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1.
Mediators Inflamm ; 2020: 8818044, 2020.
Article in English | MEDLINE | ID: mdl-33177951

ABSTRACT

BACKGROUND: Though peripheral blood is a crucial sample to study immunology, it is unclear whether the immune environment in the peripheral vasculature correlates with that at the end-organ site of infection. Using cryptococcal meningitis as a model, we investigated the correlation between serum and cerebrospinal fluid biomarkers over time. METHODS: We analyzed the cerebrospinal fluid and serum of 160 subjects presenting with first episode cryptococcal meningitis for soluble cytokines and chemokines measured by Luminex assay. Specimens were collected at meningitis diagnosis, 1-week, and 2-week post cryptococcal diagnosis. We compared paired samples by Spearman's correlation and the p value was set at <0.01. RESULTS: Of the 21 analytes tested at baseline, there was no correlation detected between nearly all analytes. A weak negative correlation was found between serum and cerebrospinal fluid levels of interferon-gamma (Rho = -0.214; p = .007) and interleukin-4 (Rho = -0.232; p = .003). There was no correlation at 1-week post cryptococcal diagnosis. However, at 2-week post cryptococcal diagnosis, there was a weak positive correlation of granulocyte-macrophage colony-stimulating factor levels (Rho = 0.25; p = .007) in serum and cerebrospinal fluid. No cytokine or chemokine showed consistent correlation overtime. CONCLUSION: Based on our analysis of 21 biomarkers, serum and cerebrospinal fluid immune responses do not correlate. There appears to be a distinct immune environment in terms of soluble biomarkers in the vasculature versus end-organ site of infection. While this is a model of HIV-related cryptococcal meningitis, we postulate that assuming the blood compartment is representative of the immune function at the end-organ site of infection may not be appropriate.


Subject(s)
Chemokines/blood , Chemokines/cerebrospinal fluid , Cytokines/blood , Cytokines/cerebrospinal fluid , Meningitis, Cryptococcal/blood , Meningitis, Cryptococcal/cerebrospinal fluid , Adult , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Female , Granulocyte Colony-Stimulating Factor/metabolism , HIV Infections/complications , Humans , Immune System , Immunocompromised Host , Interferon-gamma/blood , Interferon-gamma/cerebrospinal fluid , Interleukin-4/blood , Interleukin-4/cerebrospinal fluid , Male , Meningitis, Cryptococcal/complications , Reproducibility of Results
2.
Cytokine ; 108: 160-167, 2018 08.
Article in English | MEDLINE | ID: mdl-29625335

ABSTRACT

Multiple Sclerosis (MS) and Neuro-Behçet's Disease (NBD) are two recurrent disorders affecting the central nervous system (CNS) by causing inflammation and irreversible damage. Inaugural clinical symptoms for both diseases might be very similar and definitive diagnosis could be delayed. The present study aimed to find out possible differences at early stages in the transcription factors/cytokines expression profiles in blood and cerebrospinal fluid (CSF) of MS and NBD patients which could be useful discriminative markers. Cytokines and transcription factors related to Th1, Th2, Th17 and T regulatory populations were studied by quantitative RT-PCR simultaneously in PBMCs and CSF, from 40 patients presenting a first episode of clinical features related to CNS inflammation and 22 controls with non inflammatory neurological diseases enrolled mainly for severe headache. The follow up of 12 months did allow a definitive diagnosis of remitting relapsing MS (RRMS) in 21 patients and of NBD in the other 19 among those with CNS inflammation compared to controls. In initial blood samples, T-bet was significantly increased in NBD patients only while IFN-γ was elevated in patients who evolved into RRMS or NBD. IL-17a, GATA-3 and IL-4 were significantly lower in RRMS patients than in the NBD group. In initial CSF samples, ROR-γt, IL-17a and IFN-γ were significantly elevated in patients compared to controls. The most striking finding was the significant increase of CSF IL-10 that we did observe in NBD patients only. Thus, we propose CSF IL-10 as a predictive marker to help clinicians discriminating between these two neurological disorders.


Subject(s)
Behcet Syndrome/diagnosis , Interleukin-10/cerebrospinal fluid , Multiple Sclerosis/diagnosis , Adult , Biomarkers/cerebrospinal fluid , Blood-Brain Barrier/immunology , Central Nervous System/immunology , Diagnosis, Differential , Female , GATA3 Transcription Factor/cerebrospinal fluid , Humans , Inflammation , Interferon-gamma/cerebrospinal fluid , Interleukin-17/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Male , Middle Aged , Multiple Sclerosis/cerebrospinal fluid , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , Real-Time Polymerase Chain Reaction , Th1 Cells/immunology , Th2 Cells/immunology , Transcription Factors/cerebrospinal fluid
3.
Genet Mol Res ; 15(2)2016 May 23.
Article in English | MEDLINE | ID: mdl-27323066

