Mika Komori1, Andrew Blake1, Mark Greenwood2, Yen Chih Lin1, Peter Kosa1, Danish Ghazali1, Paige Winokur1, Muktha Natrajan1, Simone C Wuest1, Elena Romm1, Anil A Panackal3, Peter R Williamson3, Tianxia Wu4, Bibiana Bielekova1. 1. Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. 2. Department of Mathematical Sciences, Montana State University, Bozeman, MT. 3. Translational Mycology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. 4. Clinical Neuroscience Program, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD.
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. INTERPRETATION: 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. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
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. INTERPRETATION: 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. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
Authors: Sophie Desplat-Jégo; Lionel Feuillet; Jean Pelletier; Dominique Bernard; André Ali Chérif; José Boucraut Journal: J Clin Immunol Date: 2005-07 Impact factor: 8.317
Authors: Sean X Leng; Janet E McElhaney; Jeremy D Walston; Dongxu Xie; Neal S Fedarko; George A Kuchel Journal: J Gerontol A Biol Sci Med Sci Date: 2008-08 Impact factor: 6.053
Authors: Chris H Polman; Stephen C Reingold; Brenda Banwell; Michel Clanet; Jeffrey A Cohen; Massimo Filippi; Kazuo Fujihara; Eva Havrdova; Michael Hutchinson; Ludwig Kappos; Fred D Lublin; Xavier Montalban; Paul O'Connor; Magnhild Sandberg-Wollheim; Alan J Thompson; Emmanuelle Waubant; Brian Weinshenker; Jerry S Wolinsky Journal: Ann Neurol Date: 2011-02 Impact factor: 10.422
Authors: Mary C Zuniga; Thuy B Tran; Brittanie D Baughman; Gayatri Raghuraman; Elizabeth Hitchner; Allyson Rosen; Wei Zhou Journal: Ann Surg Date: 2016-10 Impact factor: 12.969
Authors: Anil A Panackal; Mika Komori; Peter Kosa; Omar Khan; Dima A Hammoud; Lindsey B Rosen; Sarah K Browne; Yen-Chih Lin; Elena Romm; Charu Ramaprasad; Bettina C Fries; John E Bennett; Bibiana Bielekova; Peter R Williamson Journal: Clin Infect Dis Date: 2016-11-10 Impact factor: 9.079
Authors: Seher Anjum; Owen Dean; Peter Kosa; M Teresa Magone; Kelly A King; Edmond Fitzgibbon; H Jeff Kim; Chris Zalewski; Elizabeth Murphy; Bridgette Jeanne Billioux; Jennifer Chisholm; Carmen C Brewer; Chantal Krieger; Waleed Elsegeiny; Terri L Scott; Jing Wang; Sally Hunsberger; John E Bennett; Avindra Nath; Kieren A Marr; Bibiana Bielekova; David Wendler; Dima A Hammoud; Peter Williamson Journal: Clin Infect Dis Date: 2021-11-02 Impact factor: 9.079
Authors: Zara A Ioannides; Peter A Csurhes; Andrew Swayne; Philippe Foubert; Blake T Aftab; Michael P Pender Journal: Mult Scler J Exp Transl Clin Date: 2021-06-03