title: Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Mika
authors: M
authors: Komori
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Andrew
authors: A
authors: Blake
authors: Department of Mathematical Sciences, Montana State University, Bozeman, MT.
authors: Mark
authors: M
authors: Greenwood
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Yen Chih
authors: YC
authors: Lin
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Peter
authors: P
authors: Kosa
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Danish
authors: D
authors: Ghazali
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Paige
authors: P
authors: Winokur
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Muktha
authors: M
authors: Natrajan
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Simone C
authors: SC
authors: Wuest
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Elena
authors: E
authors: Romm
authors: Translational Mycology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors: Anil A
authors: AA
authors: Panackal
authors: Translational Mycology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors: Peter R
authors: PR
authors: Williamson
authors: Clinical Neuroscience Program, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD.
authors: Tianxia
authors: T
authors: Wu
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Bibiana
authors: B
authors: Bielekova
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000166:cytology; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D016022:Case-Control Studies; D002555:Cerebrospinal Fluid / Q000166:cytology* / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid; D053762:Interleukin-12 Subunit p40 / Q000134:cerebrospinal fluid; D016209:Interleukin-8 / Q000134:cerebrospinal fluid; D018950:Lipopolysaccharide Receptors / Q000134:cerebrospinal fluid; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000134:cerebrospinal fluid*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid*; D009422:Nervous System Diseases / Q000134:cerebrospinal fluid; D011446:Prospective Studies; D017464:Receptors, Complement 3d / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000134:cerebrospinal fluid; D055815:Young Adult
chemical_list: D015415:Biomarkers; C508606:CXCL8 protein, human; D053762:Interleukin-12 Subunit p40; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D017464:Receptors, Complement 3d; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7