ABSTRACT

To investigate the cytokine profile in serum and cerebrospinal fluid (CSF) from patients with systemic lupus erythematosus (SLE) and central nervous system infection, we measured interferon-g (IFN-g), interleukin-1b (IL-1b), IL-4, IL-6, IL-8, IL-10, and IL-17 levels in serum and CSF from 50 SLE patients and 38 matched controls. In patients with active compared to quiescent disease, serum levels were higher for IL-1b (P = 0.042) and IL-17 (P = 0.041) but we found no significant correlation between IL-1b and IL-17 and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (r = 0.055, r = 0.219, respectively). IL-10 level in active patients was lower compared to that in quiescent controls (P = 0.032). When comparing specific disease manifestations, IL-1b levels in patients with fever (P = 0.035) and IL-6 (P = 0.048) and IL-8 (P = 0.048) levels in those showing nervous system involvement were higher than in controls. Based on MRI results, we found that only increased cerebral ischemia was associated with increased IFN-g levels (P = 0.009). In neuropsychiatric lupus erythematous patients, CSF levels of IL-6 (P = 0.002), IL-8 (P = 0.009), and IL-17 (P = 0.034) were significantly higher when compared with control patients. IL-10:IL-1b ratio in patients with moderate and quiescent disease was higher than in patients with disease activity (P = 0.000). Pro-inflammatory adaptive cytokines were elevated during disease flare, while regulatory mediators were elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may be targets for novel immunotherapeutic agents for managing autoimmune diseases.


Subject(s)
Central Nervous System Diseases/cerebrospinal fluid , Interleukin-17/cerebrospinal fluid , Interleukin-6/cerebrospinal fluid , Interleukin-8/cerebrospinal fluid , Lupus Erythematosus, Systemic/cerebrospinal fluid , Aged , Central Nervous System Diseases/blood , Central Nervous System Diseases/diagnostic imaging , Central Nervous System Diseases/pathology , Female , Humans , Interferon-gamma/blood , Interferon-gamma/cerebrospinal fluid , Interleukin-10/blood , Interleukin-10/cerebrospinal fluid , Interleukin-17/blood , Interleukin-1beta/blood , Interleukin-1beta/cerebrospinal fluid , Interleukin-4/blood , Interleukin-4/cerebrospinal fluid , Interleukin-6/blood , Interleukin-8/blood , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/diagnostic imaging , Lupus Erythematosus, Systemic/pathology , Male , Middle Aged
5.
Bipolar Disord ; 17(5): 507-17, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25929806

ABSTRACT

OBJECTIVES: Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d-AMPH). METHODS: Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1ß, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. RESULTS: The present study showed that d-AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d-AMPH increased the levels of IL-4, IL-6, IL-10, and TNF-α in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). CONCLUSIONS: Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d-AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy.


Subject(s)
Antimanic Agents/pharmacology , Behavior, Animal/drug effects , Bipolar Disorder/immunology , Brain/drug effects , Cytokines/drug effects , Lithium Compounds/pharmacology , Motor Activity/drug effects , Animals , Antimanic Agents/therapeutic use , Bipolar Disorder/chemically induced , Bipolar Disorder/drug therapy , Brain/immunology , Central Nervous System Stimulants/toxicity , Cytokines/cerebrospinal fluid , Cytokines/immunology , Dextroamphetamine/toxicity , Disease Models, Animal , Frontal Lobe/drug effects , Frontal Lobe/immunology , Hippocampus/drug effects , Hippocampus/immunology , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Hyperkinesis/immunology , Interleukin-10/cerebrospinal fluid , Interleukin-10/immunology , Interleukin-1beta/cerebrospinal fluid , Interleukin-1beta/drug effects , Interleukin-1beta/immunology , Interleukin-4/cerebrospinal fluid , Interleukin-4/immunology , Interleukin-6/cerebrospinal fluid , Interleukin-6/immunology , Lithium Compounds/therapeutic use , Male , Motor Activity/immunology , Neostriatum/drug effects , Neostriatum/immunology , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/immunology
6.
Proc Natl Acad Sci U S A ; 109(31): 12728-33, 2012 Jul 31.
Article in English | MEDLINE | ID: mdl-22802629

ABSTRACT

During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1ß, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1ß concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1ß, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1ß and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1ß, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.


Subject(s)
Arthritis, Rheumatoid/cerebrospinal fluid , Central Nervous System/metabolism , Gene Expression Regulation , Interleukin-1beta/cerebrospinal fluid , Multiple Sclerosis/cerebrospinal fluid , Adult , Animals , Disease Models, Animal , Female , Humans , Interleukin 1 Receptor Antagonist Protein/cerebrospinal fluid , Interleukin-18/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Interleukin-6/cerebrospinal fluid , Mice , Mice, Inbred NOD , Middle Aged , Tumor Necrosis Factor-alpha/cerebrospinal fluid
7.
J Immunol ; 189(9): 4213-9, 2012 Nov 01.
Article in English | MEDLINE | ID: mdl-23087426

ABSTRACT

IL-4 has been extensively studied in the context of its role in immunity. Accumulating evidence indicates, however, that it also plays a critical role in higher functions of the normal brain, such as memory and learning. In this review, we summarize current knowledge of the basic immunology of IL-4, describe how and where this cytokine appears to operate in normal brain function, and propose a hypothesis concerning its potential role in neurological pathologies.


Subject(s)
Interleukin-4/physiology , Learning/physiology , Memory/physiology , Animals , Cognition/physiology , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Interleukin-4/cerebrospinal fluid , Nervous System Diseases/immunology , Nervous System Diseases/metabolism , Nervous System Diseases/pathology , Neurogenesis/immunology
8.
Sex Transm Dis ; 40(10): 808-12, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24275734

ABSTRACT

BACKGROUND: The mechanisms underlying the process of Treponema pallidum clearance from the central nervous system have not yet been established. Considering that neurosyphilis is associated with mild cerebrospinal fluid (CSF) pleocytosis with a lymphocytic predominance, it has been suggested that cells involved in the adaptive immune response may play a role in this process. In the current study, we assessed the cytokine production profile of T-helper cells in the serum and CSF of patients with early syphilis, with and without CSF abnormalities. METHODS: Cerebrospinal fluid and blood samples were collected from 33 patients with secondary and early latent syphilis. Five patients (15%) had a reactive CSF Venereal Disease Research Laboratory test without any accompanying neurological symptoms. According to the Centers of Disease Control and Prevention classification, they were diagnosed with asymptomatic neurosyphilis. Serum and CSF levels of interferon-γ (IFN-γ; Th1-type cytokine), interleukin-4 (IL-4; Th2-type cytokine), and interleukin-17A (IL-17A; Th17-type cytokine) were determined by enzyme-linked immunosorbent assay. RESULTS: Patients with asymptomatic neurosyphilis had significantly higher levels of IL-17A (8-fold) and IFN-γ (7.8-fold) in the CSF compared with patients in the no-neurosyphilis group. Six individuals had CSF pleocytosis but a negative CSF Venereal Disease Research Laboratory test result (presumptive neurosyphilis group). In this group, CSF IFN-γ and CSF IL-17A levels were also significantly elevated when compared with no-neurosyphilis group. There was no correlation between serum and CSF concentrations of IL-17A. However, CSF pleocytosis correlated positively with both CSF IL-17A (r = 0.4, P = 0.01) and IFN-γ (r = 0.42, P = 0.01). CONCLUSIONS: Increased CSF levels of IFN-γ and IL-17A in syphilitic patients with CSF abnormalities suggest that cells of adaptive immunity (probably T-helper cells producing IFN-γ and IL-17) may contribute to the inflammatory response associated with neurosyphilis. In addition, the lack of correlation between serum and CSF IL-17A levels suggests intrathecal production of this cytokine. Further studies are needed to establish the exact nature of the immune response accompanying neurosyphilis and its clinical significance.


Subject(s)
Interferon-gamma/cerebrospinal fluid , Interleukin-17/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Neurosyphilis/cerebrospinal fluid , Treponema pallidum/isolation & purification , Adult , Cerebrospinal Fluid Proteins/cerebrospinal fluid , Humans , Interferon-gamma/blood , Interleukin-17/blood , Interleukin-4/blood , Male , Middle Aged , Neurosyphilis/blood , Neurosyphilis/immunology , Neurosyphilis/pathology
9.
PLoS One ; 18(2): e0279343, 2023.
Article in English | MEDLINE | ID: mdl-36800341

ABSTRACT

OBJECTIVE: Doublecortin (DCX) and glypican-2 (GPC2) are neurodevelopmental proteins involved in the differentiation of neural stem/progenitor cells (NSPCs) to neurons, and are developmentally downregulated in neurons after birth. In this study, we investigated whether the concentrations of DCX and GPC2 in the cerebrospinal fluid (CSF) from human pediatric patients reflect this developmental process or are associated with cerebral damage or inflammatory markers. METHODS: CSF was collected from pediatric patients requiring neurosurgical treatment. The concentrations of DCX, GPC2, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, and TNF-⍺) were measured using immunoassays. RESULTS: From March 2013 until October 2018, 63 CSF samples were collected from 38 pediatric patients (20 females; 17 patients with repeated measurements); the median term born-adjusted age was 3.27 years [Q1: 0.31, Q3: 7.72]. The median concentration of DCX was 329 pg/ml [Q1: 192.5, Q3: 1179.6] and that of GPC2 was 26 pg/ml [Q1: 13.25, Q3: 149.25]. DCX and GPC2 concentrations independently significantly associated with age, and their concentration declined with advancing age, reaching undetectable levels at 0.3 years for DCX, and plateauing at 1.5 years for GPC2. Both DCX and GPC2 associated with hydrocephalus, NSE, IL-1ß, IL-2, IL-8, IL-13. No relationship was found between sex, acute infection, S100B, IL-4, IL-6, IL-10, IFN-γ, TNF-α and DCX or GPC2, respectively. CONCLUSIONS: Concentrations of DCX and GPC2 in the CSF from pediatric patients are developmentally downregulated, with the highest concentrations measured at the earliest adjusted age, and reflect a neurodevelopmental stage rather than a particular disease state.


