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1.
Cancer Cell ; 39(2): 276-283.e3, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33508216

RESUMEN

SARS-CoV-2 infection induces a wide spectrum of neurologic dysfunction that emerges weeks after the acute respiratory infection. To better understand this pathology, we prospectively analyzed of a cohort of cancer patients with neurologic manifestations of COVID-19, including a targeted proteomics analysis of the cerebrospinal fluid. We find that cancer patients with neurologic sequelae of COVID-19 harbor leptomeningeal inflammatory cytokines in the absence of viral neuroinvasion. The majority of these inflammatory mediators are driven by type II interferon and are known to induce neuronal injury in other disease states. In these patients, levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks after convalescence from acute respiratory infection. These prolonged neurologic sequelae following systemic cytokine release syndrome lead to long-term neurocognitive dysfunction. Our findings suggest a role for anti-inflammatory treatment(s) in the management of neurologic complications of COVID-19 infection.


Asunto(s)
Encefalopatías/etiología , Mediadores de Inflamación/líquido cefalorraquídeo , Neoplasias/virología , /metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Proteínas del Líquido Cefalorraquídeo/análisis , Comorbilidad , Citocinas/líquido cefalorraquídeo , Humanos , Neoplasias/complicaciones , Neoplasias/epidemiología , Neuroimagen
2.
Zhonghua Nan Ke Xue ; 26(4): 335-340, 2020 Apr.
Artículo en Chino | MEDLINE | ID: mdl-33351301

RESUMEN

Objective: To investigate the levels of chemokines 8 and 10 (CXCL8 and CXCL10), Th1 cytokines (IL-2, IL-12 and IFN-γ) and Th2 cytokines (IL-6 and IL-10) in the serum and cerebrospinal fluid of patients with neurosyphilis and elucidate their roles in the immune response and pathogenesis of neurosyphilis. METHODS: Using ELISA, we detected the expressions of CXCL8, CXCL10, IL2, IL-2, IFN-γ, IL-6 and IL-10 in the serum and cerebrospinal fluid of 42 cases of neurosyphilis, 44 cases of syphilis and 40 cases of non-inflammatory diseases of the nervous system (the control group). RESULTS: The serum levels of CXCL8, CXCL10, IL-2, IL-12, IFN-γ, IL-6 and IL-10 were significantly lower in the neurosyphilis group than in the syphilis and control groups (P < 0.05), and so were they in the male than in the female neurosyphilis patients (P < 0.05). However, the expressions of CXCL8, CXCL10, IL-2, IL-12, IFN-γ, IL-6 and IL-10 in the cerebrospinal fluid were remarkably higher in the neurosyphilis group than in the syphilis and control groups (P < 0.05), and so were they in the male than in the female neurosyphilis patients (P < 0.05). CONCLUSIONS: Patients with neurosyphilis have cellular immune dysfunction, and their immune response involves CXCL8, CXCL10 and Th1 / Th2 cytokines.


Asunto(s)
Quimiocina CXCL10/sangre , Quimiocina CXCL10/líquido cefalorraquídeo , Interleucina-8/sangre , Interleucina-8/líquido cefalorraquídeo , Neurosífilis/sangre , Neurosífilis/líquido cefalorraquídeo , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino
3.
BMC Neurol ; 20(1): 248, 2020 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-32552792

RESUMEN

BACKGROUND: COVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients. CASE PRESENTATION: We describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion. CONCLUSION: Our findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus , Citocinas/líquido cefalorraquídeo , Encefalitis Viral , Pandemias , Neumonía Viral , Enfermedad Aguda , Anciano , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Convulsiones
4.
Emerg Infect Dis ; 26(9): 2016-2021, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32487282

RESUMEN

There are few detailed investigations of neurologic complications in severe acute respiratory syndrome coronavirus 2 infection. We describe 3 patients with laboratory-confirmed coronavirus disease who had encephalopathy and encephalitis develop. Neuroimaging showed nonenhancing unilateral, bilateral, and midline changes not readily attributable to vascular causes. All 3 patients had increased cerebrospinal fluid (CSF) levels of anti-S1 IgM. One patient who died also had increased levels of anti-envelope protein IgM. CSF analysis also showed markedly increased levels of interleukin (IL)-6, IL-8, and IL-10, but severe acute respiratory syndrome coronavirus 2 was not identified in any CSF sample. These changes provide evidence of CSF periinfectious/postinfectious inflammatory changes during coronavirus disease with neurologic complications.


Asunto(s)
Betacoronavirus , Encefalopatías/virología , Infecciones por Coronavirus/complicaciones , Citocinas/líquido cefalorraquídeo , Encefalitis Viral/virología , Neumonía Viral/complicaciones , Adulto , Encefalopatías/líquido cefalorraquídeo , Infecciones por Coronavirus/líquido cefalorraquídeo , Infecciones por Coronavirus/virología , Encefalitis Viral/líquido cefalorraquídeo , Resultado Fatal , Femenino , Georgia , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/líquido cefalorraquídeo , Neumonía Viral/virología
5.
Acta Neurol Scand ; 142(2): 161-168, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32415852

RESUMEN

OBJECTIVES: The risk of developing multiple sclerosis (MS) increases (OR: 3.1) after infectious mononucleosis (IM). However, the nature of this link is obscure. We tested the hypothesis that IM might incur long-term sequelae, including low-key inflammatory activity, with characteristics of an MS endophenotype (or presymptomatic trait) and that assays of MS-relevant cyto-/chemokines in the cerebrospinal fluid (CSF) post-IM may show a trend in this direction. MATERIALS AND METHODS: We selected seven CSF cytokines (IL-1b, IL-6, YKL-40, TNF-alpha) or chemokines (IL-8, CCL2, IP-10), representing pro-inflammatory factors previously associated with MS. We assayed the CSF levels of these seven cyto-/chemokines in healthy individuals with a median follow-up time of 10 years after serologically confirmed IM (post-IM group, n = 22), and in healthy controls without a history of IM (n = 19). A group of MS patients (n = 23) were included as reference. RESULTS: The CSF levels of IP-10, YKL-40, and CCL-2 were higher in the post-IM group than in our IM unexposed controls (P = .021, .049, .028). Seven of seven cyto-/chemokine assays showed a trend in the predicted direction (P of binomial ratio = .008). However, this trend was non-significant in a multivariate test (P = .22). A power analysis indicated that similar studies including a larger cohort would be numerically realistic. CONCLUSIONS: These results do not reject the hypothesis that the established epidemiological association between IM and MS results from a stepwise inflammatory propagation from IM sequelae to an MS endophenotype (or presymptomatic trait) in a proportion of IM patients, pending confirmation with adequate power.


Asunto(s)
Mononucleosis Infecciosa/líquido cefalorraquídeo , Mononucleosis Infecciosa/epidemiología , Mediadores de Inflamación/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/epidemiología , Adolescente , Adulto , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Citocinas/líquido cefalorraquídeo , Femenino , Humanos , Mononucleosis Infecciosa/diagnóstico , Interleucina-1beta/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Adulto Joven
6.
Immunol Med ; 43(4): 135-141, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32459601

RESUMEN

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by diverse organ damages resulting from various autoantibodies, such as antinuclear or anti-DNA antibodies. Neuropsychiatric lupus (NPSLE) refers to the neurological and psychiatric disorders complicated with SLE and can be challenging for physicians to manage. NPSLE has a broad spectrum and high heterogeneity of clinical phenotypes, including headaches, psychiatric symptoms and peripheral neuropathy. Additionally, various immune effectors have been reported to contribute to the pathogenesis, including cytokines, cell-mediated inflammation and brain-reactive autoantibodies. In some patients with SLE, neuropsychiatric symptoms develop for the first time after the initiation of the steroid treatment, hindering the differentiation from steroid psychosis. The administration of high doses of steroids in patients with SLE is believed to trigger psychiatric symptoms. No clear evidence has yet been found regarding the treatment of NPSLE. Therefore, NPSLE-specific markers need to be developed, and treatment guidelines should be established. This article provides an overview of NPSLE as well as its pathogenesis and treatment.


Asunto(s)
Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/inmunología , Trastornos Mentales/etiología , Enfermedades del Sistema Nervioso/etiología , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Anticuerpos Antinucleares , Autoanticuerpos , Citocinas/líquido cefalorraquídeo , Humanos , Hidroxicloroquina/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/inmunología , Ácido Micofenólico/uso terapéutico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/inmunología , Rituximab/uso terapéutico
7.
Sci Rep ; 10(1): 6904, 2020 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-32327682

RESUMEN

In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1-4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection.


