Multiple sclerosis risk genotypes correlate with an elevated cerebrospinal fluid level of the suggested prognostic marker CXCL13

Abstract

Background:

The mechanisms of multiple sclerosis (MS) pathogenesis are still largely unknown. The heterogeneity of disease manifestations make the prediction of prognosis and choice of appropriate treatment protocols challenging. Recently, increased cerebrospinal fluid (CSF) levels of the B-cell chemokine CXCL13 was proposed as a possible marker for a more severe disease course and conversion from clinically isolated syndrome (CIS) to relapsing–remitting MS (RRMS).

Objective:

To investigate whether there are genetic susceptibility variants in MS that correlate with the levels of CXCL13 present in the CSF of MS patients.

Methods:

We genotyped the human leukocyte antigens HLA-DRB1 and HLA-A, plus a panel of single nucleotide polymorphisms (SNPs) that have been associated with susceptibility to MS and then correlated the genotypes with the levels of CXCL13, as measured with ELISA in the CSF of a total of 663 patients with MS, CIS, other neurological diseases (OND) or OND with an inflammatory component (iOND).

Results:

Presence of the HLA-DRB1*15 and the MS risk genotypes for SNPs in the RGS1, IRF5 and OLIG3/TNFAIP3 gene regions correlated significantly with increased levels of CXCL13.

Conclusion:

Our results pointed towards a genetic predisposition for increased CXCL13 levels, which in MS patients correlates with the severity of the disease course. These findings encourage further investigation and replication, in an independent patient cohort.

Keywords

Biomarker cerebrospinal fluid CXCL13 disease progression genetic susceptibility HLA multiple sclerosis prognosis single nucleotide polymorphism

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References

Sawcer

Hellenthal

Pirinen

. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214–219.

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.

Kuenz

Lutterotti

Ehling

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

Rupprecht

Pfister

Angele

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

Courtioux

Pervieux

Vatunga

. Increased CXCL-13 levels in human African trypanosomiasis meningo-encephalitis. Trop Med Int Health 2009; 14: 529–534.

Brettschneider

Czerwoniak

Senel

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

Khademi

Kockum

Andersson

. Cerebrospinal fluid CXCL13 in multiple sclerosis: A suggestive prognostic marker for the disease course. Mult Scler 2011; 17: 335–343.

Hauser

Waubant

Arnold

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

Kappos

Calabresi

. Ocrelizumab in relapsing–remitting multiple sclerosis: A phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378: 1779–1787.

10.

Marta

Stridh

Becanovic

. Multiple loci comprising immune-related genes regulate experimental neuroinflammation. Genes Immun 2010; 11: 21–36.

11.

Jagodic

Marta

Becanovic

. Resolution of a 16.8-Mb autoimmunity-regulating rat chromosome 4 region into multiple encephalomyelitis quantitative trait loci and evidence for epistasis. J Immunol 2005; 174: 918–924.

12.

Olerup

Zetterquist

. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: An alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tiss Antigens 1992; 39: 225–235.

13.

Gamazon

Zhang

Konkashbaev

. SCAN: SNP and copy number annotation. Bioinformat 2010; 26: 259–262.

14.

Xia

Shabalin

Huang

. SeeQTL: A searchable database for human eQTLs. Bioinformat 2012; 28: 451–452.

15.

Purcell

Neale

Todd-Brown

. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

16.

Benjamini

Hochberg

Controlling the false discovery rate - A practical and powerful approach to multiple testing. J Roy Stat Soc B Met 1995; 57: 289–300.

17.

Kristjansdottir

Sandling

Bonetti

. Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations. J Med Genet 2008; 45: 362–369.

18.

Cavanillas

Alcina

Nunez

. Polymorphisms in the IL2, IL2RA and IL2RB genes in multiple sclerosis risk. Eur J Hum Genet 2010; 18: 794–799.

19.

Alcina

Vandenbroeck

Otaegui

. The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis. Genes Immun 2010; 11: 439–445.

20.

Nohra

Beyeen

Guo

. RGMA and IL21R show association with experimental inflammation and multiple sclerosis. Genes Immun 2010; 11: 279–293.

21.

Jagodic

Colacios

Nohra

. A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis. Sci Transl Med 2009; 1: 10–21.

22.

International Multiple Sclerosis Genetics Consortium (IMSGC). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes Immun 2010; 11: 397–405.

23.

Barcellos

Oksenberg

Begovich

. HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 2003; 72: 710–716.

24.

Sellebjerg

Jensen

Madsen

. HLA DRB1*1501 and intrathecal inflammation in multiple sclerosis. Tiss Antigens 2000; 55: 312–318.

25.

Moratz

Kang

Druey

. Regulator of G protein signaling 1 (RGS1) markedly impairs Gi alpha signaling responses of B lymphocytes. J Immunol 2000; 164: 1829–1838.

26.

Moratz

Hayman

. Abnormal B-cell responses to chemokines, disturbed plasma cell localization, and distorted immune tissue architecture in Rgs1-/- mice. Mol Cell Biol 2004; 24: 5767–5775.

27.

Tran

Paz

Velichko

. Interferon beta-1b induces the expression of RGS1, a negative regulator of G-Protein signaling. Int J Cell Biol 2010; 2010: 529376.

28.

Takaoka

Yanai

Kondo

. Integral role of IRF-5 in the gene induction programme activated by toll-like receptors. Nature 2005; 434: 243–249.

29.

Vosslamber

Van der Voort

Van den Elskamp

. Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of interferon beta therapy in multiple sclerosis. Genes Immun 2011; 12: 466–472.

30.

Mancl

Sangster-Guity

. Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function. J Biol Chem 2005; 280: 21078–21090.

31.

Barrett

Hansoul

Nicolae

. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 2008; 40: 955–962.

32.

Musone

Taylor

. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet 2008; 40: 1062–1064.

33.

Filippi

Tiso

Deflorian

. The basic helix-loop-helix olig3 establishes the neural plate boundary of the trunk and is necessary for development of the dorsal spinal cord. Proc Natl Acad Sci USA 2005; 102: 4377–4382.

34.

Wertz

O’Rourke

Zhou

. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004; 430: 694–699.

35.

Kool

Van Loo

Waelput

. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 2011; 35: 82–96.

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