Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis

Takaaki Ishizu, Manabu Osoegawa, Feng Jun Mei, Hitoshi Kikuchi, Masahito Tanaka, Yuka Takakura, Motozumi Minohara, Hiroyuki Murai, Futoshi Mihara, Takayuki Taniwaki, Jun Ichi Kira

Research output: Contribution to journalArticle

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Abstract

There are two distinct subtypes of multiple sclerosis in Asians, opticospinal (OS-multiple sclerosis) and conventional (C-multipie sclerosis). In OS-multiple sclerosis, selective and severe involvement of the optic nerves and spinal cord is characteristic, though its mechanisms are unknown. The present study aimed to find out possible differences in the cytokine/chemokine profiles in CSF between OS-multiple sclerosis and C-multiple sclerosis and to delineate the relationships between these profiles and neuroimaging and pathological features. Sixteen cytokines/chemokines, namely interieukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), monocyte chenioattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β), were measured simultaneously in CSF supernatants from 40 patients with relapsing-remitting multiple sclerosis (20 OS-multiple sclerosis and 20 C-multiple sclerosis) at relapse and 19 control patients with spinocerebellar degeneration (SCD), together with intracellular production of IFN-γ and IL-4 in CSF CD4 + T cells. In CSF supernatants relative to controls, IL-17, MIP-1β, IL-1β and IL-13 were only significantly increased in OS-multiple sclerosis patients, while TNF-α was only significantly increased in C-multiple sclerosis patients, using a cut-off level of 1 pg/ml. IL-8 was significantly elevated in both OS-multiple sclerosis and C-multiple sclerosis patients. MCP-1 was significantly decreased in both OS-multiple sclerosis and C-multiple sclerosis patients, while IL-7 was only significantly decreased in C-multiple sclerosis patients. IL-17, IL-8 and IL-5 were significantly higher in OS-multiple sclerosis patients than in C-multiple sclerosis patients. The increases in IL-17 and IL-8 in OS multiple sclerosis were still significant even after exclusion of the patients undergoing various immunomodulatory therapies. Assays of intracellular cytokine production revealed that both the IFN-γ+IL-4- T-cell percentage and intracellular IFN-γ/IL-4 ratio in CSF cells were significantly greater in C-multiple sclerosis patients than in controls. Contrarily, OS-multiple sclerosis patiente showed not only a significantly greater percentage of T cells than controls but also a significantly higher percentage of IFN-γ-IL-4+ T cells than C-multiple sclerosis patients. Among the cytokines elevated in multiple sclerosis, only IL-8 showed a significant positive correlation with the Expanded Disability Status Scale of Kurtzke score. Both the length of the spinal cord lesions on MRI and the CSF/serum albumin ratio had a significant positive correlation with IL-8 and EL-17 in multiple sclerosis, in which the spinal cord lesions were significantly longer in OS-multiple sclerosis than in C-multiple sclerosis. Three of six spinal cord specimens from autopsied OS-multiple sclerosis cases demonstrated numerous myeloperoxidase-positive neutrophils infiltrating necrotic lesions. These findings strongly suggest that in OS-multiple sclerosis, in addition to the Th1 cell upregulation seen in C-multiple sclerosis, intrathecal activation of the IL-17/IL-8 axis inducing heavy neutrophil infiltration contributes to extensive spinal cord lesion formation.

Original languageEnglish
Pages (from-to)988-1002
Number of pages15
JournalBrain
Volume128
Issue number5
DOIs
Publication statusPublished - May 1 2005

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Interleukin-17
Interleukin-8
Multiple Sclerosis
Interleukin-4
Interferons
Spinal Cord
Opticospinal Multiple Sclerosis
Cytokines
T-Lymphocytes
Macrophage Inflammatory Proteins
Interleukin-7
Interleukin-13
Interleukin-5
Interleukin-1
Chemokines
Monocytes
Tumor Necrosis Factor-alpha

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Ishizu, T., Osoegawa, M., Mei, F. J., Kikuchi, H., Tanaka, M., Takakura, Y., ... Kira, J. I. (2005). Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain, 128(5), 988-1002. https://doi.org/10.1093/brain/awh453

Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. / Ishizu, Takaaki; Osoegawa, Manabu; Mei, Feng Jun; Kikuchi, Hitoshi; Tanaka, Masahito; Takakura, Yuka; Minohara, Motozumi; Murai, Hiroyuki; Mihara, Futoshi; Taniwaki, Takayuki; Kira, Jun Ichi.

