TY - JOUR

T1 - Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

AU - Sørensen, Torben Lykke

AU - Tani, M

AU - Jensen, J

AU - Pierce, V

AU - Lucchinetti, C

AU - Folcik, V A

AU - Qin, Shuyuan

AU - Rottman, J

AU - Sellebjerg, F

AU - Strieter, R M

AU - Frederiksen, Jette L.

AU - Ransohoff, R M

PY - 1999/3

Y1 - 1999/3

N2 - Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-gamma-inducible protein of 10 kDa (IP-10); monokine induced by interferon-gamma (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine-chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.

AB - Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-gamma-inducible protein of 10 kDa (IP-10); monokine induced by interferon-gamma (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine-chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.

KW - Acute Disease

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Central Nervous System

KW - Chemokine CCL5

KW - Chemokine CXCL10

KW - Chemokine CXCL9

KW - Chemokines

KW - Chemokines, CXC

KW - Female

KW - Humans

KW - Intercellular Signaling Peptides and Proteins

KW - Male

KW - Middle Aged

KW - Multiple Sclerosis

KW - Receptors, CCR5

KW - Receptors, Chemokine

KW - Receptors, Cytokine

KW - T-Lymphocytes

U2 - 10.1172/JCI5150

DO - 10.1172/JCI5150

M3 - Journal article

C2 - 10079101

VL - 103

SP - 807

EP - 815

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -