视神经脊髓型多发性硬化症髓鞘内IL-17/IL-8轴的激活

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

There are two distinct subtypes of multiple sclerosis in Asians, opticospinal (OS- multiple sclerosis) and conventional (C- multipie sclerosis). In OS- mu ltiple sclerosis, selective and severe involvement of the optic nerves and spina l cord is characteristic, though its mechanisms are unknown. The present study a imed 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, I L- 5, IL- 6, IL- 7, IL- 8, IL- 10, IL- 12 (p70), IL- 13, IL- 17, interfe ron (IFN)- γ , tumour necrosis factor (TNF)- α , granulocyte colony- stimul ating factor (G- CSF), monocyte chenioattractant protein- 1 (MCP- 1) and macr ophage 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 con trol patients with spinocerebellar degeneration (SCD), together with intracellul ar 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 signi ficantly increased in OS- multiple sclerosis patients, while TNF- α was only significantly increased in C- multiple sclerosis patients, using a cut- off l evel of 1 pg/ml. IL- 8 was significantly elevated in both OS- multiple scleros is and C- multiple sclerosis patients. MCP- 1 was significantly decreased in b oth OS- multiple sclerosis and C- multiple sclerosis patients, while IL- 7 wa s only significantly decreased in C- multiple sclerosis patients. IL- 17, IL- 8 and IL- 5 were significantly higher in OSmultiple sclerosis patients than in C- multiple sclerosis patients. The increases in IL- 17 and IL- 8 in OS mult iple sclerosis were still significant even after exclusion of the patients under going various immunomodulatory therapies. Assays of intracellular cytokine produ ction revealed that both the IFN- γ + IL- 4- T- cell percentage and intrac ellular IFN- γ /IL- 4 ratio in CSF cells were significantly greater in C- mu ltiple sclerosis patients than in controls. Contrarily, OS- multiple sclerosis patiente showed not only a significantly greater percentage of T cells than cont rols 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 Expand ed 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 correl ation with IL- 8 and EL- 17 in multiple sclerosis, in which the spinal cord le sions 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 nec- rotic lesions. These findings strongly suggest that in OS- multiple sclerosi s, in addition to the Th1 cell upregulation seen in C- multiple sclerosis, intr athecal activation of the IL- 17/IL- 8 axis inducing heavy neutrophil infiltra tion contributes to extensive spinal cord lesion formation.