[Interleukins - 23, -12p40 as markers of neural tissue damage in neurosyphilis.]

To study the features of cytokines in patients with various forms of neurosyphilis. The complex laboratory examination of patients with neurosyphilis and syphilis without specific lesion of the nervous system was observed in the venereological department of the OSH "Clinical Dermatological and Venereological Dispensary" in Omsk in order to determine the concentration of interleukins - 23, 12p40 in CSF and assess their relationship with the course of syphilitic infection. The presence of regularities and features in the deviation of the immune status in the examined disease was established. Analysis of immunological changes in patients' cerebrospinal fluid showed that in patients with neurosyphilis, regardless of the presence or absence of clinical symptoms, the levels of IL-23 and IL-12p40 in CSF significantly exceed those in patients without specific lesion of the nervous system.

Reduced cerebrospinal fluid concentration of interleukin-12/23 subunit p40 in patients with cognitive impairment.

BACKGROUND: The role of inflammation in Alzheimer's disease (AD) and other cognitive disorders is unclear. In a well-defined mono-center population, we measured cytokines and chemokines in paired serum and cerebrospinal fluid (CSF) samples. METHODS: Consecutive patients with AD (n = 30), stable mild cognitive impairment (SMCI, n = 11), other dementias (n = 11), and healthy controls (n = 18) were included. None of the subjects was treated with glucocorticoids, cholinesterase inhibitors, or non-steroidal anti-inflammatory drugs. Serum and CSF concentrations of interleukin-6 (IL-6), IL-8, IL-12/23 p40, IL-15, IL-16, vascular endothelial growth factor-A (VEGF-A), and three chemokines were measured using a multiplex panel. RESULTS: After correction for multiple comparisons, only CSF IL-12/23 p40 concentration differed significantly between the total patient group (n = 52) and controls (n = 18; p = 0.002). Further analyses showed that CSF IL-12/23 p40 concentration was decreased in all patient subgroups (AD, other dementias, and SMCI) compared to healthy controls (p < 0.01, p < 0.05, and p < 0.05, respectively). In the total study population (n = 70), CSF IL-12/23 p40 concentrations correlated positively with CSF concentrations of ß-amyloid1-42 (Aß1-42) and phosphorylated tau protein (P-tau) whereas in AD patients (n = 30), CSF IL-12/23 p40 only correlated positively with CSF P-Tau (r = 0.46, p = 0.01). CONCLUSIONS: Most cytokines and chemokines were similar in patients and controls, but CSF IL-12/23 subunit p40 concentration was decreased in patients with cognitive impairment, and correlated with markers of AD disease status. Further studies are needed to evaluate the role of CSF IL-12/23 p40 in other dementias and SMCI.

Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis.

OBJECTIVE: The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools. METHODS: Because biomarkers with maximum utility reflect immune phenotypes, we included an assessment of cell specificity in purified primary immune cells. Biomarkers were quantified by optimized electrochemiluminescent immunoassays. RESULTS: Among markers with cell-specific secretion, soluble CD27 is a validated biomarker of intrathecal T-cell activation, with an area under the receiver operating characteristic curve of 0.97. Comparing the quantities of cerebrospinal fluid (CSF) immune cells and their respective cell-specific soluble biomarkers (released by CSF cells as well as their counterparts in CNS tissue) provided invaluable information about stationary CNS immune responses, previously attainable via brain biopsy only. Unexpectedly, progressive and relapsing-remitting multiple sclerosis (MS) patients have comparable numbers of activated intrathecal T and B cells, which are preferentially embedded in CNS tissue in the former group. INTERPRETATION: The cell-specific biomarkers of intrathecal inflammation may improve diagnosis and management of neuroimmunological diseases and provide pharmacodynamic markers for future therapeutic developments in patients with intrathecal inflammation that is not captured by imaging, such as in progressive MS.

Tumor Necrosis Factor-α, Interleukins-12(p40), 6, and 10 levels in cerebrospinal fluid and outcome prediction in Ossimi sheep with encephalitic listeriosis.

Encephalitic listeriosis in sheep is a life-threatening disease. However, little is known about the cytokine response and their predictive value in this disease. The aim of present study was to assess the prognostic significance of Tumor Necrosis Factor-α (TNF-α), Interleukin-12(p40) (IL-12 p40), Interleukin-6 (IL-6), and Interleukin 10 (IL-10) levels in cerebrospinal fluid (CSF) in sheep with encephalitic listeriosis. Fifty-nine ewes in 14 flocks were diagnosed clinically as having listeriosis. CSF was collected and subjected to bacteriological examination and estimation of selected cytokines. Twenty-eight ewes were confirmed to be infected with Listeria monocytogenes. Based on antimicrobial sensitivity test, sheep were treated and the outcome was recorded as survivors (n=10) and non-survivors (n=18). Cutoff points for CSF cytokines were determined by Receiver operating characteristic analysis (ROC). Association between levels of CSF cytokines and outcome of listeriosis was assessed by logistic regression. TNF-α, IL-6 and IL-12(p40) levels as well as TNF-α/IL-10 ratio were significantly higher in non-survivors than survivors (p=0.002, 0.0021, 0.0033, and 0.001, respectively). However, IL-10 level was significantly lower in non-survivors than survivors (p=0.0058). ROC analysis revealed that IL-6 and TNF-α/IL-10 ratio had the highest AUC values (0.98, 0.984, respectively). Final multivariate logistic regression model showed that TNF-α/IL-10 ratio was the only variable that has predictive value for mortality in diseased sheep (p: 0.001; OR: 7.2; 95% CI: 5.7-9.8). TNF-α showed a positive correlation with IL-12ß (r=0.917) and IL-6 (r=0.965). IL-12 (p40) showed also a positive correlation with IL-6 (r=0.906). However, IL-10 showed a negative correlation with TNF-α (r=-0.915), IL-12(p40) (r=-0.790), and IL-6 (r=-0.902). In conclusion, TNF-α/IL-10 ratio may provide predictive information about outcome of encephalitic listeriosis in sheep.

