Suvannavejh G C, Lee H O, Padilla J, Dal Canto M C, Barrett T A, Miller S D
Department of Microbiology-Immunology, Interdepartmental Immunology Center, Northwestern University Medical School, 303 E Chicago Avenue, Illinois 60611, USA.
Cell Immunol. 2000 Oct 10;205(1):24-33. doi: 10.1006/cimm.2000.1706.
To clarify the role of tumor necrosis factor (TNF) in the inflammatory aspects of autoimmunity vs its potential role in the apoptotic elimination of autoreactive effector cells, we assessed the roles of the p55 (TNFR1/Tnfrsf1a/CD120a) and p75 (TNFR2/Tnfrsf1b/CD120b) TNF receptors in the pathogenesis of MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE). TNFR p55/p75(-/-) double knockout mice were completely resistant to clinical disease. TNFR p55(-/-) single knockout mice were also totally resistant to EAE, exhibiting reduced MOG(35-55)- specific proliferative responses and Th1 cytokine production, despite displaying equivalent DTH responses. Importantly, IL-5 was significantly increased in p55(-/-) mice. In contrast, p75(-/-) knockout mice exhibited exacerbated EAE, enhanced Th1 cytokine production, and enhanced CD4(+) and F4/80(+) CNS infiltration. Thus, p55/TNFR1 is required for the initiation of pathologic disease, whereas p75/TNFR2 may be important in regulating the immune response. These results have important implications for therapies targeting p55 and p75 receptors for treating autoimmune diseases.
为了阐明肿瘤坏死因子（TNF）在自身免疫炎症方面的作用与其在自身反应性效应细胞凋亡清除中的潜在作用，我们评估了p55（TNFR1/Tnfrsf1a/CD120a）和p75（TNFR2/Tnfrsf1b/CD120b）TNF受体在髓鞘少突胶质细胞糖蛋白（MOG）（35-55）诱导的实验性自身免疫性脑脊髓炎（EAE）发病机制中的作用。TNFR p55/p75（-/-）双敲除小鼠对临床疾病完全具有抗性。TNFR p55（-/-）单敲除小鼠对EAE也完全具有抗性，尽管其迟发型超敏反应（DTH）相当，但MOG（35-55）特异性增殖反应和Th1细胞因子产生减少。重要的是，p55（-/-）小鼠中白细胞介素-5显著增加。相比之下，p75（-/-）敲除小鼠表现出EAE加重、Th1细胞因子产生增强以及CD4（+）和F4/80（+）中枢神经系统浸润增强。因此，p55/TNFR1是病理性疾病起始所必需的，而p75/TNFR2可能在调节免疫反应中起重要作用。这些结果对于靶向p55和p75受体治疗自身免疫性疾病具有重要意义。
