The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity
The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity
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DOI：
10.1172/jci.insight.127291
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发表时间：
2019-04-18
期刊：
影响因子：
8
通讯作者：
Gudjonsson, Johann E.
中科院分区：
文献类型：
--
作者：
Billi, Allison C.;Gharaee-Kermani, Mehrnaz;Gudjonsson, Johann E.
自身免疫性疾病在女性中的发病率是男性的4倍。这种偏见在很大程度上是无法解释的。女性皮肤是“自身免疫倾向”，显示许多促炎基因的上调，即使在健康女性中。我们以前确定VGLL 3作为一个假定的转录辅因子在女性皮肤中富集。在这里，我们证明，皮肤定向过表达的小鼠VGLL 3导致严重的狼疮样皮疹和全身性自身免疫性疾病，涉及B细胞扩增，自身抗体的产生，免疫复合物沉积，和终末器官损伤，过量表皮VGLL 3驱动的促炎基因表达程序，与女性皮肤和皮肤狼疮重叠。这包括增加的B细胞活化因子（BAFF），目前唯一的系统性红斑狼疮（SLE）的生物靶点; IFN-κ，皮肤狼疮的关键炎症介质;和CXCL 13，早发性SLE和肾脏受累的生物标志物。我们的研究结果表明，女性偏向因子VGLL 3的皮肤靶向过表达足以驱动皮肤和全身性自身免疫性疾病，这与SLE惊人相似。这项工作强烈暗示VGLL 3是性别偏见自身免疫的关键协调者。
Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is "autoimmunity prone," showing upregulation of many proinflammatory genes, even in healthy women. We previously identified VGLL3 as a putative transcription cofactor enriched in female skin. Here, we demonstrate that skin-directed overexpression of murine VGLL3 causes a severe lupus-like rash and systemic autoimmune disease that involves B cell expansion, autoantibody production, immune complex deposition, and end-organ damage, Excess epidermal VGLL3 drives a proinflammatory gene expression program that overlaps with both female skin and cutaneous lupus. This includes increased B cellactivating factor (BAFF), the only current biologic target in systemic lupus erythematosus (SLE); IFN-kappa, a key inflammatory mediator in cutaneous lupus; and CXCL13, a biomarker of early-onset SLE and renal involvement. Our results demonstrate that skin-targeted overexpression of the female-biased factor VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease that is strikingly similar to SLE. This work strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity.