins on the risk of infection after stroke or transient ischemic attack (TIA) remain controversial. The aim of this study was to evaluate the relationship between statins and the risk of infection after stroke or TIA by means of a meta-analysis. METHODOLOGY AND FINDINGS: Studies were found by searching major electronic databases using key terms and restricting the results to studies published in English language and human studies. Pooled odds ratio (OR) for the association between infection and statins were analyzed using Stata software. A total of five studies that included 8,791 stroke or TIA patients (3,269 patients in the statin use group and 5,522 in the placebo group) were eligible and abstracted. Pooled analysis demonstrated that statins did not significantly affect the incidence of infection after stroke or TIA compared with a placebo (OR 0.819, 95% CI 0.582-1.151, I2 = 64.2%, p= 0.025). Sensitivity analyses showed that the removal of any single study did not significantly affect the pooled OR. Cumulative meta-analysis showed that the incidence of infection did not vary by publication year. No statistical evidence of publication bias was found among the studies selected, based on the results of Egger's (p = 1.000) and Begg's (p = 0.762) tests. CONCLUSIONS: This meta-analysis does not support the hypothesis that statins reduce the risk of infections in stroke or TIA patients.
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Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infecções/tratamento farmacológico , Ataque Isquêmico Transitório/patologia , Acidente Vascular Cerebral/patologia , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Humanos , Infecções/complicações , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/metabolismo , Razão de Chances , Efeito Placebo , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismoRESUMO
BACKGROUND: Previous studies have reported that the total bilirubin (TB) level is associated with coronary artery disease, heart failure and atrial fibrillation. These heart diseases can produce cardiogenic cerebral embolism and cause cardioembolic stroke. However, whether the serum TB could be a biomarker to differentiate cardioembolic stroke from other stroke subtypes is unclear. METHODS: Our study consisted of 628 consecutive patients with ischaemic stroke. Various clinical and laboratory variables of the patients were analysed according to serum TB quartiles and stroke subtypes. RESULTS: The higher TB quartile group was associated with atrial fibrillation, larger left atrium diameter, lower left ventricular fractional shortening and cardioembolic stroke (P < 0.001, P = 0.001, P = 0.033, P < 0.001, respectively). Furthermore, serum TB was a statistically significant independent predictor of cardioembolic stroke in a multivariable setting (Continuous, per unit increase OR = 1.091, 95%CI: 1.023-1.164, P = 0.008). CONCLUSIONS: Serum TB level was independently associated with cardioembolic stroke. The combination of clinical data and serum TB may be a feasible strategy to diagnose cardioembolic stroke in the acute phase.
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Bilirrubina/sangue , Isquemia Encefálica/diagnóstico , Embolia Intracraniana/diagnóstico , Acidente Vascular Cerebral/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/sangue , Fibrilação Atrial/patologia , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/classificação , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Diagnóstico Diferencial , Estudos de Viabilidade , Feminino , Humanos , Embolia Intracraniana/sangue , Embolia Intracraniana/complicações , Embolia Intracraniana/patologia , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/classificação , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologiaRESUMO
BACKGROUND: Despite the large scale technical innovations that have been made, a number of patients with neuromyelitis optica (NMO) are lacking NMO-IgG in both serum and cerebrospinal fluid. Longitudinally extensive spinal cord (LESC) lesions and linear lesions are associated with NMO. However, differences of spinal cord magnetic resonance imaging (MRI) features, including LESC lesions and linear lesions, between NMO-IgG positive and negative patients still remain unknown. The aim of the present study was to analyze the relationship between NMO-IgG status and spinal cord MRI features in NMO patients, particularly concerned about LESC lesions and linear lesions. METHODS: Clinical data and spinal cord MRI of 52 NMO patients were retrospectively analyzed. Eight patients were NMO-IgG negative in both serum and cerebrospinal fluid, while 44 were NMO-IgG positive. Quantitative data between the two cohorts were compared by the Student's t test or Mann-Whitney U test, the chi-square test or Fisher's exact test was used to evaluate qualitative data. RESULTS: NMO-IgG negative patients had a higher sex ratio (male/female) (P = 0.014). On axial MRI, lesions in the NMO-IgG negative group were mostly located in the peripheral cord (50%), and central lesions (55%) were more common in the NMO-IgG positive group (P = 0.051). LESC lesions were common in both cohorts. None of linear lesions was found in NMO-IgG negative patients, while the NMO-IgG positive cohort had significantly more linear lesions (48%) (P = 0.016). CONCLUSIONS: Patients with NMO-IgG negativity may have different spinal cord lesion features compared to NMO-IgG positive patients. Diagnosis of NMO cannot be excluded even when NMO-IgG negativity and non-specific spinal lesions occur.
