Characterization of inflammatory cytokine profiles in cerebrospinal fluid of hand, foot, and mouth disease children with enterovirus 71-related encephalitis in Hangzhou, Zhejiang, China.

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.

Cerebrospinal Fluid Cytokine Expression Profile in Multiple Sclerosis and Chronic Inflammatory Demyelinating Polyneuropathy.

BACKGROUND: Cerebrospinal fluid (CSF) analysis in patients with particular neurologic disorders is a powerful tool to evaluate specific central nervous system inflammatory markers for diagnostic needs, because CSF represents the specific immune micro-environment to the central nervous system. METHODS: CSF samples from 49 patients with multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and non-inflammatory neurologic disorders (NIND) as controls were submitted to protein expression profiles of 47 inflammatory biomarkers by multiplex Luminex bead assay to investigate possible differences in the inflammatory process for MS and CIDP. RESULTS: Our results showed differences in CSF cytokine levels in MS and CIDP; in particular, IL12 (p40) was significantly highly expressed in MS in comparison with CIDP and NIND, while SDF-1α and SCGF-ß were significantly highly expressed in CIDP cohort when compared to MS and NIND. IL-9, IL-13, and IL-17 had higher expression levels in NIND if compared with the other groups. CONCLUSIONS: Our study showed that, despite some common pathogenic mechanisms, central and peripheral nervous system demyelinating diseases, such as MS and CIDP, differ in some specific inflammatory soluble proteins in CSF, underlining differences in the immune response involved in those autoimmune diseases.

Increased activity of the complement system in cerebrospinal fluid of the patients with Non-HIV Cryptococcal meningitis.

BACKGROUNDS: Cryptococcal meningitis (CM) has been known to lead to significant morbidity and mortality. The relative contribution of the complement system in protection and pathogenesis during CM remains largely unknown. The purpose of this study was to evaluate the baseline complement component profiles in human cerebrospinal fluid (CSF) and plasma from non-HIV patients with CM, and therefore to provide insights of possible roles of the complement system in CM. METHODS: CSF and blood samples from forty two CM patients not infected with HIV and thirteen non-CM control patients (Ctrl) were retrospectively selected and evaluated from the patients admitted to the hospital with a suspected diagnosis of CM. CSF and blood samples were collected at the admission. Enzyme-linked immunosorbent assay (ELISA) for complement components, cytokine IL-12 and western blot for C3 activation were performed on CSF and plasma samples. The levels of complement C1q, factor B (FB), mannose binding lectin (MBL), C2, C3, C4, C5, C4 binding protein (C4BP), Factor I (FI), Factor H (FH), sC5b-9 in CSF and plasma samples were compared. Pearson's correlation coefficients were calculated on variables between complement components and the levels of total protein in the CSF samples. RESULTS: Our data demonstrated that the CSF levels of complement components of C1q, FB, MBL as well as complement pathway factors sC5b-9 and complement regulator FH were all elevated in patients with CM as compared to the controls, CSF C3 breakdown products iC3b were found in both CSF and plasma samples of the CM patients. A positive correlation was found between the levels of CSF protein and MBL, C1q or FB. CONCLUSIONS: The activity of the complement system in CSF was increased in non-HIV patients with CM. C1q, MBL and FB are the important participants in the complement activation in CM. The relative contribution of each of the specific complement pathways and complement cascades in protection and inflammation resolution against CM warrant further investigation.

Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda.

In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/µL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid ß42. Individuals with CD4 351-500 cells/µL (N = 40) had significantly higher CSF levels of interleukin (IL)-1ß, amyloid ß42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.

Divergent cerebrospinal fluid cytokine network induced by non-viral and different viral infections on the central nervous system.