In: Brain, Vol. 128, No. 5, 01.05.2005, p. 988-1002.

Research output: Contribution to journalArticle

Ishizu, T, Osoegawa, M, Mei, FJ, Kikuchi, H, Tanaka, M, Takakura, Y, Minohara, M, Murai, H, Mihara, F, Taniwaki, T & Kira, JI 2005, 'Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis', Brain, vol. 128, no. 5, pp. 988-1002. https://doi.org/10.1093/brain/awh453
Ishizu T, Osoegawa M, Mei FJ, Kikuchi H, Tanaka M, Takakura Y et al. Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain. 2005 May 1;128(5):988-1002. https://doi.org/10.1093/brain/awh453
Ishizu, Takaaki ; Osoegawa, Manabu ; Mei, Feng Jun ; Kikuchi, Hitoshi ; Tanaka, Masahito ; Takakura, Yuka ; Minohara, Motozumi ; Murai, Hiroyuki ; Mihara, Futoshi ; Taniwaki, Takayuki ; Kira, Jun Ichi. / Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. In: Brain. 2005 ; Vol. 128, No. 5. pp. 988-1002.
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author = "Takaaki Ishizu and Manabu Osoegawa and Mei, {Feng Jun} and Hitoshi Kikuchi and Masahito Tanaka and Yuka Takakura and Motozumi Minohara and Hiroyuki Murai and Futoshi Mihara and Takayuki Taniwaki and Kira, {Jun Ichi}",
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AU - Ishizu, Takaaki

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AU - Mei, Feng Jun

AU - Kikuchi, Hitoshi

AU - Tanaka, Masahito

AU - Takakura, Yuka

AU - Minohara, Motozumi

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AU - Kira, Jun Ichi

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N2 - There are two distinct subtypes of multiple sclerosis in Asians, opticospinal (OS-multiple sclerosis) and conventional (C-multipie sclerosis). In OS-multiple sclerosis, selective and severe involvement of the optic nerves and spinal cord is characteristic, though its mechanisms are unknown. The present study aimed to find out possible differences in the cytokine/chemokine profiles in CSF between OS-multiple sclerosis and C-multiple sclerosis and to delineate the relationships between these profiles and neuroimaging and pathological features. Sixteen cytokines/chemokines, namely interieukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), monocyte chenioattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β), were measured simultaneously in CSF supernatants from 40 patients with relapsing-remitting multiple sclerosis (20 OS-multiple sclerosis and 20 C-multiple sclerosis) at relapse and 19 control patients with spinocerebellar degeneration (SCD), together with intracellular production of IFN-γ and IL-4 in CSF CD4 + T cells. In CSF supernatants relative to controls, IL-17, MIP-1β, IL-1β and IL-13 were only significantly increased in OS-multiple sclerosis patients, while TNF-α was only significantly increased in C-multiple sclerosis patients, using a cut-off level of 1 pg/ml. IL-8 was significantly elevated in both OS-multiple sclerosis and C-multiple sclerosis patients. MCP-1 was significantly decreased in both OS-multiple sclerosis and C-multiple sclerosis patients, while IL-7 was only significantly decreased in C-multiple sclerosis patients. IL-17, IL-8 and IL-5 were significantly higher in OS-multiple sclerosis patients than in C-multiple sclerosis patients. The increases in IL-17 and IL-8 in OS multiple sclerosis were still significant even after exclusion of the patients undergoing various immunomodulatory therapies. Assays of intracellular cytokine production revealed that both the IFN-γ+IL-4- T-cell percentage and intracellular IFN-γ/IL-4 ratio in CSF cells were significantly greater in C-multiple sclerosis patients than in controls. Contrarily, OS-multiple sclerosis patiente showed not only a significantly greater percentage of T cells than controls but also a significantly higher percentage of IFN-γ-IL-4+ T cells than C-multiple sclerosis patients. Among the cytokines elevated in multiple sclerosis, only IL-8 showed a significant positive correlation with the Expanded Disability Status Scale of Kurtzke score. Both the length of the spinal cord lesions on MRI and the CSF/serum albumin ratio had a significant positive correlation with IL-8 and EL-17 in multiple sclerosis, in which the spinal cord lesions were significantly longer in OS-multiple sclerosis than in C-multiple sclerosis. Three of six spinal cord specimens from autopsied OS-multiple sclerosis cases demonstrated numerous myeloperoxidase-positive neutrophils infiltrating necrotic lesions. These findings strongly suggest that in OS-multiple sclerosis, in addition to the Th1 cell upregulation seen in C-multiple sclerosis, intrathecal activation of the IL-17/IL-8 axis inducing heavy neutrophil infiltration contributes to extensive spinal cord lesion formation.

