Journal Article

Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment

Markus Krumbholz, Diethilde Theil, Sabine Cepok, Bernhard Hemmer, Pia Kivisäkk, Richard M. Ransohoff, Monika Hofbauer, Cinthia Farina, Tobias Derfuss, Caroline Hartle, Jia Newcombe, Reinhard Hohlfeld and Edgar Meinl

in Brain

Published on behalf of The Guarantors of Brain

Volume 129, issue 1, pages 200-211
Published in print January 2006 | ISSN: 0006-8950
Published online November 2005 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awh680
Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment

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Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing–remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFα and IL-1β but inhibited by IL-4 and IFNγ. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis.

Keywords: lymphocytes; chemokines; cerebrospinal fluid; inflammation; immune cell migration; BBB = blood–brain barrier; Ig = immunoglobulin; mAb = monoclonal antibody; NIND = non-inflammatory neurological diseases; OIND = other inflammatory neurological diseases (other than multiple sclerosis); PBMC = peripheral blood mononuclear cells; PP = primary progressive; RR = relapsing–remitting; SP = secondary progressive

Journal Article.  8681 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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