Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood-brain barrier disruption.
BACKGROUND
Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood-brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown.


OBJECTIVE
We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO.


METHODS
The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients.


RESULTS
NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions.


CONCLUSIONS
In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Tomohiko
T
Uchida
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Masahiro
M
Mori
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Akiyuki
A
Uzawa
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Hiroki
H
Masuda
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Mayumi
M
Muto
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Ryohei
R
Ohtani
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Satoshi
S
Kuwabara
D000328:Adult; D000418:Albumins / Q000134:cerebrospinal fluid*; D051401:Aquaporin 4 / Q000134:cerebrospinal fluid / Q000276:immunology; D001323:Autoantibodies / Q000134:cerebrospinal fluid; D001812:Blood-Brain Barrier; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000134:cerebrospinal fluid*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000134:cerebrospinal fluid*; D008875:Middle Aged; D009471:Neuromyelitis Optica / Q000134:cerebrospinal fluid* / Q000473:pathology
D000418:Albumins; D051401:Aquaporin 4; D001323:Autoantibodies; C508600:IL6 protein, human; D015850:Interleukin-6; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
Neuromyelitis optica; blood–brain barrier; matrix metalloproteinases; tissue inhibitors of metalloproteinases