Cerebrospinal Fluid IL-6 Concentrations Research Articles

Elevated Levels of PGE2-Metabolite in Cerebrospinal Fluid and Cox-2 Gene Polymorphisms in Patients with Chronic, Post Cholecystectomy Pain and Visceral Hyperalgesia Compared to Healthy Controls. A Hypothesis-Generating Pilot Study.

Chronic, abdominal pain remains a problem in a subset of patients after cholecystectomy. The cause is often obscure but central sensitization may be an important component and could theoretically be mediated by spinal PGE2, which is regulated by several cytokines. The aim of the study was to examine cerebrospinal fluid (CSF) of participants with post cholecystectomy syndrome and healthy volunteers for signs of PGE2 and cytokine mediated central sensitization. In phase 1 of the study, 83 subjects were included for DNA analysis, eight of these subjects with post cholecystectomy syndrome. We examined the SNPs rs5275, rs16944 and rs1800795 from the Cox-2, IL-1β and IL-6 genes respectively. In phase 2 of the study, we examined concentrations of PGE2-metabolite (PGEM), IL-1β and IL-6 in CSF and plasma from 6 patients with post cholecystectomy syndrome and visceral hyperalgesia and 11 pain free volunteers. We found a significant difference in distribution of the rs5275 SNP of the Cox-2 enzyme (CT-genotype=88% in pain group, 45% in pain free group, TT-genotype=0 in pain group, 41% in pain free group, p=0.05) but not in the other SNPs. PGEM, but not IL-6, was significantly elevated in CSF of the pain group (3.6 pg/mL, sd=1.9 vs 2.1 pg/mL, p=0.03), IL-1β was undetectable. We found elevated PGEM levels in CSF of patients with post cholecystectomy syndrome and visceral hyperalgesia, suggesting a central, possibly inflammatory component to the pain, and overrepresentation of the CT-genotype in the rs5275 SNP in the Cox2 gene, suggesting overexpression of Cox2 as a possible cause for elevated PGEM levels.

Cerebrospinal Fluid Interleukin-6 Is a Potential Diagnostic Biomarker for Central Nervous System Involvement in Adult Acute Myeloid Leukemia

Objective: We evaluated the relationship between cerebrospinal fluid (CSF) cytokine levels and central nervous system (CNS) involvement in adult acute myeloid leukemia (AML). Methods: The study sample consisted of 90 patients diagnosed with AML and 20 with unrelated CNS involvement. The AML group was divided into two sub-groups: those with (CNS+, n=30) and without CNS involvement (CNS-, n=60). We used a cytometric bead assay to measure CSF interleukin (IL)-2, -4, -6, and -10, tumor necrosis factor-α, interferon-γ, and IL-17A. We used receiver operating characteristic curves to assess the ability of CSF cytokine levels to identify CNS involvement in adult AML. Results: CSF IL-6 levels were significantly higher in CNS+adult AML patients and positively correlated with the lactate dehydrogenase levels (r=0.625, p<0.001) and white blood cell (WBC) count (r=0.534, p=0.001) in the blood, as well as the protein (r=0.404, p=0.027) and WBC count in the CSF (r=0.459, p=0.011). Using a CSF IL-6 cut-off value of 8.27 pg/ml yielded a diagnostic sensitivity and specificity was 89.29% and 88.46%, respectively (AUC, 0.9184; 95% CI, 0.8568-0.9800). After treating a subset of tested patients, their CSF IL-6 concentration decreased. Consequently, the elevated CSF IL-6 levels remaining in CNS+ adult AML patients post-treatment were associated with disease progression. Conclusion: CSF IL-6 is a promising marker for the diagnosis of adult AML with CNS involvement and a crucial dynamic indicator for therapeutic response.

Pro-Inflammatory and Anti-Inflammatory Cytokines Levels are Significantly Altered in Cerebrospinal Fluid of Unruptured Intracranial Aneurysm (UIA) Patients

Identifying all the relevant "players" in the formation and development of brain aneurysms may help understand the mechanisms responsible for the formation of an aneurysm, as well as in the search for non-invasive targets for aneurysm pharmacotherapy. The evaluation of the concentration of pro-inflammatory and anti-inflammatory cytokines in cerebrospinal fluid (CSF) and serum of patients with unruptured intracranial aneurysms (UIA) in comparison to individuals without vascular lesions in the brain. The concentration of 27 proteins in the CSF and serum of UIA patients (N = 40) and individuals without vascular lesions in the brain (N = 15) was evaluated using a multiplex ELISA kit (Bio-Plex Pro Human Cytokine 27-Plex Panel). In the CSF 13 out of 27 proteins evaluated presented a concentration 1.36-fold or greater in UIA patients in comparison to the control group. Significantly higher were IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-7, IL-8, IL-12, IL-13, TNF-α, INF-γ, MCP-1, and VEGF. In the serum none of the proteins evaluated significantly differ between UIA patients and the control group. The correlation coefficient analysis showed that CSF IL-1β, IL-8, and TNF-α positively, while IL-13 negatively correlated with the size of aneurysms. CSF IL-6 and MCP-1 concentrations positively correlated with the number of aneurysms. In patients with UIA, pro-inflammatory and anti-inflammatory mechanisms are activated simultaneously, because the concentration of promoting and suppressing inflammatory response proteins was significantly higher in CSF of UIA patients compared to the control group. The preventive therapy of brain aneurysm development should be focused on IL-1β, IL-6, IL-8, MCP-1, and TNF-α, the concentration of which in CSF positively correlated with the size and number of aneurysms.

Kappa Free Light Chains, Soluble Interleukin-2 Receptor, and Interleukin-6 Help Explore Patients Presenting With Brain White Matter Hyperintensities.

IntroductionMany patients are referred to multiple sclerosis (MS) tertiary centers to manage brain white matter hyperintensities (WMH). Multiple diagnoses can match in such situations, and we lack proper tools to diagnose complex cases.ObjectiveThis study aimed to prospectively analyze and correlate with the final diagnosis, cerebrospinal fluid (CSF) interleukin (IL)-1β, soluble IL-2 receptor (CD25), IL-6, IL-10, and kappa free light chains (KFLC) concentrations in patients presenting with brain WMH.MethodsAll patients over 18 years addressed to our MS tertiary center for the diagnostic workup of brain WMH were included from June 1, 2020, to June 1, 2021. Patients were separated into three groups—MS and related disorder (MSARD), other inflammatory neurological disorder (OIND), and non-inflammatory neurological disorder (NIND) groups—according to clinical presentation, MRI characteristics, and biological workup.ResultsA total of 176 patients (129 women, mean age 45.8 ± 14.7 years) were included. The diagnosis was MSARD (n = 88), OIND (n = 35), and NIND (n = 53). Median CSF KFLC index and KFLC intrathecal fraction (IF) were higher in MSARD than in the OIND and NIND groups; p < 0.001 for all comparisons. CSF CD25 and IL-6 concentrations were higher in the OIND group than in both the MSARD and NIND groups; p < 0.001 for all comparisons. KFLC index could rule in MSARD when compared to NIND (sensitivity, 0.76; specificity, 0.91) or OIND (sensitivity, 0.73; specificity, 0.76). These results were similar to those with oligoclonal bands (sensitivity, 0.59; specificity, 0.98 compared to NIND; sensitivity, 0.59; specificity, 0.88 compared to OIND). In contrast, elevated CSF CD25 and IL-6 could rule out MSARD when compared to OIND (sensitivity, 0.58 and 0.88; specificity, 0.95 and 0.74, respectively).DiscussionOur results show that, as OCBs, KFLC biomarkers are helpful tools to rule in MSARD, whereas elevated CSF CD25 and IL-6 rule out MSARD. Interestingly, CSF IL-6 concentration could help identify neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and central nervous system (CNS) vasculitis. These results need to be confirmed within more extensive and multicentric studies. Still, they sustain that KFLC, CSF CD25, and CSF IL-6 could be reliable biomarkers in brain WMH diagnostic workup for differentiating MSARD from other brain inflammatory MS mimickers.

