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Immunophenotyping of Cerebrospinal Fluid Cells in Multiple Sclerosis In Search of Biomarkers

Sascha Alvermann, MD1; Christian Hennig, MD2; Olaf Stüve, MD, PhD3,4; Heinz Wiendl, MD5; Martin Stangel, MD1
[+] Author Affiliations
1Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany
2Department of Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany
3Neurology Section, VA North Texas Health Care System, Medical Service Dallas, VA Medical Center, Dallas
4Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas
5Department of Neurology, University of Münster, Münster, Germany
JAMA Neurol. 2014;71(7):905-912. doi:10.1001/jamaneurol.2014.395.
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Importance  Cerebrospinal fluid (CSF) is the compartment in closest proximity to the central nervous system (CNS) parenchyma and might reflect immune pathology in inflammatory CNS disorders like multiple sclerosis (MS). Multiparameter flow cytometry is used to characterize immunological alterations in the CSF of patients with MS.

Objectives  To present a comprehensive review of the cellular alterations in CSF that distinguish MS from physiological conditions and other CNS disorders; integrate relevant findings into a model of leukocyte trafficking in the CNS; highlight treatment-related changes in leukocyte subsets; and evaluate the potential of CSF immunophenotyping in the search of novel biomarkers in MS.

Evidence Review  We searched MEDLINE articles published between 1980 and 2013 that include the flow cytometric characterization of leukocyte subsets in the CSF of patients with MS.

Findings  All of the articles have shown CSF pleocytosis in MS. Interesting results include CSF enrichment of helper T cells (subtypes TH1 and TH17) and regulatory T cells, as well as intrathecal B-cell differentiation resulting in the generation of antibody-producing plasmablasts and plasma cells. Other leukocyte populations, including natural killer cells, monocytes, and dendritic cells, show alterations as well. Characterization of CSF cells increases our understanding of MS pathogenesis and may provide useful biomarkers for individual prognosis and treatment decisions. However, validation in controlled settings is lacking in most cases.

Conclusions and Relevance  With the advent of more sophisticated approaches, immunophenotyping of CSF cells in MS might become increasingly important to correlate cellular subsets with different stages of disease activity and remission. An assessment of CSF cell numbers and composition should be incorporated into clinical trials.

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Mechanisms of Leukocyte Migration Into the CNS

Routes of leukocyte migration into the central nervous system (CNS) and associated leukocyte-endothelial interactions: from parenchymal vessels across the blood-brain barrier (BBB) into the CNS parenchyma (A), from leptomeningeal vessels into the subarachnoid space (SAS) (B), through the choroid plexus (CP) into ventricular cerebrospinal fluid (VE) (C); and chemokine-chemokine receptor interactions that support leukocyte sequestration in cerebrospinal fluid (D). NK indicates natural killer; PB, peripheral blood.

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