Cerebrospinal Fluid IL-12p40, CXCL13 and IL-8 as a Combinatorial Biomarker of Active Intrathecal Inflammation

Abstract

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.

Subclinical central inflammation is risk for RIS and CIS conversion to MS

“…12 IL-8 is produced intrathecally by a wide array of cell types, regulating recruitment of monocytes and neutrophils.…”

“…9 Importantly, elevated cerebrospinal fluid (CSF) IL-8 levels have been observed in infective and noninfective neuroinflammatory conditions, 10,11 and have been described as sensitive biomarker of central active inflammation. 12 In MS, IL-8 receptor was detected on oligodendrocytes around active and silent lesions, and hypertrophic astrocytes stain strongly for IL-8 in active MS lesions. 13 On this basis, we postulated that CSF IL-8 could be used as a valid biomarker of subclinical intrathecal inflammation, and as a sensitive predictor of disease activity in prodromal and early MS.…”

Raised Proinflammatory Cytokine Production Within Cerebrospinal Fluid Precedes Fever Onset in Patients With Neurosurgery-Associated Bacterial Meningitis*

“…Although some reports observed increased CSF IL-8 concentrations within patients with bacterial meningitis (12,21,43,(49)(50)(51), others demonstrated that IL-8 tends to be higher within aseptic meningitis cohorts (51). Regardless, IL-8 is thought to be a potent marker of oxidative stress that enables neutrophilic migration to areas of insult (49,52). Therefore, in our study, it is postulated that raised IL-8 levels may be related to the clinical presentation of meningitis in general, regardless of its etiology.…”

Pharmacodynamic effects of daclizumab in the intrathecal compartment

“…While our dynamic observations suggest pathogenic role of activated members of myeloid lineage (e.g., macrophages, microglia, and myeloid DCs) in axonal damage associated with MS, correlation cannot prove causation. Indeed, activation of myeloid lineage may also be secondary to danger‐associated molecular patterns released upon demyelination 26. This interpretation is supported by the fact that we observed only trend, which did not reach statistical significance, for systemic (i.e., serum) inhibition of CHIT3L1 levels upon initiation of daclizumab therapy, with no significant correlations between two compartments (data not shown).…”