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Imunoglobulina G/sangue , Imunoglobulina G/líquido cefalorraquidiano , Neuromielite Óptica/sangue , Neuromielite Óptica/líquido cefalorraquidiano , Medula Espinal/patologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/patologia , Estudos Retrospectivos , Adulto JovemRESUMO
AIM: To investigate the effects of Tat-NEMO-binding domain (NBD) peptide on taurocholate-induced pancreatitis and lipopolysaccharide (LPS)-stimulated AR42J acinus cells inflammatory response in rats. METHODS: Sodium taurocholate (5%) was used to induce the pancreatitis model. Forty-eight rats from the taurocholate group received an intravenous bolus of 13 mg/kg Tat-NBD (wild-type, WT) peptide, Tat-NBD (mutant-type, MT) peptide, NBD peptide or Tat peptide. The pancreatic histopathology was analyzed by hematoxylin staining. LPS was added to the culture medium to stimulate the AR42J cells. For pretreatment, cells were incubated with different peptides for 2 h before LPS stimulation. Expression of IL-1beta and TNF-alpha mRNA was analyzed using a semi-quantitative reverse-transcript polymerase chain reaction (RT-PCR) method. IL-1beta and TNF-alpha protein in culture medium were detected by enzyme linked immunosorbent assay (ELISA). NF-kappaB DNA-binding in pancreas was examined by electrophoretic mobility shift assays. P65 expression of AR42J was determined by Strept Actividin-Biotin Complex (SABC) method. RESULTS: Pretreatment with Tat-NBD (WT) peptide at a concentration of 13 mg/kg body wt showed beneficial effect in pancreaitis model. LPS (10 mg/L) resulted in an increase of IL-1beta mRNA, IL-1beta protein, TNF-alpha mRNA and TNF-alpha protein, whereas significantly inhibitory effects were observed when cells were incubated with Tat-NBD (WT). Consisting with p65 expression decrease analyzed by SABC method, NF-kappaB DNA-binding activity significantly decreased in Tat-NBD (WT) pretreatment group, especially at the largest dose. No significant changes were found in the control peptide group. CONCLUSION: Our result supports that active NF-kappaB participates in the pathogenesis of STC-induced acute pancreatitis in rats. Tat-NBD (WT) peptide has anti-inflammatory effects in this model and inhibits the inflammation of acinus simulated by LPS.
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Produtos do Gene tat/farmacologia , Inflamação/tratamento farmacológico , Pancreatite/tratamento farmacológico , Peptídeos/farmacologia , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/genética , NF-kappa B/fisiologia , Pancreatite/induzido quimicamente , Pancreatite/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/uso terapêutico , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácido Taurocólico/toxicidade , Fator de Necrose Tumoral alfa/genéticaRESUMO
OBJECTIVE: To investigate the changes in the activity of nuclear factor-kappaB (NF-kappa B) in mice with dextran sulphate sodium (DSS)-induced rat colitis and its modulalorg effect on intercellular adhesion molecule-1 (ICAM-1) expression. METHODS: Twenty normal male mice were randomized into DSS group and normal saline (NS) control group according to a matched-pair design. From days 1 to 7, the mice in DSS group were subjected to oral administration of 5%DSS solution, and from days 8 to 20, NS was given instead, for a total of 3 cycles. In the control group, only NS was administered. The colonic pathology was observed using HE staining and the mucosa 1 damage was scored for each mouse. The DNA-binding activity of NF-kappa B was tested by electrophoretic mobility shift assay, and the expressions of ICAM-1 and NF-kappa B p65 were detected using immunohistochemistry. RESULTS: The DNA-binding activity of NF-kappa B was significantly increased in DSS group as compared with NS group. ICAM-1 and p65 expressions were detected in the nuclei of the vascular endothelial and inflammatory cells, especially in the mucosa and submucosa, but such positive cells were seldom observed in NS group. A positive correlation was found between the DNA-binding activity of NF-kappa B and ICAM-1 expression. CONCLUSION: NF-kappa B activation is an important event in the development of DSS-induced colitis in that activated NF-kappa B upregulates ICAM-1 expression during colonic inflammation.