BACKGROUND: Meningoencephalitis is one of the most common disorders of the central nervous system (CNS) worldwide. Viral meningoencephalitis differs from bacterial meningitis in several aspects. In some developing countries, bacterial meningitis has appropriate clinical management and chemotherapy is available. Virus-associated and virus not detected meningoencephalitis are treatable, however, they may cause death in a few cases. The knowledge of how mediators of inflammation can induce disease would contribute for the design of affordable therapeutic strategies, as well as to the diagnosis of virus not detected and viral meningoencephalitis. Cytokine-induced inflammation to CNS requires several factors that are not fully understood yet. METHODS: Considering this, several cytokines were measured in the cerebrospinal fluid (CSF) of patients with undiagnosed and viral meningoencephalitis, and these were correlated with cellularity in the CSF. RESULTS: The results demonstrate that an altered biochemical profile alongside increased cellularity in the cerebrospinal fluid is a feature of patients with meningoencephalitis that are not associated with the detection of virus in the CNS (P < 0.05). Moreover, HIV-positive patients (n = 10) that evolve with meningoencephalitis display a distinct biochemical/cytological profile (P < 0.05) in the cerebrospinal fluid. Meningoencephalitis brings about a prominent intrathecal cytokine storm regardless of the detection of virus as presumable etiological agent. In the case of Enterovirus infection (n = 13), meningoencephalitis elicits robust intrathecal pro-inflammatory cytokine pattern and elevated cellularity when compared to herpesvirus (n = 15) and Arbovirus (n = 5) viral infections (P < 0.05). CONCLUSION: Differences in the cytokine profile of the CSF may be unique if distinct, viral or presumably non-viral pathways initially trigger the inflammatory response in the CNS.

Increased leakage of brain antigens after traumatic brain injury and effect of immune tolerance induced by cells on traumatic brain injury.

BACKGROUND: Although traumatic brain injury can lead to opening the blood-brain barrier and leaking of blood substances (including water) into brain tissue, few studies of brain antigens leaking into the blood and the pathways have been reported. Brain antigens result in damage to brain tissues by stimulating the immune system to produce anti-brain antibodies, but no treatment has been reported to reduce the production of anti-brain antibodies and protect the brain tissue. The aim of the study is to confirm the relationship between immune injury and arachnoid granulations following traumatic brain injury, and provide some new methods to inhibit the immune injury. METHODS: In part one, methylene blue was injected into the rabbits' cisterna magna after traumatic brain injury, and concentrations of methylene blue and tumor necrosis factor (TNF)-α in blood were detected to determine the permeability of arachnoid granulations. In part two, umbilical cord mesenchymal stem cells and immature dendritic cells were injected into veins, and concentrations of interleukin 1 (IL-1), IL-10, interferon (IFN)-γ, transforming growth factor (TGF)-ß, anti-brain antibodies (ABAb), and IL-12 were measured by ELISA on days 1, 3, 7, 14 and 21 after injury, and the numbers of leukocytes in the blood were counted. Twenty-one days after injury, expression of glutamate in brain tissue was determined by immunohistochemical staining, and neuronal degeneration was detected by H&E staining. RESULTS: In part one, blood concentrations of methylene blue and TNF-α in the traumatic brain injury group were higher than in the control group (P < 0.05). Concentrations of methylene blue and TNF-α in the trauma cerebrospinal fluid (CSF) injected group were higher than in the control cerebrospinal fluid injected group (P < 0.05). In part two, concentrations of IL-1, IFN-γ, ABAb, IL-12, expression of glutamate (Glu), neuronal degeneration and number of peripheral blood leukocytes were lower in the group with cell treatment compared to the control group. IL-10 and TGF-ß were elevated compared to the control group. CONCLUSIONS: Traumatic brain injury can lead to stronger arachnoid granulations (AGs) permeability; umbilical cord mesenchymal stem cells and immature dendritic cells can induce immune tolerance and reduce inflammation and anti-brain antibodies to protect the brain tissue.

Cytokine and adhesion molecule expression evolves between the neutrophilic and lymphocytic phases of viral meningitis.

Viral meningitis is characterized by cerebrospinal fluid (CSF) lymphocyte pleocytosis, although neutrophils may predominate in the early phase. The T helper 1 (Th1)/Th2 cytokine balance and expression of adhesion molecules seem to be involved in the CSF chemotaxis. We aimed to determine expression of cytokines and adhesion molecules in enteroviral meningitis. We investigated the serum and CSF levels of adhesion molecules (E-selectin, L-selectin, vascular cell adhesion molecule-1 [VCAM-1], and intracellular adhesion molecule-1 [ICAM-1]) and cytokines (interleukin-12 [IL-12] and IL-4) in 105 children during an outbreak of enteroviral meningitis. Diagnosis was confirmed with positive polymerase chain reaction (PCR) and/or serology for echovirus or Coxsackie virus, and matched with control subjects for clinical features but with negative PCR and/or serology. Apart from VCAM-1, the CSF levels of all investigated inflammatory molecules were significantly increased. In serum, sL-selectin and ICAM-1 levels were significantly higher than control subjects. Serum and CSF L-selectin, serum VCAM-1, and CSF IL-12 were all observed to be expressed in significantly higher levels in the neutrophil-dominant subgroup (72% had duration of symptoms <24 h) than in the lymphocyte-dominant group (87.5% had duration of symptoms >24 h). Serum and CSF ICAM-1 was found at significantly higher levels in the latter group. Evolving expression of adhesion molecules and cytokines indicates a shift from Th1 to Th2 immune responses as infection progresses.