Subject(s)
Doublecortin Domain Proteins , Glypicans , Child, Preschool , Female , Humans , Infant , Biomarkers/cerebrospinal fluid , Doublecortin Domain Proteins/cerebrospinal fluid , Glypicans/cerebrospinal fluid , Interleukin-10/cerebrospinal fluid , Interleukin-13/cerebrospinal fluid , Interleukin-2/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Interleukin-6/cerebrospinal fluid , Interleukin-8/cerebrospinal fluid , Phosphopyruvate Hydratase/cerebrospinal fluid , Male
10.
Clin Neurol Neurosurg ; 225: 107522, 2023 02.
Article in English | MEDLINE | ID: mdl-36706701

ABSTRACT

OBJECTIVES: Cytokines play a key role in neuroinflammation, which is present in every subset of multiple sclerosis (MS). The aim of the study was to assess levels of selected interleukins and proinflammatory factors in cerebrospinal fluid (CSF) among patients diagnosed with relapsing-remitting multiple sclerosis (RRMS). METHODS: One hundred eighteen patients diagnosed de novo with RRMS were enrolled in the study. We analysed the relationships between selected cytokines' levels depending on the age at diagnosis, time from the first symptoms to diagnosis and presence of MRI lesions. RESULTS: Among the study group the levels of IL-5 and IL-13 increased with the age at the diagnosis of MS. The concentration of IL-10 was lower in group of patients over the age of 35. The levels of IFN-γ, TNF-α, IL-5, IL-10 and IL-15 increased with the longer time from the first symptoms to diagnosis. Positive correlations were found between the levels of IL-2 and IL-12, IL-17, IL-4, IL-1RA as well as IL-1 and IL-4, IL-17. The concentration of IL-5 correlated positively with IL-4, IL-9 and IL-13. The level of IL-10 increased with IL-6 and IL-9 concentrations. A negative correlation was found for IL-10 and IL-4. In turn, between IL-13 and both IL-5 and IL-9, the relationship was positive. The level of IL-2 was significantly higher among patients without gadolinium-enhanced (Gd(+)) MRI lesions. CONCLUSIONS: The results of the study provide new insight into the role of selected molecules in the development of inflammation in MS. It might be crucial in planning the most adequate immunomodulatory therapy.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Cytokines/cerebrospinal fluid , Cytokines/chemistry , Interleukin-10 , Interleukin-13 , Interleukin-17/cerebrospinal fluid , Interleukin-2 , Interleukin-4/cerebrospinal fluid , Interleukin-5 , Interleukin-9 , Interleukins/cerebrospinal fluid , Interleukins/chemistry , Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/diagnosis , Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid , Multiple Sclerosis, Relapsing-Remitting/diagnosis
11.
Viruses ; 13(2)2021 02 22.
Article in English | MEDLINE | ID: mdl-33671821

ABSTRACT

Data on the immune response to West Nile virus (WNV) are limited. We analyzed the antiviral cytokine response in serum and cerebrospinal fluid (CSF) samples of patients with WNV fever and WNV neuroinvasive disease using a multiplex bead-based assay for the simultaneous quantification of 13 human cytokines. The panel included cytokines associated with innate and early pro-inflammatory immune responses (TNF-α/IL-6), Th1 (IL-2/IFN-γ), Th2 (IL-4/IL-5/IL-9/IL-13), Th17 immune response (IL-17A/IL-17F/IL-21/IL-22) and the key anti-inflammatory cytokine IL-10. Elevated levels of IFN-γ were detected in 71.7% of CSF and 22.7% of serum samples (p = 0.003). Expression of IL-2/IL-4/TNF-α and Th1 17 cytokines (IL-17A/IL-17F/IL-21) was detected in the serum but not in the CSF (except one positive CSF sample for IL-17F/IL-4). While IL-6 levels were markedly higher in the CSF compared to serum (CSF median 2036.71, IQR 213.82-6190.50; serum median 24.48, IQR 11.93-49.81; p < 0.001), no difference in the IL-13/IL-9/IL-10/IFN-γ/IL-22 levels in serum/CSF was found. In conclusion, increased concentrations of the key cytokines associated with innate and early acute phase responses (IL-6) and Th1 type immune responses (IFN-γ) were found in the CNS of patients with WNV infection. In contrast, expression of the key T-cell growth factor IL-2, Th17 cytokines, a Th2 cytokine IL-4 and the proinflammatory cytokine TNF-α appear to be concentrated mainly in the periphery.