Association between pro-inflammatory cytokines in cerebrospinal fluid and headache in patients with aneurysmal subarachnoid hemorrhage

ObjectiveTo investigate the relationship between the dynamic changes of pro-inflammatory cytokines in cerebrospinal fluid (CSF) and headache in patients with aneurysmal subarachnoid hemorrhage (aSAH)at hospital admission. MethodsCSF was collected from patients with aSAH at four time points (days 1, 3, 5, and 7; n = 216) from January 2017 to August 2017 at the Department of Neurosurgery of the First Affiliated Hospital of Wannan Medical College. We measured CSF levels ofinterleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α) levels using an enzyme-linked immunosorbent assay. Results were statistically analyzed to determine the relationship between the dynamic changes of pro-inflammatory cytokines in CSF and headache after aSAH. ResultsThe concentrations of IL-1β, IL-6, IL-8, and TNF-α in CSF showed dynamic changes after aSAH. Spearman correlation coefficient analysis revealed that high Hunt-hess grade and modified Fisher scale were associated with a worse headache after aSAH on days 1 and 7 (all P < 0.05). High values of intracranial pressure (ICP) and high levels of CSF pro-inflammatory cytokines were associated with a worse headache after aSAH at four time points (all P < 0.05). However, no significant associations were found between headache and sex, and age. After multiple regression analysis, the Hunt-hess grade, the levels of IL-6 and the levels of TNF-α were associated with headache severity at day 1 (all P < 0.05). The ICP, the levels of IL-1β and the levels of TNF-α were associated with headache severity on day 3, 5 and 7 (all P < 0.05). ConclusionsPro-inflammatory cytokines in CSF are closely associated with a headache after aSAH, and therefore may be a therapeutic target in the future.

IL-6 Quotient (The Ratio of Cerebrospinal Fluid IL-6 to Serum IL-6) as a Biomarker of an Unruptured Intracranial Aneurysm.

BackgroundStudies conducted so far have focused mainly on the assessment of IL-6 levels in patients with ruptured brain aneurysms. Carrying out detailed studies in patients with un-ruptured brain aneurysms (UIA) would be extremely important, as it would answer the question of whether IL-6 plays also a role in primary aneurysm formation and growth.MethodsIL-6, S100, NSE, and albumin concentrations in 67 UIA patients and 17 individuals without vascular lesions in the brain were tested using in vitro diagnostic immunoassays according to the manufacturers’ instructions. IL-6 Quotient was calculated by dividing cerebrospinal fluid (CSF) IL-6 by serum IL-6.ResultsWe showed that IL-6 Quotient was significantly higher in UIA patients (1.78) compared to the control group (0.87; p<0.001). Multivariate logistic regression analysis demonstrated that a growth in IL-6 Quotient increases the probability of UIA diagnosis. In UIA patients CSF IL-6 concentration was significantly higher (4.55 pg/ml) compared to the serum concentration (2.39 pg/ml; p<0.001). In both the study and control group, the blood-brain barrier was intact, thus the CSF-blood gradient of the IL-6 concentration in UIA patients was likely to be the expression of local synthesis of the cytokine within the central nervous system. Patients with multiple brain aneurysms had significantly higher CSF IL-6 levels (5.08 pg/ml) compared to individuals with a single aneurysm (4.14 pg/ml; p=0.0227).ConclusionThis totality of the may suggest IL-6 as a biomarker for UIA formation; however, further studies are needed to unequivocally confirm clinical application of IL-6 concentration evaluation.

Effect of adjunctive lidocaine-based scalp block and laryngotracheal local anesthesia vs general anesthesia only on plasma and cerebrospinal fluid pro-inflammatory cytokine concentrations in patients with cerebral aneurysm: a randomized controlled trial

AimTo compare the effect of adjunctive lidocaine-based scalp block and laryngotracheal local anesthesia vs general anesthesia only on pro-inflammatory cytokine concentrations in patients with non-ruptured brain aneurysms undergoing elective open surgery.MethodsThis parallel, randomized, controlled, open-label trial was conducted at Clinical Hospital Center Zagreb between March 2019 and March 2020. At the beginning of anesthesia, lidocaine group received 40 mg of 2% lidocaine for laryngotracheal topical anesthesia and 4 mg/kg for the scalp block. Control group underwent general anesthesia only. Plasma concentrations of IL-6, TNF-α, and IL-1β were measured before anesthesia (S0); at the incision (S1); at the end of surgery (S2); 24 hours postoperatively (S3). Cerebrospinal fluid (CSF) cytokine concentrations were measured at the incision (L1) and the end of surgery (L2).ResultsForty patients (each group, 20) were randomized; 37 were left in the final analysis. IL-6 plasma concentrations increased significantly compared with baseline at S3 in lidocaine group, and at S2 and S3 in control group. In both groups, changes in TNF-α and IL-1β were not significant. CSF cytokine concentrations in lidocaine group did not change significantly; in control group IL-6 and IL-1β were significantly higher at L2 than at L1. CSF IL-6 in control group significantly increased at L2, but TNF-α and IL-1β did not. No differences in clinical outcome and complication rates were observed.ConclusionAdjunctive lidocaine-based scalp block and laryngotracheal local anesthesia might attenuate CSF IL-6 concentration increase in patients with brain aneurysm.Trial registrationClinical Trials NCT03823482