Asunto(s)
Aminoquinolinas/administración & dosificación , Aminoquinolinas/uso terapéutico , Asfixia/embriología , Encéfalo/patología , Feto/patología , Imidazoles/administración & dosificación , Imidazoles/uso terapéutico , Nacimiento Prematuro/tratamiento farmacológico , Receptor Toll-Like 7/agonistas , Aminoquinolinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Presión Arterial/efectos de los fármacos , Asfixia/sangre , Asfixia/líquido cefalorraquídeo , Asfixia/fisiopatología , Análisis de los Gases de la Sangre , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Caspasa 3/metabolismo , Polaridad Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Femenino , Feto/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Concentración de Iones de Hidrógeno , Imidazoles/farmacología , Inyecciones Intraventriculares , Masculino , Metaboloma/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/patología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Oligodendroglía/patología , Tamaño de los Órganos/efectos de los fármacos , Nacimiento Prematuro/sangre , Nacimiento Prematuro/líquido cefalorraquídeo , Nacimiento Prematuro/fisiopatología , Ovinos , Factores de Tiempo , Cordón Umbilical/patología
8.
J Neuroimmunol ; 343: 577219, 2020 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-32224326

RESUMEN

INTRODUCTION: Chronic radicular neuropathic pain is a major clinical problem with a life time prevalence of more than 50%. Pulsed radiofrequency (PRF) treatment is a recognised therapy. However, the pathophysiology of chronic neuropathic pain (CNP) and the mechanism of action of PRF remains ill-defined. Improving our knowledge of the mechanisms of CNP and PRF action will enhance our ability to treat patients with this common debilitating problem more effectively. This study aims to characterise the CSF cellular and peptide constituents in patients with CNP and the effect of pulsed radiofrequency (PRF) on these constituents and reported pain. MATERIALS AND METHODS: Prospective randomised tripled-blinded control trial of patients receiving PRF treatment versus sham for radicular pain. All patients received local anaesthetic to the appropriate dermatome to confirm diagnosis. Clinical assessment using standard clinical assessment tools and examination of CSF using flow cytometry and ELISA for cellular and peptide constituents was carried out before and 3 months after treatment. RESULTS: Ten patients were randomised to PRF (n = 5) or Sham (n = 5) treatment. PRF resulted in a significant reduction in pain score (NRS) at 3 months (6.8 to 2.6, p < .05). PRF reduced the TNF-α concentration and CD3+ count in CSF. CD4/CD8 ratio of patients with CNP was lower than historical controls (1.4 versus 3.0-4.2). The majority of CD3+ cells in the CNP patients were activated effector memory cells (80%) versus the surveillance central memory cells (85%) seen in healthy controls. CONCLUSIONS: PRF is superior to local anaesthetic administration for the management of radicular pain and is associated with CSF constituent modulation in vivo. Patients with CNP have lymphocyte characteristics which suggest immune activation.


Asunto(s)
Citocinas/líquido cefalorraquídeo , Neuralgia/inmunología , Neuralgia/terapia , Tratamiento de Radiofrecuencia Pulsada/métodos , Linfocitos T/microbiología , Adulto , Femenino , Ganglios Espinales , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
9.
J Clin Neurosci ; 75: 176-180, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32217048

RESUMEN

Data indexing the contribution of various immuno-inflammatory components in the cerebrospinal fluid (CSF) towards the pathophysiology of Guillain Barré Syndrome (GBS) are limited. Th17 pathway plays crucial role in many immune mediated disorders of the nervous system. This study was aimed at exploring the role of Th17 pathway related cytokines in the CSF of patients with GBS. Levels of multiple key cytokines of Th17 pathway in CSF of patients with GBS (N = 37) and controls (N = 37) were examined in this prospective study using Bio-plex Pro Human Th17 cytokine assays in a Multiplex Suspension Array platform. The findings were correlated with clinical features and electrophysiological subtypes. Three key cytokines of Th17 pathway (IL-6, IL-17A and IL-22) were significantly elevated in CSF of patients with GBS as compared to controls. There was a positive correlation between the levels of IL-6 and IL-17A as well as between the levels of IL-17A and IL-22 in the CSF of patients with GBS. The CSF levels of IL-6 and IL-22 were negatively correlated with the duration of symptoms of GBS. None of the studied cytokines correlated with functional disability scores at admission to hospital or with the electrophysiological subtypes. Identification of Th17 pathway signatures in CSF sheds more insights into the pathogenic role of Th17 cells in GBS. These findings complement the contemporary knowledge and tender further support towards the involvement of Th17 pathway in GBS.