Subject(s)
Cytokines/cerebrospinal fluid , Meningitis/immunology , Meningoencephalitis/immunology , West Nile Fever/immunology , West Nile virus/immunology , Aged , Cytokines/blood , Cytokines/immunology , Female , Humans , Interleukin-17/blood , Interleukin-17/cerebrospinal fluid , Interleukin-17/immunology , Interleukin-4/blood , Interleukin-4/cerebrospinal fluid , Interleukin-4/immunology , Male , Meningitis/blood , Meningitis/cerebrospinal fluid , Meningitis/virology , Meningoencephalitis/blood , Meningoencephalitis/cerebrospinal fluid , Meningoencephalitis/virology , Middle Aged , Th17 Cells/immunology , West Nile Fever/genetics , West Nile Fever/virology , West Nile virus/genetics , West Nile virus/physiology
12.
J Neurovirol ; 15(5-6): 390-400, 2009 Sep.
Article in English | MEDLINE | ID: mdl-20001608

ABSTRACT

The objective of this study was to evaluate immune cytokine expression in cerebrospinal fluid (CSF) of patients with human immunodeficiency virus-1 (HIV-1)-associated dementia (HAD) using a novel cytokine array assay. HIV-1 induces a condition resembling classical subcortical dementia, known as HAD. The immune mechanisms contributing to HAD have not been elucidated. Cytokine expression in CSF was determined by solid-phase protein array in 33 neurologically asymptomatic HIV-positive male patients and were compared to levels in non-HIV controls and patients with HAD. Neurological examinations and lumbar and venous punctures were conducted in all patients and controls. Interleukin (IL)-1, IL-4, and IL-10, were up-regulated in all treated acquired immunodeficiency syndrome (AIDS) patients independent of neurological status compared to controls. In contrast, interferon gamma (IFN-gamma), IL-1alpha, IL-15, and tumor necrosis factor alpha (TNF-alpha) were highly expressed in patients with HAD compared to undemented HIV-positive patients. These results show that solid-phase protein array can detect immunological changes in patients infected with HIV. Cytokine expression levels differ in different disease stages and in patients on different treatment paradigms. Pending further validation on a larger number of patients, this method may be a useful tool in CSF diagnostics and the longitudinal evaluation of patient with HAD.


Subject(s)
AIDS Dementia Complex/cerebrospinal fluid , AIDS Dementia Complex/immunology , Cytokines/cerebrospinal fluid , HIV-1 , Inflammation Mediators/cerebrospinal fluid , Protein Array Analysis/methods , AIDS Dementia Complex/diagnosis , AIDS Dementia Complex/epidemiology , Adult , Biomarkers/cerebrospinal fluid , Humans , Interferon-gamma/cerebrospinal fluid , Interleukin-10/cerebrospinal fluid , Interleukin-15/cerebrospinal fluid , Interleukin-1alpha/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Male , Middle Aged , Neuropsychological Tests , Protein Array Analysis/standards , Reproducibility of Results , Risk Factors , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , Tumor Necrosis Factor-alpha/cerebrospinal fluid
13.
Cytokine ; 44(1): 149-53, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18722137

ABSTRACT

BACKGROUND: Recently, non-herpetic acute limbic encephalitis (NHALE) was identified as a new subgroup of limbic encephalitis. The immunological pathophysiology of NHALE is still unclear. METHODS: We measured the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in the cerebrospinal fluid (CSF) of 15 patients with NHALE and 13 with herpes simplex encephalitis (HSE) by cytometric bead array or ELISA. RESULTS: The CSF concentrations of IL-6 in patients with NHALE and IFN-gamma, IL-6, IL-10, and sTNFR1 in HSE patients were significantly higher than those of controls (p<0.001, p=0.004, p<0.001, p=0.018, and p<0.001, respectively). There were significant correlations among CSF IL-6, IL-10, and sTNFR1 levels in HSE patients. The CSF concentrations of IFN-gamma and sTNFR1 levels of patients with HSE were significantly higher than those with NHALE (p=0.001 and p=0.002, respectively). CONCLUSIONS: CSF cytokine levels in NHALE were relatively low compared with those in HSE. These results may be related to the favorable prognosis of NHALE.