Interleukin-6–Mediated Inflammation May Cause Methotrexate-Induced Leukoencephalopathy

Children with leukemia treated with methotrexate (MTX) may develop MTX-induced leukoencephalopathy, which can present as seizures or focal neurological deficits. However, the precise pathophysiology has not been fully elucidated. Differences in cytokine/chemokine profiles in cerebrospinal fluid (CSF) between children with MTX-induced leukoencephalopathy and those with posterior reversible encephalopathy syndrome (PRES), an acute neurological condition associated with hypertension, were investigated. Interleukin (IL)-1β, 2, 4, 5, 6, 7, 8, 10, 12, 13, and 17, tumor necrosis factor-alpha, interferon-gamma, granulocyte monocyte colony-stimulating factor, granulocyte colony-stimulating factor, macrophage inflammatory protein-1β, and monocyte chemoattractant protein-1 concentrations were measured in CSF supernatants from 3 children with acute leukemia with MTX-induced leukoencephalopathy, 3 children with acute leukemia with PRES, 6 children with acute leukemia without neurological complications, and 8 children with acute encephalopathy. CSF IL-6 concentrations were higher in children with MTX-induced leukoencephalopathy than in children with acute leukemia with PRES, with acute leukemia without neurological complications, and with acute encephalopathy. We concluded that IL-6 may be involved in the pathogenesis of MTX-induced leukoencephalopathy.

Correlations of cytokine levels in cerebrospinal fluid and peripheral blood with outcome of HHV-6B encephalitis after hematopoietic stem cell transplantation.

Human herpesvirus (HHV)-6B encephalitis has been recognized as a serious complication after allogeneic hematopoietic cell transplantation (allo-HCT). Little is known about the pathogenic mechanism for its progression. We retrospectively evaluated the 16 kinds of cytokines and chemokines in cerebrospinal fluid (CSF) and plasma in patients who developed HHV-6B encephalitis. Among a total of 20 patients, 12 were categorized as the poor prognosis group (died of encephalitis; n=8 and retained sequelae; n=4), and other eight patients were categorized as the good prognosis group (complete recovery; n=8). Concentrations of CSF IL-6 and IL-8 at the onset of encephalitis were significantly higher in the poor prognosis group than in the good prognosis group (median CSF IL-6, 28.27pg/mL vs 14.32pg/mL, P=.004; median CSF IL-8, 128.70pg/mL vs 59.43pg/mL, P=.043). Regarding plasma, the concentration of each cytokine at the onset of encephalitis was not significantly different between the two groups, except IL-5. However, higher levels of IL-6, IL-7, and MCP-1 and lower levels of IL-12 were observed 1week before the development of encephalitis in patients with poor prognosis (median IL-6; 464.17pg/mL vs 47.82pg/mL, P=.02; median IL-12; 1.63pg/mL vs 6.57pg/mL, P=.03). We found that one week before onset of HHV-6B encephalitis, poor prognosis patients had high plasma concentrations of IL-6, IL-7, and MCP-1 and low concentrations of IL-12. At the onset of encephalitis, high concentrations of IL-6 and IL-8 in CSF were more common in the poor prognosis group, consistent with other evidence that IL-6 can have a role in CNS disturbances. Our findings show that specific cytokine status is associated with severe brain damage in patients with HHV-6B encephalitis, demonstrate prognostic value of plasma IL-6 concentrations, and suggest evaluation of anti-cytokine therapeutics in patients with HHV-6B encephalitis.

