The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity
The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity
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DOI：
10.1172/jci126250
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发表时间：
2019-09-03
影响因子：
15.9
通讯作者：
Voskuhl, Rhonda R.
中科院分区：
文献类型：
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作者：
Itoh, Yuichiro;Golden, Lisa C.;Voskuhl, Rhonda R.
多发性硬化（MS）是一种公认的T细胞介导的自身免疫性疾病。与许多自身免疫性疾病一样，女性比男性更容易受到影响。两性异形可能是由于性激素，性染色体，或两者的差异。关于性染色体基因，一小部分X染色体基因逃脱X失活，并且与男性（XY）相比，女性（XX）中的I表达更高。在这里，在CD4（+）T细胞中的高通量基因表达分析显示，最高的性二态基因是Kdm 6a，一种X染色体上的组蛋白脱甲基酶。在人类和小鼠中，与雄性相比，女性中Kdm 6a的表达更高，并且与XY相比，四个核心基因型（FCG）小鼠模型i在XX中显示出更高的表达。在经典的CD4（+）T细胞介导的自身免疫性疾病实验性自身免疫性脑脊髓炎（EAE）中，CD4（+）T细胞中Kdm6a的缺失改善了临床疾病并减少了神经病理学。对来自Kdm6a特异性缺失的EAE小鼠的CD4（+）T细胞的全局转录组分析显示，Th2和Th1活化途径上调，神经炎症信号通路下调。总之，这些数据表明，X逃逸Kdm6a调节多种免疫反应基因，提供了自身免疫性疾病易感性的性别差异机制。
Multiple sclerosis (MS) is a putative T cell-mediated autoimmune disease. As with many autoimmune diseases, females are more susceptible than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape X inactivation and have higher I expression in females (XX) compared with males (XY). Here, high-throughput gene expression analysis in CD4(+) T cells showed that the top sexually dimorphic gene was Kdm6a, a histone demethylase on the X chromosome. There was higher expression of Kdm6a in females compared with males in humans and mice, and the four core genotypes (FCG) mouse model i showed higher expression in XX compared with XY. Deletion of Kdm6a in CD4(+)T cells ameliorated clinical disease and reduced I: neuropathology in the classic CD4(+)T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4(+)T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and down regulation of neuroinflammation signaling pathways. Together, these data demonstrate that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.