Subject(s)
Cytokines/cerebrospinal fluid , Encephalitis, Herpes Simplex/cerebrospinal fluid , Limbic Encephalitis/cerebrospinal fluid , Adolescent , Adult , Aged , Child , Cytokines/immunology , Female , Humans , Interferon-gamma/cerebrospinal fluid , Interleukin-10/cerebrospinal fluid , Interleukin-2/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Interleukin-6/cerebrospinal fluid , Limbic Encephalitis/immunology , Limbic Encephalitis/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Receptors, Tumor Necrosis Factor, Type I/cerebrospinal fluid , Temporal Lobe/pathology , Tumor Necrosis Factor-alpha/cerebrospinal fluid
14.
Arch Neurol ; 62(10): 1591-4, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16216944

ABSTRACT

BACKGROUND: In neurodegenerative diseases, increasing attention has been focused on inflammatory mediators such as pro-inflammatory and anti-inflammatory cytokines and their potential influence in the process of neurodegeneration. In prion diseases, much data has been gained on the cell culture and animal disease models level, but only limited information is available on humans affected by Creutzfeldt-Jakob disease (CJD). OBJECTIVE: To obtain data on anti-inflammatory cytokines interleukin 4 and interleukin 10 in the cerebrospinal fluid of patients with CJD, patients with other dementia, and nondemented neurological patients and controls. DESIGN: Cerebrospinal fluid samples were collected from CJD patients and control subjects, and concentrations of the anti-inflammatory cytokines interleukin 4 and interleukin 10 were determined using an enzyme-linked immunosorbent assay. PATIENTS: Cerebrospinal fluid samples from 61 patients were analyzed. The group was composed of patients with CJD (n = 20), patients with other forms of dementia (n = 10), patients with motoneuron disease (n = 6), patients with normal pressure hydrocephalus (n = 5), and control subjects (n = 20). RESULTS: Interleukin 10 levels were significantly elevated in the cerebrospinal fluid of CJD patients (median, 9.8 pg/mL). The elevation was significant to other dementia (median, 7.9 pg/mL, P<.05), motoneuron disease (median, 7.9 pg/mL, P<.05), normal pressure hydrocephalus (median, 7.0 pg/mL, P<.05), and controls (median, 1.3 pg/mL, P<.001). Levels of interleukin 4 were significantly elevated in cerebrospinal fluid of patients with CJD (median, 26.4 pg/mL) compared with control subjects (median, 6.2 pg/mL, P<.001) and patients with a motoneuron disease (median, 10.5 pg/mL, P<.001) CONCLUSIONS: Elevated levels of the anti-inflammatory cytokines interleukin 4 and interleukin 10 in cerebrospinal fluid of patients with CJD are new findings. The data of the present study provide a clue toward the possible role of cytokines as immunological modifiers in the neurodegenerative process of CJD.


Subject(s)
Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Interleukin-10/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Adult , Aged , Dementia/cerebrospinal fluid , Enzyme-Linked Immunosorbent Assay , Female , Humans , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Male , Middle Aged , Motor Neuron Disease/cerebrospinal fluid
15.
Neurology ; 50(1): 217-23, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9443483

ABSTRACT

Acute unilateral monosymptomatic optic neuritis (ON) is a common first manifestation of MS if associated with multiple MS-like lesions on brain MRI and oligoclonal IgG bands (OB) in the CSF, whereas ON patients lacking these laboratory abnormalities are considered to have a good prognosis regarding future MS development. Several cytokines involved in immune regulation are upregulated in blood and even more noticeable in CSF in MS. To study a possible relation between cytokine profiles and presence versus absence of MS-like brain MRI lesions and CSF OB, we used in situ hybridization to examine mRNA expression of the proinflammatory interleukin-12 (IL-12), interferon-gamma, and tumor necrosis factor-alpha and the immune response downregulating IL-10, transforming growth factor-beta, and IL-4 in blood and CSF mononuclear cells (MNC) from 59 patients with untreated ON. There were no differences in numbers of MNC in blood or CSF expressing any of the cytokines under study, upon subgrouping the ON patients regarding presence (n = 31) versus absence (n = 28) of MRI lesions, presence (n = 45) versus absence (n = 14) of OB, or duration after onset of ON (<1 month, n = 30, versus >1 month, n = 29). Similarly, no differences were observed for numbers of myelin basic protein-reactive blood MNC expressing any of these cytokines after subgrouping according to these variables. Our findings suggest that the cytokine profile, as examined in this study, is less useful to determine the risk of future development of clinically definite MS in ON patients or as indicator for therapeutic interventions in ON. An upregulation of both pro- and anti-inflammatory cytokines in ON patients seems to be more related to the CNS disease per se, whether limited to the optic nerve or not, than to the inflammatory process characteristic for MS.


Subject(s)
Cytokines/genetics , Optic Neuritis/diagnosis , Optic Neuritis/immunology , Adolescent , Adult , Cytokines/cerebrospinal fluid , Female , Gene Expression/drug effects , Gene Expression/immunology , Humans , In Situ Hybridization , Interferon-gamma/cerebrospinal fluid , Interferon-gamma/genetics , Interleukin-10/cerebrospinal fluid , Interleukin-10/genetics , Interleukin-12/cerebrospinal fluid , Interleukin-12/genetics , Interleukin-4/cerebrospinal fluid , Interleukin-4/genetics , Leukocytes, Mononuclear/chemistry , Leukocytes, Mononuclear/immunology , Magnetic Resonance Imaging , Male , Middle Aged , Myelin Basic Protein/pharmacology , Oligonucleotide Probes , Optic Neuritis/genetics , RNA, Messenger/analysis , Transforming Growth Factor beta/cerebrospinal fluid , Transforming Growth Factor beta/genetics , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Tumor Necrosis Factor-alpha/genetics
16.
J Neuroimmunol ; 38(1-2): 105-13, 1992 May.
Article in English | MEDLINE | ID: mdl-1374422

ABSTRACT

T cell sensitization to two myelin components, myelin basic protein (MBP) and myelin proteolipid protein (PLP), may be important to the pathogenesis of multiple sclerosis (MS). Using the limiting dilution assay, we demonstrated that the blood of MS patients had an increased frequency of MBP-reactive T cells compared with normal subjects and patients with other neurological diseases (OND) and rheumatoid arthritis. There was no difference in T cell frequency to a synthetic peptide, PLP139-151, or Herpes simplex virus. Within cerebrospinal fluid (CSF), 37% of IL-2/IL-4-reactive T cell isolates from MS patients responded either to MBP or PLP139-151 while only 5% of similar isolates from OND patients responded to these myelin antigens. The mean relative frequency of MBP-reactive T cells within CSF from MS patients was significantly higher than that of OND patients (22 x 10(-5) cells versus 1 x 10(-5) cells) and was similar to that of MBP reactive T cells within the central nervous system of rats with experimental autoimmune encephalomyelitis. These results lend new support to the hypothesis that myelin-reactive T cells mediate disease in MS.


Subject(s)
Blood Cells/immunology , Cerebrospinal Fluid/immunology , Multiple Sclerosis/immunology , Myelin Basic Protein/immunology , Myelin Proteins/immunology , T-Lymphocytes/immunology , Amino Acid Sequence , Amino Acids/chemistry , Amino Acids/pharmacology , Cerebrospinal Fluid/cytology , Humans , Indicator Dilution Techniques , Interleukin-2/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Leukocyte Count , Molecular Sequence Data , Multiple Sclerosis/blood , Multiple Sclerosis/cerebrospinal fluid , Myelin Proteolipid Protein
17.
J Neuroimmunol ; 95(1-2): 185-9, 1999 Mar 01.
Article in English | MEDLINE | ID: mdl-10229129

ABSTRACT

The levels of interleukin-12 (IL-12) (p70 heterodimer), total IL-12 (p70 heterodimer plus p40 chains), interferon-gamma (IFN-gamma) as Th1 cytokine, and those of interleukin-4 (IL-4) and interleukin-10 (IL-10) as Th2 cytokines in sera and cerebrospinal fluid (CSF) from 22 patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) were compared with those of 22 patients with other neurological diseases (OND), including nine anti-HTLV-I-seropositive carriers. Both serum IL-12 (total and p70 heterodimer) and CSF IFN-gamma, measured by the enzyme-linked immunosorbent assay (ELISA), were significantly elevated in patients with HAM as compared to the patients with OND, including the anti-HTLV-I-seropositive carriers. Serum IFN-gamma also was significantly elevated in the HAM patients as compared to the controls. There was no significant difference in the CSF levels of IL-12 (total and p70 heterodimer) between the HAM patients and controls, whereas, for the Th2 cytokines IL-4 was detected in the CSF of four anti-HTLV-I-seropositive carriers of the 13 control patients but not in any of the patients with HAM. No significant difference was found in the serum levels of IL-4 and IL-10, nor in the CSF levels of IL-10 in the patients with HAM and in the controls. These findings indicate that in patients with HAM, the immunological balance of helper T lymphocytes between Th1 and Th2 is toward Th1 in the periphery and that Th1-mediated immunological status in the central nervous system is involved in the pathogenesis of HAM.


Subject(s)
Interferon-gamma/blood , Interleukin-12/blood , Paraparesis, Tropical Spastic/immunology , Paraparesis, Tropical Spastic/virology , Adult , Aged , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interferon-gamma/cerebrospinal fluid , Interleukin-10/blood , Interleukin-10/cerebrospinal fluid , Interleukin-12/cerebrospinal fluid , Interleukin-4/blood , Interleukin-4/cerebrospinal fluid , Male , Middle Aged , Th1 Cells/immunology , Th1 Cells/virology , Th2 Cells/immunology , Th2 Cells/virology
18.
Intern Med ; 38(9): 717-21, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10480302