P14.90 Interleukin 6 is a useful marker for pseudotumoral inflammatory CNS lesions suspicious of lymphoma

Abstract BACKGROUND Interleukin (IL)-6 is a dual pro and anti-inflammatory cytokine and its presence in the cerebrospinal fluid (CSF) is considered as a marker of central nervous system (CNS) inflammation. Our aim was to analyze the diagnostic significance of CSF IL-6 levels among various CNS pseudotumoral inflammatory lesions (PIL) and primary CNS lymphoma (PCNSL). MATERIAL AND METHODS We retrospectively analyzed the CSF IL-6 concentrations in 43 patients with a differential diagnosis of PCNSL. Finally, 28 patients were positively diagnosed with PCNSL and 15 with other inflammatory CNS disorders. We verified the results with CSF IL-10, a biomarker for PCNSL. IL concentrations were measured by flow cytometry using the cytometric bead array (CBA) technique (BD Biosciences) with a detection limit set at 2.5 pg/ml. RESULTS In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5 - 18.5. For the patients with other PIL the median concentration was of 70 pg/ml, IQR 5 - 1368. A group comparison disclosed significantly higher CSF IL-6 levels in patients with PIL compared to the group with PCNSL (p=0.032). Moreover, IL-6 was correlated with CSF cell count for the whole cohort (r=0.45, p=0.002), as well as for the PIL group (r=0.56, p=0.028), but not for the PCNSL group (r=0.3, p=0.13). We found significantly higher CSF IL-10 levels in patients with PCNSL compared to the group with other CNS inflammatory lesions (p&lt;0.001). CONCLUSION Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the diagnosis of CNS PIL that may mimic PCNSL.

Abstract P1-19-06: The prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid in trastuzumab naïve breast cancer patients diagnosed with meningeal carcinomatosis

Abstract Background With the improvements in treatment of patients with metastatic HER2-positive breast cancer (BC) the development of CNS metastases has become a major limitation of life expectancy and quality of life for many patients. Meningeal carcinomatosis represents approximately 10-20% of CNS metastases. The prognosis of meningeal carcinomatosis remains extremely poor. In the present study, we analysed the prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid (CSF) of meningeal carcinomatosis. Methods Between June 1985 and August 1992 sixty-nine CSF samples were collected at Herlev Hospital from trastuzumab naïve BC patients suspected of meningeal carcinomatosis. The cohort was composed of BC patients from two previous studies. Meningeal carcinomatosis was confirmed by tumour cells in CSF (or autopsy/scans). The samples were centrifuged, frozen and kept at -80oC. The concentrations of YKL-40, IL-6 and HER2 in CSF were measured by commercial ELISA (Quidel and R&amp;D) or Luminez (HER2 in second study). Overall survival in meningeal carcinomatosis was analysed with Kaplan-Meier curves and log rank tests using the median CSF value of HER2, YKL40 and IL-6 as cut off. Results 20 patients (29%) had meningeal carcinomatosis (18 patients had tumour cells in CFS, one was diagnosed by autopsy and one by CT scan; 13 of these patients participated in the first study and 7 in the second).10 patients had concomitant brain metastasis. The median survival was 35 days (4-305 days). The median [IQR] CSF concentration of YKL-40 was 284 ng/ml (187-597), IL-6 was15.9 pg/ml (6.5-51.0) and HER2 was 1.5 (0.36-8.70) in the patients with meningeal carcinomatosis. The survival was significantly shorter in patients with high levels of YKL-40 (p=0.03) and IL-6 (p=&amp;lt;0.01). The CSF HER2 level (p=0.51) or presence of brain metastasis (p=0.77) were not associated with survival. Conclusion In this cohort high levels of YKL-40 and IL-6 in CSF were associated with short survival in patients with BC and meningeal carcinomatosis. This was not found for HER2 in CSF or concomitant brain metastasis. Citation Format: Ryberg M, Johansen JS, Grantzau TL, Dehlendorff C, Nielsen DL. The prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid in trastuzumab naïve breast cancer patients diagnosed with meningeal carcinomatosis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-06.