Interleukin-15 and interleukin-12 are elevated in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

BACKGROUND: There is evidence that immunological factors may be involved in pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). Interleukin (IL)-15 and IL-12 are proinflammatory cytokines produced by activated blood and glial cells. They promote T cell differentiation and proliferation. PATIENTS AND METHODS: We measured by ELISA serum and cerebrospinal fluid (CSF) levels of IL-15 and IL-12 in 21 patients with ALS and 19 patients with other noninflammatory neurological disorders (NIND) studied as a control group. IL-15 and IL-12 serum and CSF levels were also correlated with duration of the disease, the disability level determined using the revised ALS Functional Rating Scale and the clinical subtype of the disease onset in patients with ALS. RESULTS: IL-15 and IL-12 serum levels were higher in patients with ALS as compared with patients with NIND (p = 0.014 and p = 0.011, respectively). IL-15 and IL-12 CSF levels were also increased in patients with ALS (p = 0.011 and p = 0.005, respectively). IL-15 and IL-12 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients. CONCLUSIONS: Our findings suggest that these molecules may be involved in the pathogenic mechanisms acting as potential markers of immune activation in ALS.

Cerebrospinal fluid levels of interleukin-6 and interleukin-12 in children with meningitis.

PURPOSE: Certain cytokines play important roles in the pathophysiology of meningitis. The main purpose of this study was to investigate if the levels of interleukin-6 (IL-6) and interleukin-12 (IL-12) in cerebrospinal fluid (CSF) could be diagnostic predictors of bacterial meningitis in children. METHODS: CSF was obtained from 95 patients suspected with meningitis. These cases were classified to the bacterial meningitis (n = 12), aseptic meningitis (n = 41), and nonmeningitis (n = 42) groups. The levels of IL-6 and IL-12 in CSF were measured using the enzyme-linked immmunosorbent assays test. RESULTS: The CSF IL-6 levels in the bacterial meningitis group (45.2 +/- 50.0 pg/ml) were significantly higher than those in the aseptic meningitis group (12.9 +/- 10.2 pg/ml) and the nonmeningitis group (6.5 +/- 7.8 pg/ml; p < 0.05). The CSF IL-12 levels in the bacterial meningitis group (69.8 +/- 67.1 pg/ml) were significantly higher than those in the aseptic meningitis group (22.9 +/- 10.8 pg/ml) and the nonmeningitis group (15.3 +/- 11.2 pg/ml; p < 0.05). With regard to diagnosis, the measurement of CSF IL-6 and IL-12 levels showed sensitivities of 96% and 96%, respectively, and specificities of 51% and 75%, respectively. CONCLUSION: It is suggested that the CSF IL-6 and IL-12 levels are useful markers for distinguishing bacterial meningitis from aseptic meningitis.

[Concentrations of pro-inflammatory cytokines IFN-gamma, IL-6, IL-12 and IL-15 in serum and cerebrospinal fluid in patients with neuroborreliosis undergoing antibiotic treatment]. / Zmiany stezenia wybranych cytokin prozapalnych IFN-gamma, IL-6, IL-12 i IL-15 w surowicy oraz plynie mózgowo-rdzeniowym pod wplywem antybiotykoterapii u chorych na neuroborelioze.

