Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course

Abstract

Background: Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the cerebrospinal fluid (CSF) during multiple sclerosis (MS) and are associated with markers of MS activity. Levels decrease upon effective treatments.

Objective: Here we validate the potential role of CSF CXCL13 as a biomarker for aspects of MS in a large amount of clinical material, the majority collected at early diagnostic work-up.

Methods: CXCL13 was measured by ELISA in 837 subjects: relapsing–remitting MS (RRMS; n = 323), secondary progressive MS (SPMS; n = 40), primary progressive MS (PPMS; n = 24), clinically isolated syndrome (CIS; n = 79), other neurological diseases (ONDs; n = 181), ONDs with signs of inflammation or viral/bacterial infections (iONDs; n = 176) and healthy controls (n = 14).

Results: Subjects with viral/bacterial infections had extremely high CXCL13 levels compared to all included groups (p < 0.0001). CXCL13 was otherwise significantly higher in MS compared to the remaining controls (p < 0.0001), and CIS (p < 0.01). A significant and positive correlation between CXCL13 and relapse rate, the results obtained for the Expanded Disability Status Scale (EDSS) and the number of lesions detected by MRI was demonstrated. CXCL13 was increased in CIS conversion to clinically definite MS (p < 0.001). Oligoclonal immunoglobulin band (OCB)-positive CIS or MS had significantly increased CXCL13 levels compared to OCB-negative CIS or MS (p < 0.001 and p < 0.0001, respectively).

Conclusion: CXCL13 was associated with disease exacerbations and unfavourable prognosis in RRMS. Increased CXCL13 was not specific for MS since subjects with viral/bacterial infections exhibited even higher levels. High levels predicted CIS conversion to MS. We suggest that measurement of CSF CXCL13 can be part of the armamentarium in the diagnostic and prognostic work-up in MS and be of help in future treatment decisions.

Keywords

cerebrospinal fluid CXCL13 prognostic biomarker relapsing–remitting multiple sclerosis

Get full access to this article

View all access options for this article.

References

Compston

Coles

. Multiple sclerosis. Lancet 2002; 359: 1221–1231.

Compston

Coles

. Multiple sclerosis. Lancet 2008; 372: 1502–1517.

Daumer

Neuhaus

Herbert

Ebers

. Prognosis of the individual course of disease: The elements of time, heterogeneity and precision. J Neurol Sci 2009; 287(Suppl 1): S50–S55.

Salzer

Svenningsson

Sundstrom

. Neurofilament light as a prognostic marker in multiple sclerosis. Mult Scler 2010; 16: 287–292.

Norgren

Rosengren

Stigbrand

. Elevated neurofilament levels in neurological diseases. Brain Res 2003; 987: 25–31.

Steinman

. The development of rational strategies for selective immunotherapy against autoimmune demyelinating disease. Adv Immunol 1991; 49: 357–379.

Bielekova

Martin

. Development of biomarkers in multiple sclerosis. Brain 2004; 127: 1463–1478.

Martin

Bielekova

Hohlfeld

Utz

. Biomarkers in multiple sclerosis. Dis Markers 2006; 22: 183–185.

Link

Tibbling

. Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. Scand J Clin Lab Invest 1977; 37: 397–401.

10.

Archelos

Storch

Hartung

. The role of B cells and autoantibodies in multiple sclerosis. Ann Neurol 2000; 47: 694–706.

11.

Kuenz

Lutterotti

Ehling

. Cerebrospinal fluid B cells correlate with early brain inflammation in multiple sclerosis. PLoS One 2008; 3: e2559.

12.

Hauser

Waubant

Arnold

. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N Engl J Med 2008; 358: 676–688.

13.

Lucchinetti

Gavrilova

Metz

. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain 2008; 131: 1759–1775.

14.

Ransohoff

Kivisakk

Kidd

. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003; 3: 569–581.

15.

Sorensen

Roed

Sellebjerg

. Chemokine receptor expression on B cells and effect of interferon-beta in multiple sclerosis. J Neuroimmunol 2002; 122: 125–131.

16.

Krumbholz

Theil

Cepok

. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 2006; 129: 200–211.

17.

Sellebjerg

Bornsen

Khademi

. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS. Neurology 2009; 73: 2003–2010.

18.

Vissers

Hartgers

Lindhout

Figdor

Adema

. BLC (CXCL13) is expressed by different dendritic cell subsets in vitro and in vivo. Eur J Immunol 2001; 31: 1544–1549.

19.

Narayan

Dail

. The nervous system as ectopic germinal center: CXCL13 and IgG in lyme neuroborreliosis. Ann Neurol 2005; 57: 813–823.

20.

Rupprecht

Pfister

Angele

Kastenbauer

Wilske

Koedel

. The chemokine CXCL13 (BLC): a putative diagnostic marker for neuroborreliosis. Neurology 2005; 65: 448–450.

21.

Ljostad

Mygland

. CSF B-lymphocyte chemoattractant (CXCL13) in the early diagnosis of acute Lyme neuroborreliosis. J Neurol 2008; 255: 732–737.

22.

Rupprecht

Kirschning

Popp

. Borrelia garinii induces CXCL13 production in human monocytes through Toll-like receptor 2. Infect Immun 2007; 75: 4351–4356.

23.

Festa

Hankiewicz

Kim

. Serum levels of CXCL13 are elevated in active multiple sclerosis. Mult Scler 2009; 15: 1271–1279.

24.

Brettschneider

Czerwoniak

Senel

. The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS). PLoS One 2010; 5: e11986.

25.

McDonald

Compston

Edan

. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001; 50: 121–127.

26.

Iacobaeus

Ryschkewitsch

Gravell

. Analysis of cerebrospinal fluid and cerebrospinal fluid cells from patients with multiple sclerosis for detection of JC virus DNA. Mult Scler 2009; 15: 28–35.

27.

Rudick

Cookfair

Simonian

. Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNbeta-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. J Neuroimmunol 1999; 93: 8–14.

28.

Miller

Weinshenker

Filippi

. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler 2008; 14: 1157–1174.

29.

Piccio

Naismith

Trinkaus

. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis. Arch Neurol 2010; 67: 707–714.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.40 MB