An observational study examining the effects of a surgically induced inflammatory response on the distribution of morphine and its metabolites into cerebrospinal fluid

Morphine is administered intravenously for pain management in the perioperative period. The effect of the inflammatory response to surgery on morphine distribution across the blood-brain barrier (BBB) in humans was investigated. We hypothesized that a graded surgically induced, systemic inflammatory response alters cerebrospinal fluid (CSF) levels of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a temporary reduction in BBB drug efflux transporter function. We conducted a prospective pharmacokinetic study of the plasma and CSF distribution of the P-glycoprotein (PGP) substrate morphine in 33 patients undergoing open thoracic (n=18) or endovascular (n=15) aortic aneurysm repair. Morphine was administered with induction of anesthesia and in the intensive care unit. Plasma and CSF concentrations of interleukin (IL)-6, morphine, M3G, M6G, and albumin were measured prior to surgery (baseline), during surgery, and postoperatively every six hours until removal of the CSF drain. The area under the curve (AUC) was determined for plasma and CSF IL-6, morphine, M3G, and M6G concentrations vs time. The primary endpoint measures were the correlations between the morphine, M6G, and M3G AUC CSF/plasma ratios and systemic inflammation as quantified by the time-normalized IL-6 exposure, which was calculated for each individual by dividing the total exposure (AUC) by time (t). A Bonferroni corrected P<0.017 indicated a significant correlation. Plasma and CSF IL-6 concentrations increased postoperatively. The median [interquartile range] IL-6 exposures were significantly higher in the open vs endovascular surgical group for plasma (105 [40-256] pg·mL-1 vs 29 [16-70] pg·mL-1, respectively; P=0.013) and CSF (79 [26-133] pg·mL-1 vs 16 [9-80] pg·mL-1, respectively; P=0.013). For the primary endpoint, the plasma IL-6 AUC/t did not correlate with the CSF accumulation of morphine (r=-0.009; P=0.96) or M3G (r=0.37; P=0.04) when corrected for surgical procedure, age, and sex. There were insufficient data on CSF concentration to complete the primary analysis for M6G. Morphine distribution into the CSF was not significantly altered in patients undergoing thoracic aortic aneurysm repair. This suggests that BBB PGP function may not be affected by the perioperative inflammatory response. www.clinicaltrials.gov , NCT 00878371. Registered 7 April 2009.

Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms.

Systemic inflammation is accompanied by profound behavioral and mood changes that resemble symptoms of depression. Findings in animals suggest that pro-inflammatory cytokines released by activated immune cells in the periphery evoke these behavioral symptoms by driving inflammatory changes in the brain. However, experimental data in humans are lacking. Here we demonstrate in healthy male volunteers (10 endotoxin treated, 8 placebo treated) that intravenous administration of low-dose endotoxin (0.8 ng/kg body weight), a prototypical pathogen-associated molecular pattern that activates the innate immune system, not only induces a significant increase in peripheral blood cytokine concentrations (that is, tumor necrosis factor-α, interleukin (IL)-6, IL-10) but also results, with some latency, in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF). Moreover, we found a strong association between the endotoxin-induced increase of IL-6 in the CSF and the severity of mood impairment, with larger increases in CSF IL-6 concentration followed by a greater deterioration in mood. Taken together, these findings suggest that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration, identifying IL-6 as a potential therapeutic target in mood disorders.

IgM, lgG and IL-6 profiles in the Trypanosoma brucei brucei monkey model of human African trypanosomiasis

Human African trypanosomiasis (HAT) patients manifest immunological profiles, whose variations over time can be used to indicate disease progression. However, monitoring of these biomarkers in human patients is beset by several limitations which can be offset by using chronic animal models. A recent improved monkey model of HAT using a Trypanosoma brucei brucei isolate has been developed but the immunological profile has not been elucidated. The objectives of the current study was to determine the IgM, IgG and IL-6 profiles in blood and cerebrospinal fluid (CSF) in vervet monkeys infected with T. b. brucei. Three vervet monkeys were infected intravenously with 105T. b. brucei, monitored for disease development and subsequently treated 28days post infection (dpi) sub-curatively using diminazene aceturate (DA) to induce late stage disease and curatively treated with melarsoprol (Mel B) at 119 dpi, respectively. Matched serum and cerebrospinal fluid (CSF) samples were obtained at regular intervals and immunospecific IgM, immunoglobulin G (IgG) were quantified by ELISA while IL-6 was assayed using a cytometric bead array (CBA) kit.Results showed that following infection, CSF IgM, IgG, IL-6 and serum IL-6 were significantly (p<0.05) elevated with peak levels coinciding with relapse parasitaemia. The IgG levels increased to reach OD peak levels of 0.442±0.5 at 126 dpi. After curative treatment with MelB, the serum IgM and Ig G levels fell rapidly to attain pre-infection levels within 35 and 49days, respectively. This shows that the profile of these immunoglobulins can be used as an indicator of curative treatment. CSF IL-6 concentrations of infected vervet monkeys showed no significant change (P>0.05) between infection and 35 dpi but levels increased significantly (P<0.05) with the highest level of 55.53pg/ml recorded at112 dpi. IL-6 elevation from 35 dpi may be indicative of parasite neuroinvasion hence can be used as possible candidate marker for late stage disease in the monkey model. Further, the marker can also be used in conjunction with IgG and IgM as markers for development of test of cure for HAT.

