Overexpression of X-linked genes in T cells from women with lupus.
Overexpression of X-linked genes in T cells from women with lupus.
复制标题
DOI：
10.1016/j.jaut.2012.12.006
复制
发表时间：
2013-03
影响因子：
12.8
通讯作者：
Richardson B
中科院分区：
文献类型：
--
作者：
Hewagama A;Gorelik G;Patel D;Liyanarachchi P;McCune WJ;Somers E;Gonzalez-Rivera T;Michigan Lupus Cohort;Strickland F;Richardson B
女性比男性更容易患狼疮，其原因尚不完全清楚。有证据表明，患有克氏综合症（XXY）的男性与女性患狼疮的几率大致相同，这表明第二条X染色体起了作用。然而，由于第二个X通常是失活的，它是如何易患狼疮的尚不清楚。DNA甲基化导致女性一条X染色体沉默，CD4+ T细胞DNA去甲基化导致狼疮样自身免疫的发展。这表明，失活X染色体上基因的去甲基化可能使女性易患狼疮，这一假设得到了一份报告的支持，该报告称，编码在X染色体上的免疫基因CD40LG在患有狼疮的女性而不是男性的T细胞中去甲基化并过度表达。失活X染色体上其他免疫基因的过度表达也可能使女性易患此病。因此，我们比较了来自女性和男性的实验性去甲基化T细胞以及来自女性和男性狼疮患者的T细胞中的mRNA和miRNA表达谱。用DNA甲基转移酶抑制剂5-氮杂胞苷处理健康男性和女性的T细胞，然后用寡核苷酸阵列检测x -连锁mrna，用PCR阵列检测x -连锁miRNA。CD40LG、CXCR3、OGT、miR-98、let-7f-2*、miR 188-3p、miR-421和miR-503是女性相对于男性过表达的基因。MiRNA靶标预测分析发现CBL是miR-188-3p和miR-98靶向的基因，CBL下调T细胞受体信号，在狼疮T细胞中减少。转染miR-98和miR-188-3p可抑制CBL的表达。与男性相比，女性狼疮患者的CD4+ T细胞中同样的mRNA和miRNA转录物也被去甲基化和过表达。总之，这些结果进一步支持X染色体去甲基化在女性红斑狼疮易感性中的作用。
Women develop lupus more frequently than men and the reason remains incompletely understood. Evidence that men with Klinefelter’s Syndrome (XXY) develop lupus at approximately the same rate as women suggests that a second X chromosome contributes. However, since the second X is normally inactivated, how it predisposes to lupus is unclear. DNA methylation contributes to the silencing of one X chromosome in women, and CD4+ T cell DNA demethylation contributes to the development of lupus-like autoimmunity. This suggests that demethylation of genes on the inactive X may predispose women to lupus, and this hypothesis is supported by a report that CD40LG, an immune gene encoded on the X chromosome, demethylates and is overexpressed in T cells from women but not men with lupus. Overexpression of other immune genes on the inactive X may also predispose women to this disease. We therefore compared mRNA and miRNA expression profiles in experimentally demethylated T cells from women and men as well as in T cells from women and men with lupus. T cells from healthy men and women were treated with the DNA methyltransferase inhibitor 5-azacytidine, then X-linked mRNAs were surveyed with oligonucleotide arrays, and X-linked miRNA’s surveyed with PCR arrays. CD40LG, CXCR3, OGT, miR-98, let-7f-2*, miR 188-3p, miR-421 and miR-503 were among the genes overexpressed in women relative to men. MiRNA target prediction analyses identified CBL, which downregulates T cell receptor signaling and is decreased in lupus T cells, as a gene targeted by miR-188-3p and miR-98. Transfection with miR-98 and miR-188-3p suppressed CBL expression. The same mRNA and miRNA transcripts were also demethylated and overexpressed in CD4+ T cells from women relative to men with active lupus. Together these results further support a role for X chromosome demethylation in the female predisposition to lupus.
登录
查看更多内容
影响因子：
5.3
作者：
Balagopalan, Lakshmi;Barr, Valarie A.;Samelson, Lawrence E.
通讯作者：
Samelson, Lawrence E.
影响因子：
4.4
作者：
Higuchi, T;Aiba, Y;Tsubata, T
通讯作者：
Tsubata, T
影响因子：
4.4
作者：
Gorelik, Gabriela;Fang, Jing Yuan;Richardson, Bruce
通讯作者：
Richardson, Bruce
影响因子：
20.3
作者：
Brembilla, Nicolo C.;Weber, Johann;Doucey, Marie-Agnes
通讯作者：
Doucey, Marie-Agnes
DOI：
10.1016/j.clim.2008.08.009
发表时间：
2009-02
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Liu Y;Kuick R;Hanash S;Richardson B
通讯作者：
Richardson B