Asunto(s)
Síndrome de Guillain-Barré/líquido cefalorraquídeo , Interleucina-17/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Interleucinas/líquido cefalorraquídeo , Transducción de Señal/fisiología , Células Th17/metabolismo , Adulto , Biomarcadores/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Citocinas/inmunología , Femenino , Síndrome de Guillain-Barré/inmunología , Humanos , Interleucina-17/inmunología , Interleucina-6/inmunología , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Células Th17/inmunología
10.
Pediatr Infect Dis J ; 39(3): 239-243, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32032308

RESUMEN

BACKGROUND: Borrelia burgdorferi and tick-borne encephalitis (TBE) virus are 2 types of tick-borne pathogens that can cause central nervous system infection. Routine diagnostics have so far included analysis of cerebrospinal fluid (CSF) cell numbers, CSF serology for Borrelia burgdorferi and serum serology for TBE virus. However, early diagnosis may be difficult based on antibody detection which takes time to analyze, and with the possibility of false negative results, thus delaying treatment. Cytokine analyses are becoming increasingly available in clinical routine care and may offer important information. METHODS: Fifteen cytokines and chemokines were measured in the CSF from the diagnostic lumbar puncture of 37 children with TBE, 34 children with neuroborreliosis and 19 children without evidence of central nervous system infection, using Luminex technology. RESULTS: Significantly higher levels of proinflammatory interleukin-6 were detected in the samples from TBE-infected children, when compared with neuroborreliosis or controls. In comparison, children with neuroborreliosis had significantly higher levels of interleukin-7, interleukin-8, interleukin-10, and interleukin-13 when compared with TBE infected or controls. Furthermore, the ratio between interleukin-6 and interleukin-10 was significantly different between the 2 types of tick-borne infections. CONCLUSIONS: The interleukin-6/interleukin-10 ratio can be used as a rapid diagnostic cue upon suspected tick-borne infection, enabling fast and correct treatment. Also, in serology-negative results, such information may strengthen a clinical suspicion.


Asunto(s)
Virus de la Encefalitis Transmitidos por Garrapatas , Encefalitis Transmitida por Garrapatas/líquido cefalorraquídeo , Encefalitis Transmitida por Garrapatas/diagnóstico , Interleucina-10/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Biomarcadores , Quimiocinas/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Encefalitis Transmitida por Garrapatas/virología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico
11.
Biomarkers ; 25(2): 171-178, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31916867

RESUMEN

Purpose: Given the challenge in the diagnosis of bacterial meningitis (BM), we assessed different cytokines in the cerebrospinal fluid (CSF) of antibiotics pre-treated patients.Materials and methods: Laboratory tests and polymerase chain reaction (PCR) were performed for 480 CSF samples from children (2 m to 14 y), suspicious to meningitis and pre-treated with antibiotics, to detect bacterial and viral aetiologies. Sixty-one CSF were included and the levels of 13 cytokines such as IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, IL-22, IFN-γ and TNF-α were measured using flow-cytometry.Results: All bacterial cultures were negative, but 29 and eight CSF were positive for bacterial and viral agents by PCR. IL-6, IL-10 and IFN-γ were significantly up-regulated in BM. T helper (Th) subset cytokines showed significant upregulation of Th1, Th2, Th17, Th22 and Tfh cytokines in BM. Common Th subsets cytokines (IL-6, IL-10 and TNF-α) were significantly different between the study groups. ROC curve analysis revealed good AUC for common Th related cytokines in discriminating BM.Conclusions: In pre-treated BM patients with negative bacterial cultures, cytokines IL-6, IL-10 and IFN-γ can predict BM which could be beneficial for rapid diagnosis and treatment to decrease the sequela of the disease.


Asunto(s)
Profilaxis Antibiótica , Citocinas/líquido cefalorraquídeo , Meningitis Bacterianas/diagnóstico , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Biomarcadores/líquido cefalorraquídeo , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Interferón gamma/líquido cefalorraquídeo , Interleucina-10/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Masculino , Meningitis Bacterianas/tratamiento farmacológico , Pediatría/métodos
12.
Brain Dev ; 42(2): 185-191, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31787380

RESUMEN

BACKGROUND: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. METHODS: Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis). RESULTS: The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC. CONCLUSION: Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.


