Research: markers of severity?

Epub: Lindén et al. Multiple sclerosis risk genotypes correlate with an elevated cerebrospinal fluid level of the suggested prognostic marker CXCL13. Mult Scler. 2012 Nov.

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).

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

METHODSWe 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).

RESULTSPresence of the HLA-DRB1*15 (MHC transplantation antigen involved in immune recognition) and the MS risk genotypes for SNPs in the RGS1 (Regulator of G-protein signaling 1) , IRF5 (Interferon regulatory factor 5. This acts as a molecular switch that controls whether macrophages will promote or inhibit inflammation) and OLIG3/TNFAIP3 gene regions (Oligodendrocyte transcription factor 3/Tumor necrosis factor, alpha-induced protein 3 whcih controls inflammation correlated significantly with increased levels of CXCL13.

CONCLUSIONOur results pointed towards a genetic predisposition for increased CXCL13 levels, which in MS patients correlates with the severity of the disease course.

CXCL13 is a small cytokine belonging to the CXC chemokine family. As its name suggests, this chemokine is selectively chemotactic for B cells and elicits its effects by interacting with chemokine receptor CXCR5. CXCL13 and its receptor CXCR5 control the organization of B cells within follicles of lymphoid tissues. One hypothesis about the course of MS is that severity depends on B cell follicles. The chemokine CXCL13 has been implicated in this. In this study the authors examine if they could find clusters of MS susceptibility genes that are associated with more CXCL13. They found a cluster of 5 genes, which are linked to control of inflammation. This study will need to be replicated.

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