TLR7 escapes X chromosome inactivation in immune cells
TLR7 escapes X chromosome inactivation in immune cells
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DOI：
10.1126/sciimmunol.aap8855
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发表时间：
2018-01-01
影响因子：
24.8
通讯作者：
Guery, Jean-Charles
中科院分区：
文献类型：
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作者：
Souyris, Melanie;Cenac, Claire;Guery, Jean-Charles
toll样受体7 （TLR7）对诱导抗病毒免疫至关重要，但TLR7的剂量也是系统性红斑狼疮（SLE）的关键致病因素，SLE是一种具有强烈女性偏见的自身免疫性疾病。携带一条或多条多余X染色体的Klinefelter综合征患者SLE患病率也升高，提示X染色体补体有助于SLE易感性。TLR7是由一个X染色体位点编码的，我们在这里研究了TLR7基因是否通过X染色体失活在女性和Klinefelter综合征男性的免疫细胞中逃避沉默。TLR7等位基因表达的单细胞分析表明，不仅在女性中，而且在Klinefelter综合征男性中，原代B淋巴细胞、单核细胞和浆细胞样树突状细胞的大部分在两条X染色体上表达TLR7。来自女性的双等位B淋巴细胞比单等位细胞表现出更高的TLR7转录表达，这与女性白细胞群中TLR7蛋白表达高于男性相关。在tlr7驱动的CD27（+）浆细胞增殖过程中，双等位B细胞优先富集。此外，在tlr7驱动的、依赖T细胞的幼稚B淋巴细胞向免疫球蛋白分泌细胞的分化过程中，双等位基因细胞的免疫球蛋白G类转换倾向比单等位基因细胞增加了两倍以上。TLR7脱离X失活使B细胞腔室对TLR7配体的反应性增强。这一发现支持了这样的假设，即双等位基因导致TLR7表达增强，导致患有Klinefelter综合征的女性和男性发生SLE和其他自身免疫性疾病的风险更高。
Toll-like receptor 7 (TLR7) is critical to the induction of antiviral immunity, but TLR7 dosage is also a key pathogenic factor in systemic lupus erythematosus (SLE), an autoimmune disease with strong female bias. SLE prevalence is also elevated in individuals with Klinefelter syndrome, who carry one or more supernumerary X chromosomes, suggesting that the X chromosome complement contributes to SLE susceptibility. TLR7 is encoded by an X chromosome locus, and we examined here whether the TLR7 gene evades silencing by X chromosome inactivation in immune cells from women and Klinefelter syndrome males. Single-cell analyses of TLR7 allelic expression demonstrated that substantial fractions of primary B lymphocytes, monocytes, and plasmacytoid dendritic cells not only in women but also in Klinefelter syndrome males express TLR7 on both X chromosomes. Biallelic B lymphocytes from women displayed greater TLR7 transcriptional expression than the monoallelic cells, correlated with higher TLR7 protein expression in female than in male leukocyte populations. Biallelic B cells were preferentially enriched during the TLR7-driven proliferation of CD27(+) plasma cells. In addition, biallelic cells showed a greater than twofold increase over monoallelic cells in the propensity to immunoglobulin G class switch during the TLR7-driven, T cell-dependent differentiation of naive B lymphocytes into immunoglobulin-secreting cells. TLR7 escape from X inactivation endows the B cell compartment with added responsiveness to TLR7 ligands. This finding supports the hypothesis that enhanced TLR7 expression owing to biallelism contributes to the higher risk of developing SLE and other autoimmune disorders in women and in men with Klinefelter syndrome.