Asunto(s)
Encefalopatías/inmunología , Encefalopatías/patología , Citocinas/análisis , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Quimiocinas/análisis , Quimiocinas/sangre , Quimiocinas/líquido cefalorraquídeo , Preescolar , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Encefalitis/líquido cefalorraquídeo , Femenino , Humanos , Lactante , Oxidorreductasas Intramoleculares/sangre , Oxidorreductasas Intramoleculares/líquido cefalorraquídeo , Factor Inhibidor de Leucemia/sangre , Factor Inhibidor de Leucemia/líquido cefalorraquídeo , Factores Inhibidores de la Migración de Macrófagos/sangre , Factores Inhibidores de la Migración de Macrófagos/líquido cefalorraquídeo , Masculino , Osteopontina/sangre , Osteopontina/líquido cefalorraquídeo , Convulsiones/etiología , Convulsiones Febriles/complicaciones , Convulsiones Febriles/inmunología , Convulsiones Febriles/patología
13.
Ann Neurol ; 87(2): 246-255, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31725947

RESUMEN

OBJECTIVE: Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. No disease-modifying therapy exists for the treatment of patients with HD. The purpose of this study was therefore to investigate early disease mechanisms that potentially could be used as a target therapeutically. METHODS: Lymphocyte activity in cerebrospinal fluid (CSF) from 4 cohorts of HTT gene expansion carriers (n = 121 in total) and controls was analyzed by techniques based on flow cytometry and enzyme-linked immunosorbent assays. RESULTS: The data of this study provide evidence of immune abnormalities before motor onset of disease. In CSF of HTT gene expansion carriers, we found increased levels of proinflammatory cytokines, including IL-17, and increased consumption of the lymphocyte growth factor IL-7 before motor onset of HD. In concordance, we observed an increased prevalence of IL-17-producing Th17.1 cells in the CSF of HTT gene expansion carriers, predominantly in pre-motor manifest individuals. The frequency of intrathecal Th17.1 cells correlated negatively with progression of HD and the level of neurodegeneration, suggesting a role of Th17.1 cells in the early disease stage. We also observed a skewing in the balance between proinflammatory and regulatory T cells potentially favoring a proinflammatory intrathecal environment in HTT gene expansion carriers. INTERPRETATION: These data suggest that Th17.1 cells are implicated in the earliest pathogenic phases of HD and suggest that treatment to dampen T -cell-driven inflammation before motor onset might be of benefit in HTT gene expansion carriers. ANN NEUROL 2020;87:246-255.


Asunto(s)
Enfermedad de Huntington/inmunología , Enfermedad de Huntington/fisiopatología , Activación de Linfocitos/inmunología , Células Th17/inmunología , Adulto , Anciano , Proliferación Celular , Citocinas/líquido cefalorraquídeo , Citocinas/metabolismo , Femenino , Heterocigoto , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/líquido cefalorraquídeo , Enfermedad de Huntington/genética , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/inmunología , Células Th17/metabolismo , Expansión de Repetición de Trinucleótido/genética
14.
Int J Infect Dis ; 90: 104-110, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31678190

RESUMEN

OBJECTIVE: To evaluate the clinical, laboratory, and immune characteristics of Zika virus (ZIKV)-associated encephalitis in pediatric patients after the epidemic in Huila, southern Colombia. METHODS: A pediatric neuro-surveillance hospital study was conducted in a referral health center in southern Colombia, from October 2016 to October 2017. Cases of encephalitis were confirmed by nucleic acid amplification tests and serological methods in cerebrospinal fluid (CSF), plasma, and/or urine. Levels of six cytokines were evaluated by flow cytometry. Patients underwent daily clinical and laboratory follow-up. RESULTS: Twenty children with probable encephalitis were included for further studies and 16 of them were confirmed. Four cases of bacterial meningoencephalitis (Streptococcus pneumoniae, group B Streptococcus, Staphylococcus epidermidis, and Escherichia coli) and 12 cases of viral encephalitis were identified, six of them associated with ZIKV infection. Other viral encephalitis cases were caused by herpes viruses (n=3), enterovirus (n=2), and dengue virus type 2 (DENV-2; n=1) infections. ZIKV-associated encephalitis symptoms subsided faster than those of patients with encephalitis caused by other agents. CSF analysis revealed lymphocytic pleocytosis. Compared to healthy controls, children with ZIKV-associated encephalitis presented modest plasma interleukin (IL)-10 but not IL-2, IL-4, IL-6, interferon gamma (IFN-γ), or tumor necrosis factor alpha (TNF-α). Cytokine expression was differentially regulated, as dramatically elevated IL-6, IL-10, and IFN-γ levels were observed in CSF but not in paired plasma samples in one of the patients with ZIKV detectable in CSF. CONCLUSIONS: This study provides evidence that ZIKV is responsible for pediatric encephalitis in endemic areas, and the local presence of the virus may induce cephalic but not systemic expression of cytokines.