Interleukin-12p40 in the spinal fluid as a biomarker for clinically isolated syndrome.

BACKGROUND: The cerebrospinal (CSF) constitutes a specific immune micro-environment to the central nervous system, thus it may contain specific biomarkers involved in the pathogenesis of multiple sclerosis (MS). OBJECTIVES: We aimed to study a large array of inflammatory CSF biomarkers in patients with suspected MS to recognize potential early diagnostic markers. METHODS: CSF samples were obtained from 115 patients who presented with neurological symptomatology suggestive of MS as follows: clinically isolated syndrome (CIS) = 49, relapsing-remitting multiple sclerosis (RRMS) = 29, and other neurologic disorders (OND) = 37. Protein expression profiles of 30 inflammatory biomarkers were measured by multiplex Luminex bead assay and further analyzed by group comparison statistics, correlation studies and receiver-operating characteristic (ROC) analysis. RESULTS: Interleukin-12 subunit p40 (IL12p40) demonstrated a significant differential expression pattern between the groups (CIS vs OND: p = 1.17*10(-7); RRMS vs OND: p = 4.98*10(-5)), with higher levels in CIS and RRMS patients. ROC analysis demonstrated excellent diagnostic performance of IL12p40 for discrimination between CIS and OND patients (area under the curve = 0.87 (95% CI 0.78-0.93), p = 0.0001). No associations were found with disease activity or severity measures. CONCLUSIONS: An increased IL12p40 level characterizes the CSF of MS patients and appears to be helpful in identifying CIS and OND patients early in the process of clinical diagnostic assessment.

Cerebrospinal fluid IL-12p40, CXCL13 and IL-8 as a combinatorial biomarker of active intrathecal inflammation.

Diagnosis and management of the neuroinflammatory diseases of the central nervous system (CNS) are hindered by the lack of reliable biomarkers of active intrathecal inflammation. We hypothesized that measuring several putative inflammatory biomarkers simultaneously will augment specificity and sensitivity of the biomarker to the clinically useful range. Based on our pilot experiment in which we measured 18 inflammatory biomarkers in 10-fold concentrated cerebrospinal fluid (CSF) derived from 16 untreated patients with highly active multiple sclerosis (MS) we selected a combination of three CSF biomarkers, IL-12p40, CXCL13 and IL-8, for further validation.Concentrations of IL-12p40, CXCL13 and IL-8 were determined in a blinded fashion in CSF samples from an initial cohort (n = 72) and a confirmatory cohort (n = 167) of prospectively collected, untreated subjects presenting for a diagnostic work-up of possible neuroimmunological disorder. Diagnostic conclusion was based on a thorough clinical workup, which included laboratory assessment of the blood and CSF, neuroimaging and longitudinal follow-up. Receiver operating characteristic (ROC) curve analysis in conjunction with principal component analysis (PCA), which was used to combine information from all three biomarkers, assessed the diagnostic value of measured biomarkers.Each of the three biomarkers was significantly increased in MS and other inflammatory neurological disease (OIND) in comparison to non-inflammatory neurological disorder patients (NIND) at least in one cohort. However, considering all three biomarkers together improved accuracy of predicting the presence of intrathecal inflammation to the consistently good to excellent range (area under the ROC curve = 0.868-0.924).Future clinical studies will determine if a combinatorial biomarker consisting of CSF IL-12p40, CXCL13 and IL-8 provides utility in determining the presence of active intrathecal inflammation in diagnostically uncertain cases and in therapeutic development and management.

Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline.

The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-ß (Aß). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aß species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.

Increased osteopontin levels in the cerebrospinal fluid of patients with multiple sclerosis.

OBJECTIVE: To determine cerebrospinal fluid levels of osteopontin (OPN), a proinflammatory cytokine that was found to be overexpressed in multiple sclerosis lesions and increased in plasma during relapses and in secondary progressive multiple sclerosis. DESIGN: Case series. Osteopontin, interleukin 12p40 (IL-12p40), IL-10, and matrix metalloproteinase 9 were measured by enzyme-linked immunosorbent assay by an investigator unaware of the patients' diagnoses. PATIENTS: Consecutive patients with multiple sclerosis (n = 27), or other inflammatory (n = 11) or non-inflammatory (n = 23) neurological diseases, undergoing lumbar puncture, were investigated. RESULTS: Osteopontin was significantly elevated in the cerebrospinal fluid of patients with multiple sclerosis (mean [SD], 415 [186] ng/mL) and other inflammatory diseases (563 [411] ng/mL) compared with those with noninflammatory neurological diseases (286 [150] ng/mL). Cerebrospinal fluid OPN levels were slightly higher than plasma OPN levels. Cerebrospinal fluid OPN levels positively correlated with the ability to detect cerebrospinal fluid IL-12p40. CONCLUSION: Osteopontin in the cerebrospinal fluid may be, in part, of central nervous system origin, and may play an important role in central nervous system inflammation.