Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis

Komori, Mika; Blake, Andrew; Greenwood, Mark C.; Lin, Yen Chih; Kósa, Péter; Ghazali, Danish; Winokur, Paige; Natrajan, Muktha S.; Wuest, Simone C.; Romm, Elena; Panackal, Anil A.; Williamson, Peter R.; Wu, Tianxia; Bielekova, Bibiana

doi:10.1002/ana.24408

Cited by 134 publications

(192 citation statements)

References 46 publications

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“…To assess effect of daclizumab on cells of adaptive immunity, we measured surface molecules released specifically from B cells (sCD21) and activated T cells (sCD27, shed from activated more than resting T cells and from CD8 T cells more than CD4 T cells) 4. While sCD21 is a specific B‐cell marker, it is highly expressed on naïve cells and its expression diminishes as B cells mature.…”

Section: Resultsmentioning

confidence: 99%

“…Electrochemiluminescent assays were developed or optimized to quantify the concentrations of serum and CSF biomarkers using the Meso Scale Discovery ® platform (MSD; Meso Scale Diagnostics, Rockville, MD, https://www.mesoscale.com/) as described previously 4. The concentration of interleukin 12p40 (IL‐12p40) was measured by MSD V‐plex using the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…The concentration of interleukin 12p40 (IL‐12p40) was measured by MSD V‐plex using the manufacturer's protocol. The assays for CSF soluble CD21 (sCD21), sCD27, sCD14, sCD163, chitinase‐3‐like protein 1 (CHI3L1), and chemokine C‐X‐C motif ligand 13 (CXCL13) and serum/CSF daclizumab were developed through de novo 4. Neurofilament light protein (NFL) was measured using a UmanDiagnostics ELISA (UmanDiagnostics AB Sweden).…”

Section: Methodsmentioning

confidence: 99%

“…Threshold for abnormal values was based on mean + 2 standard deviation (SD) of healthy donors’ data4 (HD; n = 43, yielding 56 different CSF samples as some HD contributed two samples 1 year apart; Table S2). The HD samples were collected by the same group of investigators using identical SOP and prospectively assigned the alphanumeric code that does not allow laboratory personnel to differentiate MS from HD samples, resulting in random distribution of MS and HD samples on assay plates.…”

Section: Methodsmentioning

confidence: 99%

“…However, we recently demonstrated that intrathecal inflammation, as measured by cerebrospinal fluid (CSF) biomarkers specific for cells of adaptive immunity (i.e., T and B cells and plasma cells) and innate immunity (e.g., microglia/macrophages), is as prevalent in patients who lack CELs (including primary progressive MS [PPMS] patients) as it is in relapsing–remitting MS (RRMS) 4. This observation prompted a hypothesis that subclinical MS disease activity may be mediated by residual inflammation compartmentalized to the central nervous system (CNS) and therefore mostly inaccessible to current DMTs.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacodynamic effects of daclizumab in the intrathecal compartment

Komori

Kósa

Stein

et al. 2017

Ann Clin Transl Neurol

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ObjectiveIt was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.MethodsForty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open‐label clinical trials. MRI contrast‐enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease.ResultsRapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant (P < 0.0001) decreases in CSF levels of T‐cell activation marker CD27 and IgG index. Interleukin 2 (IL‐2) CSF levels increased from baseline levels during treatment, consistent with reduced IL‐2 consumption by T cells, as a consequence of daclizumab's saturation of high‐affinity IL‐2 receptors. CSF levels of IL‐12p40, chitinase‐3‐like protein‐1 (CHI3L1), chemokine C‐X‐C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression.InterpretationThese observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacodynamic effects of daclizumab in the intrathecal compartment

Komori

Kósa

Stein

et al. 2017

Ann Clin Transl Neurol

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Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome

et al. 2017

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IMPORTANCE There is a growing number of therapies that could be administered after the first symptom of central nervous system demyelination. These drugs can delay multiple sclerosis (MS) diagnosis and slow down future disability. However, treatment of patients with benign course may not be needed; therefore, there is a need for biomarkers to predict long-term prognosis in patients with clinically isolated syndrome (CIS).OBJECTIVE To investigate whether the T-cell activation marker soluble CD27 (sCD27) measured in cerebrospinal fluid of patients at time of a first attack is associated with a subsequent diagnosis of MS and a higher relapse rate. DESIGN, SETTING, AND PARTICIPANTSThis prospective study included 77 patients with CIS between March 2002 and May 2015 in a tertiary referral center for multiple sclerosis, in collaboration with several regional hospitals. Patients with CIS underwent a lumbar puncture and magnetic resonance imaging scan within 6 months after first onset of symptoms.MAIN OUTCOMES AND MEASURES Soluble CD27 levels were determined in cerebrospinal fluid using a commercially available enzyme-linked immunosorbent assay. Cox regression analyses was used to calculate univariate and multivariate hazard ratios for MS diagnosis. Association between sCD27 levels and relapse rate was assessed using a negative binomial regression model. RESULTS Among 77 patients with CIS, 50 were female (79.5%), and mean (SD) age was 32.7 (7.4) years. Mean (SD) age in the control individuals was 33.4 (9.5) years, and 20 were female (66.7%).Patients with CIS had higher cerebrospinal fluid sCD27 levels than control individuals (geometric mean, 31.3 U/mL; 95% CI, 24.0-40.9 vs mean, 4.67 U/mL; 95% CI, 2.9-7.5; P < .001). During a mean (SD) follow-up of 54.8 (35.1) months, 39 of 77 patients (50.6%) were diagnosed as having MS. In a model adjusted for magnetic resonance imaging and cerebrospinal fluid measurements, sCD27 levels were associated with a diagnosis of MS (hazard ratio, 2.4 per 100 U/mL increase in sCD27 levels; 95% CI, 1.27-4.53; P = .007). Additionally, patients with MS with high sCD27 levels (median, >31.4 U/mL) at the time of CIS had a 5.5 times higher annualized relapse rate than patients with low sCD27 levels (annualized relapse rate, 0.06 vs 0.33; P = .02).CONCLUSIONS AND RELEVANCE Soluble CD27 in cerebrospinal fluid of patients with CIS was associated with MS diagnosis and a high relapse rate. Therefore, sCD27 is an activation molecule directly related to the immunopathology of the disease and is a potential clinical marker to help in treatment decisions after a first attack of suspected MS.

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Risk of Multiple Sclerosis After a Clinically Isolated Syndrome

Gelfand

2017

JAMA Neurol

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Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis

Cited by 134 publications

References 46 publications

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome

Risk of Multiple Sclerosis After a Clinically Isolated Syndrome

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