Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis

被引：114

作者：

Komori, Mika ^{[1
]}

Blake, Andrew ^{[1
]}

Greenwood, Mark ^{[2
]}

Lin, Yen Chih ^{[1
]}

Kosa, Peter ^{[1
]}

Ghazali, Danish ^{[1
]}

Winokur, Paige ^{[1
]}

Natrajan, Muktha ^{[1
]}

Wuest, Simone C. ^{[1
]}

Romm, Elena ^{[1
]}

Panackal, Anil A. ^{[3
]}

Williamson, Peter R. ^{[3
]}

Wu, Tianxia ^{[4
]}

Bielekova, Bibiana ^{[1
]}

机构：

[1] NINDS, Neuroimmunol Dis Unit, NIH, Bethesda, MD 20892 USA

[2] Montana State Univ, Dept Math Sci, Bozeman, MT 59717 USA

[3] NIAID, Translat Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA

[4] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA

来源：

ANNALS OF NEUROLOGY | 2015年 / 78卷 / 01期

关键词：

TRANSPLANTATION FAILS; DISEASE; CXCL13; CELLS; MRI; HETEROGENEITY; ACTIVATION; BIOMARKERS; UTILITY; LESIONS;

D O I：

10.1002/ana.24408

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

ObjectiveThe 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. MethodsBecause 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. ResultsAmong 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. InterpretationThe 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. Ann Neurol 2015;78:3-20

引用

页码：3 / 20

页数：18

共 46 条

[1] The influence of disease duration, clinical course, and immunosuppressive therapy on the synthesis of intrathecal oligoclonal IgG bands in multiple sclerosis [J].

Axelsson, Markus ;

Mattsson, Niklas ;

Malmestrom, Clas ;

Zetterberg, Henrik ;

Lycke, Jan .

JOURNAL OF NEUROIMMUNOLOGY, 2013, 264 (1-2) :100-105

[2] MRI as a marker for disease heterogeneity in multiple sclerosis [J].

Bielekova, B ;

Kadom, N ;

Fisher, E ;

Jeffries, N ;

Ohayon, J ;

Richert, N ;

Howard, T ;

Bash, CN ;

Frank, JA ;

Stone, L ;

Martin, R ;

Cutter, G ;

McFarland, HF .

NEUROLOGY, 2005, 65 (07) :1071-1076

[3] Development of biomarkers in multiple sclerosis [J].

Bielekova, B ;

Martin, R .

BRAIN, 2004, 127 :1463-1478

[4] How implementation of systems biology into clinical trials accelerates understanding of diseases [J].

Bielekova, Bibiana ;

Vodovotz, Yoram ;

An, Gary ;

Hallenbeck, John .

FRONTIERS IN NEUROLOGY, 2014, 5

[5] SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation [J].

Blewitt, Marnie E. ;

Gendrel, Anne-Valerie ;

Pang, Zhenyi ;

Sparrow, Duncan B. ;

Whitelaw, Nadia ;

Craig, Jeffrey M. ;

Apedaile, Anwyn ;

Hilton, Douglas J. ;

Dunwoodie, Sally L. ;

Brockdorff, Neil ;

Kay, Graham F. ;

Whitelaw, Emma .

NATURE GENETICS, 2008, 40 (05) :663-669

[6] Intrathecal IgG Synthesis: A Resistant and Valuable Target for Future Multiple Sclerosis Treatments [J].

Bonnan, Mickael .

MULTIPLE SCLEROSIS INTERNATIONAL, 2015, 2015

[7] IMMUNOHISTOLOGICAL ANALYSIS OF LYMPHOCYTE-T SUBSETS IN THE CENTRAL NERVOUS-SYSTEM IN CHRONIC PROGRESSIVE MULTIPLE-SCLEROSIS [J].

BOOSS, J ;

ESIRI, MM ;

TOURTELLOTTE, WW ;

MASON, DY .

JOURNAL OF THE NEUROLOGICAL SCIENCES, 1983, 62 (1-3) :219-232

[8] Body fluid biomarkers in multiple sclerosis [J].

Comabella, Manuel ;

Montalban, Xavier .

LANCET NEUROLOGY, 2014, 13 (01) :113-126

[9] Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis [J].

Comabella, Manuel ;

Fernandez, Marta ;

Martin, Roland ;

Rivera-Vallve, Stephanie ;

Borras, Eva ;

Chiva, Cristina ;

Julia, Eva ;

Rovira, Alex ;

Canto, Ester ;

Carlos Alvarez-Cermeno, Jose ;

Maria Villar, Luisa ;

Tintore, Mar ;

Montalban, Xavier .

BRAIN, 2010, 133 :1082-1093

[10] Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity [J].

Crow, Yanick J. ;

Rehwinkel, Jan .

HUMAN MOLECULAR GENETICS, 2009, 18 :R130-R136

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