Asunto(s)
Encefalitis Viral/virología , Infección por el Virus Zika/virología , Adolescente , Niño , Preescolar , Colombia , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Encefalitis Viral/diagnóstico , Encefalitis Viral/inmunología , Femenino , Humanos , Lactante , Interferón gamma/sangre , Interferón gamma/líquido cefalorraquídeo , Masculino , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Virus Zika/aislamiento & purificación , Infección por el Virus Zika/diagnóstico , Infección por el Virus Zika/inmunología
15.
J Microbiol Immunol Infect ; 53(2): 216-224, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30448438

RESUMEN

BACKGROUND: There has been a great deal of evidence indicating that cytokines participate in meningeal inflammation. Different cytokine profiles may be presented in central nervous system (CNS) infection due to different pathogens. We have attempted to investigate cytokine profiles in cerebrospinal fluid (CSF) of patients with CNS infection. METHODS: Forty-three patients with CNS infection including tuberculous meningitis, purulent meningitis and cryptococcal meningitis were enrolled and 11 patients with normal CSF were enrolled as control group. The concentrations of Th1-, Th2- and Th17-type cytokines in CSF were detected using multiplex cytokine assay. Furthermore, the correlation between CSF cytokines and CSF parameters in CNS infection was analyzed. RESULTS: The CSF levels of IL-1ß, IL-4, IL-6, IL-10, IL-17, IL-23, IL-33, IFN-γ, TNF-α and sCD40L among the patients with CNS infection were all higher than control group (all P < 0.05). A remarkable elevation of CSF IL-6 in the patients with CNS infection was observed with the least overlap of the CSF concentrations compared to controls. Moreover, CSF IL-6 levels were strongly negatively correlated with CSF glucose and the CSF/blood glucose ratio (r = -0.4375, P = 0.0042; r = -0.4991, P = 0.0009). CONCLUSIONS: The excessive activation of immune response characterized by elevated levels of CSF Th1-, Th2- and Th17-type cytokines has been observed during CNS infection. Furthermore, we observed negative correlations between CSF IL-6 levels and CSF glucose and CSF/blood glucose ratio in CNS infection. And we suggested that combined CSF IL-6 levels with CSF glucose may serve as a novel biomarker pool for the differential of CNS infection.


Asunto(s)
Citocinas/líquido cefalorraquídeo , Hospitales Generales , Meningitis/líquido cefalorraquídeo , Centros de Atención Terciaria , Adulto , Anciano , Biomarcadores/líquido cefalorraquídeo , Glucemia , Líquido Cefalorraquídeo/química , China , Cryptococcus neoformans , Citocinas/metabolismo , Femenino , Glucosa , Humanos , Interleucina-6/líquido cefalorraquídeo , Masculino , Meningitis/diagnóstico , Meningitis/microbiología , Meningitis Criptocócica , Persona de Mediana Edad , Células TH1 , Células Th17 , Células Th2 , Adulto Joven
16.
Turk Neurosurg ; 30(4): 513-519, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31099887

RESUMEN

AIM: To measure cytokine and lactate levels in the cerebrospinal fluid (CSF) of patients with suspected post-neurosurgical meningitis. MATERIAL AND METHODS: Interleukin (IL)-8,-12, and -13, interferon (IFN) gamma, and lactate concentrations were determined in the CSF of patients diagnosed with meningitis, who were undergoing follow-up after neurosurgical procedures at the Neurosurgery Clinic between May 2016 and November 2017. The demographic, clinical, biochemical, CSF cell count, CSF biochemistry, and CSF culture results of 119 patients were recorded. RESULTS: The study group consisted of 39 patients diagnosed with post-neurosurgical meningitis. The control group comprised of 80 patients without pleocytosis, who had undergone lumbar puncture due to various indications. In the study group, 59% of the patients had fever, 66.7% had deterioration in the level of consciousness, and 35.9% had neck stiffness. The levels of IL-8 (96.5 ng/L vs. 86.6 ng/L, p < 0.001), IL-12 (10.1 ng/L vs. 3 ng/L, p < 0.001), and lactate (5.9 mmol/L vs. 2.1 mmol/L, p < 0.001) were higher in the CSF of the patient group compared to the control group. However, IL-13 (32.7 ng/L vs. 42.5 ng/L, p=0.003) and IFN gamma (73.3 ng/L vs. 260.4 ng/L, p < 0.001) levels were lower in patients compared to controls. The mortality rate in post-neurosurgical meningitis patients was estimated to be 35.9%. CONCLUSION: Post-neurosurgical meningitis prolongs the duration of hospital stay and causes long-term sequelae. Therefore, measurement of CSF cytokine and lactate levels alongside meningitis diagnostic processes may facilitate early and accurate diagnosis. Measuring CSF lactate is inexpensive and cost effective, particularly in post-neurosurgical patients.