IL-6, IL-8, IP-10, MCP-1 and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus.

To determine whether the intrathecal concentrations of cytokines/chemokines are associated with, or influenced by, serum concentrations in patients with central neuropsychiatric systemic lupus erythematosus (NPSLE), and to ascertain whether the increased production of cytokines/chemokines intrathecally relative to serum levels is associated with the presence of central NPSLE. 52 SLE patients (30 with central NPSLE and 22 with non-NPSLE), for whom the CSF and serum samples were obtained at the same time, were enrolled. 27 kinds of cytokine/chemokine concentrations other than IFN-α in the cerebrospinal fluid (CSF) and serum samples were measured by Bio-Plex Pro Assays. IFN-α concentration and anti-ribosomal P protein antibody (anti-P) titres in CSF and serum samples were measured by ELISA. The mean concentrations of IL-6, IL-8, IP-10, MCP-1, G-CSF and GM-CSF were higher in the CSF than in the sera, respectively, while the mean concentrations of other 22 cytokines/chemokines, including RANTES and IFN-α, in the CSF were much lower than those in the sera, respectively. Furthermore, the concentrations of IL-6, IL-8, IP-10, MCP-1 and G-CSF in the CSF of the 30 patients with NPSLE were significantly higher than in the 22 patients with non-NPSLE (p = 6.82 × 10(-5), p = 0.00037, p = 0.0028, p = 0.00065, and p = 0.0001, respectively), while the concentration of GM-CSF in the CSF of the 30 patients with NPSLE was not significantly higher than in the 22 patients with non-NPSLE. Most importantly, the largest difference occurred in CSF IL-6 concentrations. A significant positive correlation between CSF anti-P titres and serum anti-P titres in 52 patients with SLE (r = 0.6316, p = 6.44 × 10(-6)) was found, while no significant positive correlation was observed between CSF levels and serum levels of each cytokine/chemokine in the 52 SLE patients. In central NPSLE the production of IL-6, IL-8, IP-10, MCP-1 and G-CSF might take place in the central nervous system (CNS). These increased CSF cytokines/chemokines along with anti-P might have a prerequisite role in the pathogenesis of central NPSLE.

Cerebrospinal fluid Th1/Th2 cytokine profiles in children with enterovirus 71‐associated meningoencephalitis

Enterovirus 71 (EV71) infection can cause severe neurological complications including meningoencephalitis (ME) in some patients with hand, foot and mouth disease (HFMD). However, to date no studies have reported changes in cytokine concentrations and their correlations with clinical variables in patients with ME following EV71 infection. In this study, responses of Th1/Th2 cytokine, including IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ, in cerebrospinal fluid (CSF) from patients with EV71-related HFMD with ME and patients with febrile convulsions (FC) were analyzed using cytometric bead array technology. It was found that CSF IL-6 and IFN-γ concentrations were significantly higher in patients with EV71-related ME than in those with FC. Additionally, both CSF IL-6 and IFN-γ concentrations were correlated with CSF cytology, fever duration and duration of hospital stay. More interestingly, a positive correlation between CSF IL-6 and IFN-γ concentrations was observed. Finally, receiver operating characteristic analysis revealed that when a cutoff value of 9.40 pg/mL was set for IL-6, the sensitivity and specificity were 84.5% and 85.5%, respectively, for discriminating EV71-related ME from FC. In conclusion, IL-6 and IFN-γ may be associated with EV71-induced neuropathology.

