Navikas V, He B, Link J, Haglund M, Söderström M, Fredrikson S, Höjeberg J, Qiao J, Olsson T, Link H
Division of Neurology, Huddinge Hospital, Sweden.
Brain. 1996 Feb;119 ( Pt 1):213-23. doi: 10.1093/brain/119.1.213.
The involvement of proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and lymphotoxin (LT) in multiple sclerosis is suggested by the parallel occurrence of these proinflammatory cytokines in acute and chronic active multiple sclerosis brain lesions. We describe the use of in situ hybridization with radiolabelled cDNA oligonucleotide probes to detect and enumerate TNF-alpha and LT mRNA expressing mononuclear cells without culture, and after culture in the presence of myelin basic protein (MBP), control antigens or without antigen. Compared with patients with aseptic meningo-encephalitis, non-inflammatory neurological diseases and healthy controls, the multiple sclerosis patients had elevated numbers of TNF-alpha and LT mRNA expressing mononuclear cells in blood when enumerated without previous culture, and also after culture with MBP. The MBP-induced upregulation of TNF-alpha and LT was major histocompatibility complex (MHC) class II molecule dependent. Tumour necrosis factor-alpha mRNA expressing mononuclear cells were further enriched in the multiple sclerosis patients' CSF. Positive correlations were observed in multiple sclerosis between TNF-alpha and LT mRNA expressing blood mononuclear cells, MBP-reactive TNF-alpha and LT mRNA expressing cells, and TNF-alpha and interferon-gamma (INF-gamma) mRNA expressing mononuclear cells. Upregulation of TNF-alpha correlated positively with exacerbation, enhanced disability and the secondary progressive phase of multiple sclerosis. Patients with optic neuritis, in many instances representing very early multiple sclerosis, had TNF-alpha and LT positive blood mononuclear cells that were elevated to the same extent as patients with clinically definite multiple sclerosis. The findings support the hypothesis that TNF-alpha and LT play a harmful role in the development of multiple sclerosis and suggest that TNF-alpha could be useful as a disease activity marker in multiple sclerosis.
促炎细胞因子肿瘤坏死因子-α（TNF-α）和淋巴毒素（LT）与多发性硬化症的关联，是由这些促炎细胞因子在急性和慢性活动性多发性硬化症脑损伤中同时出现所提示的。我们描述了使用放射性标记的cDNA寡核苷酸探针进行原位杂交，以检测和计数表达TNF-α和LT mRNA的单核细胞，无需培养，以及在髓鞘碱性蛋白（MBP）、对照抗原存在下培养或无抗原培养后。与无菌性脑膜脑炎患者、非炎性神经疾病患者和健康对照相比，多发性硬化症患者在未进行预先培养时以及与MBP培养后，血液中表达TNF-α和LT mRNA的单核细胞数量增加。MBP诱导的TNF-α和LT上调依赖于主要组织相容性复合体（MHC）II类分子。表达TNF-α mRNA的单核细胞在多发性硬化症患者的脑脊液中进一步富集。在多发性硬化症中，表达TNF-α和LT mRNA的血液单核细胞、表达MBP反应性TNF-α和LT mRNA的细胞以及表达TNF-α和干扰素-γ（INF-γ）mRNA的单核细胞之间观察到正相关。TNF-α的上调与多发性硬化症的病情加重、残疾加剧和继发进展期呈正相关。视神经炎患者，在许多情况下代表非常早期的多发性硬化症，其TNF-α和LT阳性血液单核细胞升高到与临床确诊的多发性硬化症患者相同的程度。这些发现支持了TNF-α和LT在多发性硬化症发展中起有害作用的假说，并表明TNF-α可作为多发性硬化症疾病活动的标志物。
