Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF.
BACKGROUND
Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML).


OBJECTIVE
We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37).


METHODS
Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid.


RESULTS
In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid.


CONCLUSIONS
Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany clemens.warnke@med.uni-duesseldorf.de.
Clemens
C
Warnke
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
Mark
M
Stettner
Department of Neurology, University of Ulm, Ulm, Germany.
Vera
V
Lehmensiek
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
Thomas
T
Dehmel
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
Anne K
AK
Mausberg
National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
Gloria
G
von Geldern
Department of Neurology, Ruhr University, Bochum, Germany.
Ralf
R
Gold
Institute of Clinical Neuroimmunology, Ludwig Maximilian University and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Tania
T
Kümpfel
Institute of Clinical Neuroimmunology, Ludwig Maximilian University and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Reinhard
R
Hohlfeld
Department of Neurology, Caritas Hospital, Bad Mergentheim, Germany.
Mathias
M
Mäurer
Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hanover Medical School, Hanover, Germany.
Martin
M
Stangel
Department of Neurology, Johannes Wesling Hospital Minden, Minden, Germany.
Vera
V
Straeten
Department of Neurology, Merheim Hospital, Cologne, Germany.
Volker
V
Limmroth
Department of Neurology, Marienhospital Hamburg, Hamburg, Germany.
Thomas
T
Weber
Department of Neurology, University Hospital Wuerzburg, Wuerzburg, Germany.
Christoph
C
Kleinschnitz
MS Center Amsterdam and Department of Radiology, Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, the Netherlands.
Mike P
MP
Wattjes
Department of Pharmacology and Clinical Neuroscience, Umea University Hospital, Umea, Sweden.
Anders
A
Svenningsson
Department of Neurology, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Tomas
T
Olsson
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
Hans-Peter
HP
Hartung
Institute for Clinical Chemistry and Laboratory Diagnostics, University Hospital Duesseldorf, Germany.
Derik
D
Hermsen
Department of Neurology, University of Ulm, Ulm, Germany.
Hayrettin
H
Tumani
Institute for Virology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
Ortwin
O
Adams
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
Bernd C
BC
Kieseier
D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000097:blood / Q000134:cerebrospinal fluid; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D016516:CD4-CD8 Ratio; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000134:cerebrospinal fluid; D007075:Immunoglobulin M / Q000097:blood / Q000134:cerebrospinal fluid; D007155:Immunologic Factors / Q000009:adverse effects* / Q000627:therapeutic use; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D000069442:Natalizumab / Q000009:adverse effects* / Q000627:therapeutic use; D043025:Oligoclonal Bands / Q000276:immunology; D055815:Young Adult
D018941:Antigens, CD19; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007155:Immunologic Factors; D000069442:Natalizumab; D043025:Oligoclonal Bands
JC virus; Progressive multifocal leukoencephalopathy; Tysabri; disease-modifying therapies; immunosuppression; multiple sclerosis; natalizumab