TY - JOUR
T1 - Chemokines in multiple sclerosis
T2 - CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment
AU - Krumbholz, Markus
AU - Theil, Diethilde
AU - Cepok, Sabine
AU - Hemmer, Bernhard
AU - Kivisäkk, Pia
AU - Ransohoff, Richard M.
AU - Hofbauer, Monika
AU - Farina, Cinthia
AU - Derfuss, Tobias
AU - Hartle, Caroline
AU - Newcombe, Jia
AU - Hohlfeld, Reinhard
AU - Meinl, Edgar
N1 - Funding Information:
We thank D. Zech for technical assistance, Dr S. Wagenpfeil for help with the statistical analyses, and Dr A. Flügel and Dr D. Jenne for comments on the manuscript. This work was supported by the DFG (SFB 571, GRK 688, He2386/5-1 and 5-2), the DMSG, the Verein zur Förderung der Therapieforschung für MS-Kranke and the USA National Institutes of Health (PO1 NS38667 to R.M.R.). The Institute for Clinical Neuroimmunology is supported by the Hermann and Lilly Schilling Foundation.
PY - 2006/1
Y1 - 2006/1
N2 - 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 CXCLI2 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.
AB - 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 CXCLI2 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.
KW - Cerebrospinal fluid
KW - Chemokines
KW - Immune cell migration
KW - Inflammation
KW - Lymphocytes
UR - http://www.scopus.com/inward/record.url?scp=30344446249&partnerID=8YFLogxK
U2 - 10.1093/brain/awh680
DO - 10.1093/brain/awh680
M3 - Article
C2 - 16280350
AN - SCOPUS:30344446249
SN - 0006-8950
VL - 129
SP - 200
EP - 211
JO - Brain
JF - Brain
IS - 1
ER -