ABSTRACT

OBJECT: Previously, we reported the efficacy of pentoxifylline (PTX) treatment in human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM). Here, we clarify the relationship between the clinical efficacy of PTX treatment and elevation of T helper type 2 (Th2) cytokine levels in HAM patients. PATIENTS AND METHODS: PTX (300 mg) was administered daily by the oral route to 12 HAM patients for 4 weeks. We assessed the relationship between the changes in neurological status (motor disability scores, the degree of spasticity on neurological examination, and the time required to walk 10 m) and the changes in serum and cerebrospinal fluid (CSF) levels of interferon-gamma (IFN-gamma) as a Th1 cytokine and interleukin-4 and -10 (IL-4 and -10) as Th2 cytokines measured by an EASIA (enzyme-amplified sensitivity immunoassay) kit. RESULTS: PTX treatment induced incremental increases in the levels of IL-4 and IL-10 in both sera and CSF of 6 HAM patients. Clinical improvement was associated with this elevation in IL-4 and IL-10. PTX treatment also induced a decrease in IFN-gamma levels in the sera of 6 HAM patients, but this was not correlated with clinical improvement. CONCLUSION: These results suggest that the correction of the immunological imbalance in Th1 to Th2 cytokine responses, with upregulation of IL-4 and IL-10, may account for the clinical improvement in HAM patients treated with PTX.


Subject(s)
Interleukin-10/blood , Interleukin-4/blood , Paraparesis, Tropical Spastic/blood , Paraparesis, Tropical Spastic/drug therapy , Pentoxifylline/therapeutic use , Phosphodiesterase Inhibitors/therapeutic use , Th2 Cells/immunology , Administration, Oral , Adult , Aged , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interferon-gamma/blood , Interferon-gamma/cerebrospinal fluid , Interleukin-10/cerebrospinal fluid , Interleukin-4/cerebrospinal fluid , Male , Middle Aged , Paraparesis, Tropical Spastic/cerebrospinal fluid , Pentoxifylline/administration & dosage , Phosphodiesterase Inhibitors/administration & dosage , Th1 Cells/immunology , Treatment Outcome
19.
Vojnosanit Pregl ; 69(2): 151-6, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22500369

ABSTRACT

BACKGROUND/AIM: Multiple sclerosis (MS) is an immune-mediated central nervous system disease characterized by inflammation, demyelination and axonal degeneration. Cytokines are proven mediators of immunological process in MS. The aim of this study was to investigate whether there is a difference in the production of the tumor necrosis factor alpha (TNF-alpha) and interleukin-4 (IL-4) in cerebrospinal fluid (CSF) and plasma in the MS patients and the controls (other neurological non-inflammatory diseases) and to determine a possible difference in these cytokines in plasma and CSF in different clinical forms of MS. METHODS: This study involved 60 consecutive MS patients--48 patients with relapsing-remitting MS (RRMS) and 12 patients with secondary progressive MS (SPMS). The control group consisted of 20, age and sex matched, non-immunological, neurological patients. According to the clinical presentation of MS at the time of this investigation, 34 (56.7%) patients had relapse (RRMS), 14 (23.3%) were in remission (RRMS), while the rest of the patients, 12 (20.0%), were SPMS. TNF-alpha and IL-4 concentrations were measured in the same time in CSF and plasma in the MS patients and the controls. Extended disability status score (EDSS), albumin ratio and IgG index were determined in all MS patients. RESULTS: The MS patients had significantly higher CSF and plasma levels of TNF-alpha than the controls (p < 0.001 for both samples). IL-4 CSF levels were significantly lower in the MS patients than in the controls (p < 0.001), however plasma levels were similar. The patients in relapse (RRMS) and with progressive disease (SPMS) had higher concentrations of CSF TNF-alpha levels than the patients in remission (p < 0.001). IL-4 CSF levels in relapse (RRMS) and SPMS groups were lower than in the patients in remission. The patients in remission had an unmeasurable plasma TNF-alpha level and the patients with SPMS had significantly lower IL-4 levels in plasma than the patients in relapse and remission (p < 0.001). The only significant correlation between cytokine level with either EDSS, or albumin ratio, or IgG index, was found between CSF TNF-alpha levels and albumin ratio in the patients with relapse (R square = 0.431, p < 0.001). CONCLUSION: According to the obtained data MS relapse was characterized by high concentrations of TNF-alpha in CSF and plasma and low concentrations of IL-4 in CSF. Remission was characterized by high concentrations of IL-4 and low concentrations of TNF-alpha both in CSF and plasma. SPMS was characterized with lower concentrations of TNF-alpha and IL-4 compared to relapse, both in CSF and plasma.


Subject(s)
Interleukin-4/cerebrospinal fluid , Multiple Sclerosis, Chronic Progressive/cerebrospinal fluid , Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Adult , Female , Humans , Interleukin-4/blood , Male , Multiple Sclerosis, Chronic Progressive/blood , Multiple Sclerosis, Relapsing-Remitting/blood , Tumor Necrosis Factor-alpha/blood
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