Asunto(s)
Biomarcadores/líquido cefalorraquídeo , Meningitis Bacterianas/líquido cefalorraquídeo , Meningitis Bacterianas/diagnóstico , Meningitis Bacterianas/etiología , Procedimientos Neuroquirúrgicos/efectos adversos , Complicaciones Posoperatorias/líquido cefalorraquídeo , Adulto , Citocinas/líquido cefalorraquídeo , Femenino , Humanos , Ácido Láctico/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico
17.
Medicine (Baltimore) ; 98(52): e18464, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31876729

RESUMEN

Enterovirus 71 (EV71) is an important etiological agent of hand, foot, and mouth disease (HFMD), which can also lead to severe neurological complications (eg, encephalitis) in young children. Although a series of reports on EV71 infection have been published, the pathogenic mechanism of EV71 infection is still not fully understood.We evaluated the cerebrospinal fluid (CSF) levels of the inflammatory cytokines interleukin (IL)-8, IL-1ß, IL-6, IL-10, tumor necrosis factor (TNF)-α, and IL-12p70 in 88 children with EV71-related encephalitis and 19 children with febrile convulsion (FC) with the use of commercial cytometric bead array kits.The levels of IL-8, IL-1ß, IL-6, and IL-10 in CSF were significantly higher in encephalitis group when compared with those observed in FC group, while no significant changes were noted in the levels of TNF-α and IL-12p70. In addition, significant and positive correlations among CSF IL-8, IL-1ß, IL-6, and IL-10 were observed in encephalitis group. Furthermore, receiver operator characteristic analysis determined a cut-off value of 10.62 pg/mL for IL-6 to discriminate encephalitis patients from FCs with the sensitivity and specificity of 89.8% and 84.2%, respectively. Moreover, logistic regression analyses revealed that IL-6 was an independent predictor of EV71-related encephalitis (odds ratio = 23.241, P < .001).Our results indicate that 4 inflammatory cytokines (IL-8, IL-1ß, IL-6, and IL-10) play important roles in the pathogenesis of EV71 infection. IL-6 may be used for the evaluation of EV71-related encephalitis and as a potential therapy candidate for EV71 infection.


Asunto(s)
Citocinas/líquido cefalorraquídeo , Encefalitis Viral/líquido cefalorraquídeo , Enterovirus Humano A , Enfermedad de Boca, Mano y Pie/líquido cefalorraquídeo , Preescolar , China/epidemiología , Encefalitis Viral/virología , Femenino , Enfermedad de Boca, Mano y Pie/virología , Humanos , Lactante , Interleucina-10/líquido cefalorraquídeo , Interleucina-12/líquido cefalorraquídeo , Interleucina-1beta/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Interleucina-8/líquido cefalorraquídeo , Masculino , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo
18.
J Neuroinflammation ; 16(1): 219, 2019 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-31727097