UNLABELLED: Pathogenesis of Lyme disease, including neuroborreliosis, remains unclear. However, pro-inflammatory cytokines seem to be involved and might be used to monitor the course of the disease. It has been also shown that B. burgdorferi protects itself from elimination by modulating function of the host's immune system. THE AIM OF THIS STUDY: The purpose of this study was to evaluate the serum and cerebrospinal fluid (CSF) concentrations of selected cytokines in patients with neuroborreliosis and their change during antibiotic treatment. MATERIAL AND METHODS: The group of 25 patients was examined, all undergoing antibiotic therapy due to meningitis caused by Borrelia burgdorferi infection. The group included 10 (40%) females and 15 (60%) males in the mean age x = 42,3 years. The control group for serum measurements consisted of 25 healthy individuals (mean age x =43, 1) while control group for CSF study included 10 patients (aged x = 53,5 years) from whom CSF with normal parameters was taken during diagnostic procedures neurosurgical. We examined serum and CSF before and after antibiotics for concentrations of interferon-gamma (INF-gamma), interleukin-6 (IL-6), interleukin-12 (IL-12) and interleukin-15 (IL-15). RESULTS: In the first examination the significant increase of IFN-gamma, IL-6, IL-2, IL-15 serum and CSF concentration was detected in comparison to control group. After 4-weeks antibiotic treatment the concentrations of studied cytokines decreased significantly in serum as well as in CSF but remained increased in comparison with controls. CONCLUSIONS: Although antibiotic treatment leads to withdrawal of clinical symptoms of neuroborreliosis and normalization of CSF general parameters, pro-inflammatory cytokines' concentrations in serum and CSF remain elevated. It may be explained by the persistence of inflammatory conditions, perhaps related to surviving of a fraction of Borrelia burgdorferi spirochetes within CNS tissue. This phenomenon might lead to development of chronic CNS lesions.

Interleukin-12 is reduced in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia.

UNLABELLED: Interleukin-12 is a heterodimeric cytokine produced by activated blood monocytes, macrophages and glial cells. It enhances differentiation and proliferation of T cells and increases production of proinflammatory cytokines, such as Interferon-gamma and Tumor Necrosis Factor-alpha. There is little information about the involvement of IL-12 in the pathophysiology of Alzheimer's disease (AD) and other tauopathies. OBJECTIVES: The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with AD and frontotemporal dementia (FTD). PATIENTS AND METHODS: We measured by immunoassay cerebrospinal fluid (CSF) IL-12 levels in 19 patients with AD and 7 patients with FTD in comparison with CSF IL-12 levels in 30 patients with non-inflammatory neurological diseases served as neurological control patients (NCTRL). IL-12 levels were correlated with age, age of disease onset, disease duration, MMSE score, and rate of dementia progression. Abeta42 and Total tau (tau(T)) levels in CSF were also measured. RESULTS: Patients with AD had significantly lower CSF IL-12 levels compared with NCTRL patients (p<0.001). Patients with FTD had also lower CSF IL-12 levels compared with NCTRL patients (p<0.05). Age, sex, disease duration and MMSE score did not affect IL-12 levels in any of the groups. In AD a significant positive correlation was noted between IL-12 levels and tau(T) levels (Rs=0.46, p=0.048). CONCLUSIONS: Our findings may suggest a reduced inflammatory reaction during the course of AD and FTD. A neurotrophic role of IL-12 and other proinflammatory cytokines cannot be excluded.

Increased intrathecal TGF-beta1, but not IL-12, IFN-gamma and IL-10 levels in Alzheimer's disease patients.

An inflammatory response has been hypothesised to be involved in the pathogenesis of primary dementias, above all Alzheimer's disease (AD). This study was aimed at evaluating interleukin (IL)-12 and a panel of related cytokine levels in paired CSF and sera of demented patients. IL-12 (p70 heterodimer and total IL-12 p40 chain), interferon (IFN)-gamma, IL-10 and transforming growth factor (TGF)-beta1 levels were measured in 30 patients with probable Alzheimer's disease (PrAD), 57 patients with other dementing disorders, including probable vascular dementia (PrVD), Parkinson's disease (PD) and normal pressure hydrocephalus (NPH), and 25 cognitively normal control subjects. In the presence of unchanged concentrations of IL-12, IFN-gamma and IL-10, the mean CSF level of TGF-beta1 and the correspondent TGF-beta1 index, but not the serum level, were significantly increased in PrAD compared to controls and PrVD, whereas no difference was found vs. NPH and PD. Our results support the pathophysiological role of TGF-beta1 system in AD.

The interleukin-10 levels as a potential indicator of positive response to interferon beta treatment of multiple sclerosis patients.