AB - There are two distinct subtypes of multiple sclerosis in Asians, opticospinal (OS-multiple sclerosis) and conventional (C-multipie sclerosis). In OS-multiple sclerosis, selective and severe involvement of the optic nerves and spinal cord is characteristic, though its mechanisms are unknown. The present study aimed to find out possible differences in the cytokine/chemokine profiles in CSF between OS-multiple sclerosis and C-multiple sclerosis and to delineate the relationships between these profiles and neuroimaging and pathological features. Sixteen cytokines/chemokines, namely interieukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), monocyte chenioattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β), were measured simultaneously in CSF supernatants from 40 patients with relapsing-remitting multiple sclerosis (20 OS-multiple sclerosis and 20 C-multiple sclerosis) at relapse and 19 control patients with spinocerebellar degeneration (SCD), together with intracellular production of IFN-γ and IL-4 in CSF CD4 + T cells. In CSF supernatants relative to controls, IL-17, MIP-1β, IL-1β and IL-13 were only significantly increased in OS-multiple sclerosis patients, while TNF-α was only significantly increased in C-multiple sclerosis patients, using a cut-off level of 1 pg/ml. IL-8 was significantly elevated in both OS-multiple sclerosis and C-multiple sclerosis patients. MCP-1 was significantly decreased in both OS-multiple sclerosis and C-multiple sclerosis patients, while IL-7 was only significantly decreased in C-multiple sclerosis patients. IL-17, IL-8 and IL-5 were significantly higher in OS-multiple sclerosis patients than in C-multiple sclerosis patients. The increases in IL-17 and IL-8 in OS multiple sclerosis were still significant even after exclusion of the patients undergoing various immunomodulatory therapies. Assays of intracellular cytokine production revealed that both the IFN-γ+IL-4- T-cell percentage and intracellular IFN-γ/IL-4 ratio in CSF cells were significantly greater in C-multiple sclerosis patients than in controls. Contrarily, OS-multiple sclerosis patiente showed not only a significantly greater percentage of T cells than controls but also a significantly higher percentage of IFN-γ-IL-4+ T cells than C-multiple sclerosis patients. Among the cytokines elevated in multiple sclerosis, only IL-8 showed a significant positive correlation with the Expanded Disability Status Scale of Kurtzke score. Both the length of the spinal cord lesions on MRI and the CSF/serum albumin ratio had a significant positive correlation with IL-8 and EL-17 in multiple sclerosis, in which the spinal cord lesions were significantly longer in OS-multiple sclerosis than in C-multiple sclerosis. Three of six spinal cord specimens from autopsied OS-multiple sclerosis cases demonstrated numerous myeloperoxidase-positive neutrophils infiltrating necrotic lesions. These findings strongly suggest that in OS-multiple sclerosis, in addition to the Th1 cell upregulation seen in C-multiple sclerosis, intrathecal activation of the IL-17/IL-8 axis inducing heavy neutrophil infiltration contributes to extensive spinal cord lesion formation.

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