RESUMEN

BACKGROUND: Cytokines play multiple roles during neuro-inflammatory processes and several cytokines have been studied in the context of specific diseases. This study provides a comprehensive picture of cerebrospinal fluid (CSF) changes during neuro-inflammation by analyzing multiple cytokines in combination with immune cell subsets and standard CSF parameters. METHODS: Using multiplex assays, we simultaneously measured 36 cytokines (CCL1-3, CCL7, CCL8, CCL11, CCL13, CCL19, CCL20, CCL22-27, CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, CXCL9, CXCL11-13, CXCL16, CX3CL1, IL2, IL4, IL6, IL10, IL16, GM-CSF, IFNγ, MIF, TNFα, and MIB1ß) in the CSF and serum of 75 subjects. Diagnoses included clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS, n = 18), secondary progressive MS (n = 8), neuro-syphilis (n = 6), Lyme neuro-borreliosis (n = 13), bacterial and viral meningitis (n = 20), and patients with non-inflammatory neurological diseases (NIND, n = 10). Cytokine concentrations were correlated with CSF standard parameters and CSF immune cell subsets (CD4 and CD8 T cells, B cells, plasmablasts, monocytes, and NK cells) quantified by flow cytometry. RESULTS: We observed increased levels of multiple cytokines (26/36) in patients with neuro-inflammatory diseases when compared to NIND that consistently correlated with CSF cell count and QAlbumin. Most CSF cytokine concentrations correlated with each other, but correlations between CSF and serum values were scarce (3/36). Within the CSF compartment, CXCL13 showed a strong association with B cells when analyzing all patients, as well as patients with an intact blood-brain barrier (BBB). NK cells positively correlated with CSF concentrations of multiple cytokines (22/36) when analyzing all patients. These correlations were maintained when looking at patients with a disrupted BBB but not detectable in patients with an intact BBB. CONCLUSIONS: Under conditions of neuro-inflammation, multiple CSF cytokines are regulated in parallel and most likely produced locally. A combined increase of CSF CXCL13 levels and B cells occurs under conditions of an intact BBB. Under conditions of a disrupted BBB, CSF NK cells show significantly increased values and seem to have a major contribution to overall inflammatory processes, reflected by a strong correlation with multiple cytokines. Future studies are necessary to address the exact kinetics of these cytokines during neuro-inflammation and their relation to specific diseases phenotypes.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/líquido cefalorraquídeo , Células Asesinas Naturales/inmunología , Meningitis Bacterianas/inmunología , Monocitos/inmunología , Esclerosis Múltiple/inmunología , Neurosífilis/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Citometría de Flujo , Humanos , Inflamación/líquido cefalorraquídeo , Inflamación/inmunología , Masculino , Meningitis Bacterianas/líquido cefalorraquídeo , Persona de Mediana Edad , Esclerosis Múltiple/líquido cefalorraquídeo , Neurosífilis/líquido cefalorraquídeo , Adulto Joven
19.
Ann Clin Transl Neurol ; 6(11): 2304-2316, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31657126

RESUMEN

OBJECTIVE: To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti-neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti-NF155 antibodies (NF155- CIDP). METHODS: Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155- CIDP, and 28 with non-inflammatory neurological disease (NIND). RESULTS: CSF CXCL8/IL-8, IL-13, TNF-α, CCL11/eotaxin, CCL2/MCP-1, and IFN-γ were significantly higher, while IL-1ß, IL-1ra, and G-CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155- CIDP, CXCL8/IL-8 and IL-13 were significantly higher, and IL-1ß, IL-1ra, and IL-6 were lower, in NF155+ CIDP. CXCL8/IL-8, IL-13, CCL11/eotaxin, CXCL10/IP-10, CCL3/MIP-1α, CCL4/MIP-1ß, and TNF-α levels were positively correlated with markedly elevated CSF protein, while IL-13, CCL11/eotaxin, and IL-17 levels were positively correlated with increased CSF cell counts. IL-13, CXCL8/IL-8, CCL4/MIP-1ß, CCL3/MIP-1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155- CIDP had significantly increased IFN-γ compared with NIND, and exhibited positive correlations of IFN-γ, CXCL10/IP-10, and CXCL8/IL-8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155- CIDP were separable, and that IL-4, IL-10, and IL-13 were the three most significant discriminators. INTERPRETATION: Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti-NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.


Asunto(s)
Autoanticuerpos , Moléculas de Adhesión Celular/inmunología , Citocinas/líquido cefalorraquídeo , Factores de Crecimiento Nervioso/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/líquido cefalorraquídeo , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
20.
Pediatr Rheumatol Online J ; 17(1): 70, 2019 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-31660995

RESUMEN

BACKGROUND: Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders. CASE PRESENTATION: We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene. CONCLUSION: Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.


Asunto(s)
Enfermedades Autoinflamatorias Hereditarias/genética , Adolescente , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colágeno Tipo VI/genética , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Fiebre/etiología , Variación Genética/genética , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Cariotipificación , Masculino , Proteínas de Microtúbulos/genética , Receptores Inmunológicos/genética , Secuenciación Completa del Genoma
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