OBJECTIVES: Only a part of MS patients treated with interferon beta (IFN) respond positively to the applied treatment and to date no parameter predicting the response to treatment has been found. The aim of the study was to determine whether the levels of interleukin-10 and -12 (IL-10 and IL-12) might be the parameters enabling us to distinguish those patients who would best respond to therapy before the IFN treatment. PATIENTS AND METHODS: The study included 29 patients with clinically definite relapsing-remitting MS treated with IFN beta. In all of them the levels of IL-10 and IL-12 in blood serum and cerebrospinal fluid were determined before treatment using ELISA method. After the 2-year therapy the patients responding and nonresponding to IFN therapy were distinguished on the basis of clinical parameters. RESULTS: In the patients responding positively to IFN treatment the level of IL-10 in blood serum before treatment was found to be significantly lower (p<0.05) and distinctively differentiated responders from nonresponders. The IL-12 levels were similar both in cerebrospinal fluid and serum and no significant differences between responders and nonresponders were found. CONCLUSION: Our observations suggest that IL-10 level may be a useful parameter to identify the patients potentially responding to IFN therapy.

Elevated interleukin-12 and CXCL10 in subacute sclerosing panencephalitis.

Immunosuppression associated with measles virus (MV) can be demonstrated by cytokine production failure in subacute sclerosing panencephalitis (SSPE) and may have implications on the pathogenesis of the disease. Cytokines (IL-12, IL-10, IL-4, IL-17, IL-18, IFN-alpha, IFN-gamma) and chemokines (CXCL8, CXCL10, CCL2 and CCL5) were measured in the cerebrospinal fluid (CSF) and serum samples from 60 patients with SSPE, 36 patients with infectious and/or inflammatory (IN) and 28 with other non-inflammatory (NIN) neurological diseases by ELISA. IL-12 p70+p40 was elevated in CSF and sera of SSPE when compared to the NIN group. However, the CSF levels of IL-12 p70 alone were not increased, indicating an increase of p40. The CSF of SSPE patients also showed relatively higher levels of IL-10 than that of the NIN group. CXCL10 levels in CSF were significantly higher in SSPE, whereas CXCL8 was increased in sera compared to NIN. No difference was detected in IFN-gamma, IFN-alpha, IL-17, IL-18, IL-4 or CCL2 and CCL5 levels. These results demonstrate that immune response against MV in SSPE may be impaired, although some T cell/Th1 inducing stimulations are present.

[Interleukin 12 measurement in the cerebrospinal fluid of infants with purulent meningitis].

We measured IL-12 concentrations in the CSF of patients with purulent meningitis. Twenty-three infants who were admitted between 1997 and 2003 and diagnosed as having purulent meningitis were included in this study. All patients in this study were admitted by the 3rd day of illness. After admission, appropriate antibiotics were administered to all infants. Two infants died and two other infants developed cerebral palsy and mental retardation (adverse outcome group). None of the other patients showed any neurologic abnormalities at discharge (good outcome group). As a control group, 16 infants who were diagnosed with diseases other than purulent meningitis were also investigated. The CSF IL-12 p40 concentrations in meningitis infants on admission (median [range], 1,890 [< 15-7,770] pg/ml) were significantly higher compared with those in the control group (p < 0.001). Among infants with meningitis, there were no significant differences on admission between patients with adverse outcome group and those with good outcome group. Consecutive measurements were performed in 17 infants with meningitis including the 2 infants with adverse outcome group. The concentration in the infants with adverse outcome group seemed to decrease more gradually than that in those with good outcome group. IL-12 induces production of interferon-gamma, which enhances the function of polymorphonuclear leukocytes. IL-12 may contribute to local host defenses in the subarachnoid space.

Interleukin-12 and interferon-gamma are not detectable in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

The cause of sporadic amyotrophic lateral sclerosis (SALS) is unknown. We investigated the immune-mediated inflammatory hypothesis of SALS by assaying interleukin-12 (IL-12), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) in the cerebrospinal fluid (CSF) of patients with SALS. These cytokines were measured in the CSF from patients with SALS (n=11), patients with immune-mediated inflammatory central nervous system or nerve root disorders (n=12), and patients with other neurological diseases (n=15) by high sensitivity sandwich enzyme linked immunosorbent assay (ELISA). All samples were below the assay detection limits of 0.5 pg/ml for IL-12 and 8 pg/ml for IFN-gamma. There was no difference between the groups in the mean concentration of IL-6. There is no evidence in cerebrospinal fluid for induction of a T(H)1 immune response in SALS.