Canine model of ischemic stroke with permanent middle cerebral artery occlusion: clinical features, magnetic resonance imaging, histopathology, and immunohistochemistry

The purpose of this study was to identify time-related changes in clinical, MRI, histopathologic, and immunohistochemical findings associated with ischemic stroke in dogs. Additionally, the association of cerebrospinal fluid (CSF) and tissue levels of interleukin (IL)-6 with clinical prognosis was assessed. Ischemic stroke was induced by permanent middle cerebral artery occlusion (MCAO) in nine healthy experimental dogs. The dogs were divided into three groups according to survival time and duration of the experimental period: group A (survived only 1 day), group B (1-week experimental period), and group C (2-week experimental period). Neurologic status was evaluated daily. Magnetic resonance imaging (MRI) was performed according to a predetermined schedule. Concentration of IL-6 in CSF was measured serially after ischemic stroke. Postmortem examination was performed for all experimental dogs. During histopathological examination, variable degrees of cavitation and necrosis due to neuronal cytopathic effects, such as pyknotic nuclei and cytoplasmic shrinkage, were observed on the affected side of the cerebral cortex in all dogs. Immunohistochemistry specific for IL-6 showed increased expression in the ischemic lesions. CSF IL-6 concentrations and ischemic lesion volumes 1 day after ischemic stroke were significantly higher in group A compared to groups B and C.

Expression of suppressor of cytokine signaling 3 in cerebrospinal fluid after subarachnoid hemorrhage.

BackgroundIL-6 is a proinflammatory cytokine reported to play an important role in the induction of cerebral vasospasm after subarachnoid hemorrhage (SAH). Suppressor of cytokine signaling 3 (SOCS3) is known to act as an inhibitor of signal transduction of IL-6. However, there have been no reports on the expression of SOCS3 in cerebrospinal fluid (CSF) after SAH.FindingsThe concentration of IL-6 was measured serially up until day 10, in CSF of eight patients with SAH. CSF samples obtained from patients suffering from an unruptured aneurysm were used as controls. The expression of SOCS3 in CSF was further examined by immunoprecipitation methods. Concentrations of IL-6 in CSF increased immediately after the onset of SAH and remained chronically elevated over control values. SOCS3 was significantly expressed in CSF on days 1 to 3 after SAH.ConclusionsOur findings suggest that SOCS3 regulates IL-6 signaling as an antagonist in CSF, immediately following SAH. As the expression of SOCS3 decreases after day 5, IL-6 signals might then be more easily transmitted, presumably resulting in cerebral vasospasm.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0142-2) contains supplementary material, which is available to authorized users.

The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial

BackgroundInterleukin-1 (IL-1) is a key mediator of ischaemic brain injury induced by stroke and subarachnoid haemorrhage (SAH). IL-1 receptor antagonist (IL-1Ra) limits brain injury in experimental stroke and reduces plasma inflammatory mediators associated with poor outcome in ischaemic stroke patients. Intravenous (IV) IL-1Ra crosses the blood–brain barrier (BBB) in patients with SAH, to achieve cerebrospinal fluid (CSF) concentrations that are neuroprotective in rats.MethodsA small phase II, double-blind, randomised controlled study was carried out across two UK neurosurgical centres with the aim of recruiting 32 patients. Adult patients with aneurysmal SAH, requiring external ventricular drainage (EVD) within 72 hours of ictus, were eligible. Patients were randomised to receive IL-1Ra (500 mg bolus, then a 10 mg/kg/hr infusion for 24 hours) or placebo. Serial samples of CSF and plasma were taken and analysed for inflammatory mediators, with change in CSF IL-6 between 6 and 24 hours as the primary outcome measure.ResultsSix patients received IL-1Ra and seven received placebo. Concentrations of IL-6 in CSF and plasma were reduced by one standard deviation in the IL-1Ra group compared to the placebo group, between 6 and 24 hours, as predicted by the power calculation. This did not reach statistical significance (P = 0.08 and P = 0.06, respectively), since recruitment did not reach the target figure of 32. No adverse or serious adverse events reported were attributable to IL-1Ra.ConclusionsIL-1Ra appears safe in SAH patients. The concentration of IL-6 was lowered to the degree expected, in both CSF and plasma for patients treated with IL-1Ra.

Efficacy of infliximab in neuro-Behçet’s disease presenting with isolated longitudinally extensive transverse myelitis

Efficacy of infliximab in neuro-Behçet’s disease presenting with isolated longitudinally extensive transverse myelitis