NEUROLOGY 2009;73:2003-2010
© 2009 American Academy of Neurology
Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS
F. Sellebjerg, DMSci,
L. Börnsen, MD,
M. Khademi, PhD,
M. Krakauer, PhD,
T. Olsson, PhD,
J. L. Frederiksen, DMSci and
P. S. Sørensen, DMSci
From the University of Copenhagen and Danish MS Research Center (F.S., L.B., M. Khademi, P.S.), Department of Neurology, Copenhagen University Hospital Rigshospitalet, Denmark; Neuroimmunology Unit (M. Krakauer, T.O.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; and MS Clinic (J.L.F.), Department of Neurology, Copenhagen University Hospital Glostrup, Denmark.
Address correspondence and reprint requests to Dr. Finn Sellebjerg, Department of Neurology, Section 2082, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, DK2100 Copenhagen, Denmark sellebjerg{at}dadlnet.dk
Background: Accumulating evidence supports a major role of B cells in multiple sclerosis (MS) pathogenesis. How B cells are recruited to the CNS is incompletely understood. Our objective was to study B-cell chemokine concentrations in MS, their relationship with disease activity, and how treatment with methylprednisolone and natalizumab affected the concentration in CSF.
Methods: Using a cross-sectional design, CSF and blood samples were obtained from cohorts of patients with clinically isolated syndromes (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or secondary progressive MS (SPMS), and noninflammatory neurologic disease control subjects. Some patients with RRMS were studied before and after treatment with methylprednisolone or natalizumab.
Results: In CSF, concentrations of CXCL13, but not CXCL12, were higher in patients with CIS, RRMS, SPMS, and PPMS than in controls. CSF concentrations of CXCL13 correlated with the CSF B-cell count, with markers of immune activation, and with disease activity in patients with CIS and RRMS. CSF concentrations of CXCL13 decreased after treatment with high-dose methylprednisolone and natalizumab. High CSF concentrations of CXCL13 correlated with low expression of messenger RNA encoding the immunoregulatory cytokines interleukin 10 and transforming growth factor β1, but not with the expression of T-helper type 1 (Th1) and Th17 factors.
Conclusion: The chemokine CXCL13 may play a major role in recruitment of B cells and T-cell subsets expressing the chemokine receptor CXCR5 to the CNS in multiple sclerosis (MS), and may be a useful biomarker for treatment effects in MS. Furthermore, CXCL13 or its receptor CXCR5 should be considered as therapeutic targets in MS.
Abbreviations: cDNA = complementary DNA; CIS = clinically isolated syndromes; EAE = experimental autoimmune encephalomyelitis; Gd = gadolinium; IgG = immunoglobulin G; IL = interleukin; IQR = interquartile range; MBP = myelin basic protein; MMP = metalloproteinase; MNC = mononuclear cell; mRNA = messenger RNA; MS = multiple sclerosis; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; SRCC = Spearman rank correlation coefficient; TGF = transforming growth factor.
Supplemental data at www.neurology.org
Supported by grants from the Danish Multiple Sclerosis Society, the Warwara Larsen Foundation, the Johnsen Memorial Foundation, the Lily Benthine Lund Foundation, the Novo Nordisk Foundation, the Danish Medical Research Council, Brdr. Rønje Holding, the Ludvig and Sara Elsass Foundation, the Toyota Foundation, the Swedish Research Council, the Montel Williams Foundation, Bibbi and Niels Jensens Foundation, FP6 Neuropromise (LSHM-CT-2005-018637), and research grants from Biogen Idec.
Disclosure: Author disclosures are provided at the end of the article.
Received May 6, 2009. Accepted in final form September 17, 2009.