Cytokines and chemokines in neuro-Behçet's disease compared to multiple sclerosis and other neurological diseases.

Cytokines and chemokines in cerebrospinal fluid (CSF) can have implications on the pathogenesis of neuro-Behçet's disease (NB). CSF and serum samples from 33 patients with NB, 25 with multiple sclerosis (MS), 20 patients with infectious and/or inflammatory neurological diseases (IN) and 14 with other noninflammatory neurological diseases (NIN) were investigated by ELISA. In the CSF, CXCL10 levels were significantly higher in NB and IN than NIN and MS, whereas CXCL8 was increased in NB compared to NIN. CCL2 levels in MS CSF and sera were lower, whereas CXCL8 in MS sera was higher than the other groups. IL-12 was elevated in CSF of IN compared to NB and NIN and also in the CSF of MS compared to NIN. No difference was detected for IL-10 and IL-17. These results reflect that NB has a mediator pattern in resemblance with non-specific inflammations such as neuro-infections compared to autoimmune disorders such as multiple sclerosis, suggesting that a currently unknown infection might be the trigger of a vasculitic process in the central nervous system (CNS).

Increased expression of the Th1-inducing cytokines interleukin-12 and interleukin-18 in cerebrospinal fluid but not in sera from patients with Lyme neuroborreliosis.

Lyme neuroborreliosis is a complex disease with different clinical outcomes and where immunopathological mechanisms are probably involved. In this study, sera and cerebrospinal fluid (CSF) from 21 neuroborreliosis patients and 26 control patients were analyzed for the Th1-inducing cytokines, interleukin (IL)-12 and IL-18, and the Th2 associated, soluble CD30 (sCD30) by ELISA. The results showed an increased number of neuroborreliosis patients expressing IL-12 (p<0.05) and IL-18 (p<0.05) in the CSF when compared with the controls, but no indication of increased levels in the sera. Nor were there any differences regarding levels of sCD30 in the sera or the CSF, indicating a local Th1-generating milieu in the target organ of neuroborreliosis.

IL-12/IL-12R system in multiple sclerosis.

IL-12/IL-12 receptor (IL-12R) system orchestrates the Th1 pathway of the immune system by maintaining one of the major bridges between innate and adaptive immune responses. Here, we studied both sides of this system in patients with multiple sclerosis (MS) and in controls. MS patients displayed elevated IL-12Rbeta1 and IL-12Rbeta2 expression on PHA-activated T cells compared to healthy subjects. Higher percentages of IL-12Rbeta1 and IL-12Rbeta2 positive T cells in cerebrospinal fluid (CSF) compared to blood were observed both in MS and other neurological diseases (OND). In contrast, numbers of IL-12 secreting blood mononuclear cells (MNC) were similar in MS and controls. The functional importance of high IL-12Rbeta2 in MS was underlined by the finding that IL-12 stimulated IFN-gamma production and proliferation of PHA-activated T cells correlated with levels of IL-12Rbeta2 expression. Our data indicates a dysregulation of the IL-12/IL-12R system in MS. It is suggested that even in the absence of increased IL-12 levels, the net effect of IL-12 might be augmented in MS by elevated expression of its receptor.

Interleukin-12 is detectable in sera of patients with multiple sclerosis - association with chronic progressive disease course?

Multiple sclerosis (MS) is widely accepted as a systemic T- cell-mediated autoimmune disease with a T-helper type-1 (TH-1) profile of cytokine production. We addressed the question whether interleukin-12 (IL-12), as a central mediator of TH-1-cell activities, is detectable in sera of MS patients, and if there is any association with disease activity. We analysed 171 sera of patients with MS and meningitis, and healthy controls. IL-12 p40 protein was detectable at low levels in MS patients (median 43 pg/ml) and controls (median 49 pg/ml). Analysing different disease courses and activities, a significant elevation in stable primary progressive MS cases compared with controls (median 66 pg/ml) was found. IL-12 p40 protein was not detectable in cerebrospinal fluid probes of 10 patients. We conclude that the function of IL-12 in MS depends on expression and degradation of the different proteins. These could act proinflammatory as well as limiting the disease process.