Division of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
Front Immunol. 2018 Oct 8;9:2311. doi: 10.3389/fimmu.2018.02311. eCollection 2018.
Genome-wide association studies as well as lymphatic expression analyses have linked both Cbl-b and GM-CSF to human multiple sclerosis as well as other autoimmune diseases. Both Cbl-b and GM-CSF have been shown to play a prominent role in the development of murine encephalomyelitis; however, no functional connection between the two has yet been established. In this study, we show that knockout mice demonstrated significantly exacerbated severity of experimental autoimmune encephalomyelitis (EAE), augmented T cell infiltration into the central nervous system (CNS) and strongly increased production of GM-CSF in T cells and .GM-CSF neutralization demonstrated that the increased susceptibility of mice to EAE was dependent on GM-CSF. Mechanistically, p50 binding to the GM-CSF promoter and the IL-3/GM-CSF enhancer element "CNSa" was strongly increased in nuclear extracts from Cbl-b-deficient T cells. This study suggests that Cbl-b limits autoimmunity by preventing the pathogenic effects of GM-CSF overproduction in T cells.
全基因组关联研究以及淋巴表达分析将 Cbl-b 和 GM-CSF 与人类多发性硬化症以及其他自身免疫性疾病联系起来。Cbl-b 和 GM-CSF 均被证明在鼠脑脊髓炎的发展中发挥重要作用；然而，两者之间尚未建立功能联系。在这项研究中，我们表明，Cbl-b 基因敲除小鼠表现出实验性自身免疫性脑脊髓炎（EAE）严重程度显著加重，T 细胞浸润中枢神经系统（CNS）增强，T 细胞和 中 GM-CSF 产生显著增加。GM-CSF 中和表明，Cbl-b 基因敲除小鼠对 EAE 的易感性增加依赖于 GM-CSF。从机制上讲，Cbl-b 缺陷 T 细胞核提取物中，p50 与 GM-CSF 启动子和 IL-3/GM-CSF 增强子元件“CNSa”的结合显著增加。这项研究表明，Cbl-b 通过防止 T 细胞中 GM-CSF 过度产生的致病性作用来限制自身免疫。
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