Role of the gender biased transcription factor VGLL3 in promoting autoimmune responses in SLE

性别偏向转录因子 VGLL3 在促进 SLE 自身免疫反应中的作用

• 批准号: 10733674
• 负责人: Johann Eli Gudjonsson
• 金额: $ 46.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-06 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733674
• 关键词: Address; Affect; Age; American; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Basement membrane; Binding; Biological; Cell Nucleus; Chronic; Cre driver; Cutaneous; Cytoplasm; Data; Dependence; Deposition; Development; Disease; Disease susceptibility; Epidermis; FOXM1 gene; Family; Female; Future; Genes; Genetic Transcription; Gonadal Steroid Hormones; Human; IL7 gene; Immune; Immune Response Genes; Immune response; Immunoglobulin G; In Vitro; Inflammatory; Interferon Activation; Interferon Type I; Interferons; Interleukin 7 Receptor; Kidney; Knock-out; Knockout Mice; Life; Location; LoxP-flanked allele; Lupus; Lymphoid Tissue; Mediating; Modeling; Morbidity - disease rate; Mus; Myeloid Cells; Nephritis; Neurofibromin 2; Nuclear; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Predisposition; Process; Protein Isoforms; Proteins; Regulation; Regulatory Pathway; Response Elements; Role; SLEB1 gene; SLEB3 gene; SOX7 gene; Sex Bias; Sex Chromosomes; Sex Differences; Signal Pathway; Signal Transduction; Skin; Systemic Lupus Erythematosus; T-Cell Development; T-Lymphocyte; TLR7 gene; Thymus Gland; Transgenic Mice; Transgenic Organisms; Woman; Work; anti-dsDNA antibodies; autoreactive T cell; autosome; cell type; cofactor; cytokine; ds-DNA; hormone regulation; human male; in silico; in vivo; keratin 5; keratinocyte; male; member; men; mouse model; novel; novel strategies; overexpression; pathogen; prevent; programmed cell death protein 1; promoter; protein transport; response; sex determination; sexual dimorphism; systemic autoimmune disease; systemic inflammatory response; therapeutic target; trafficking; transcription factor

PROJECT SUMMARY/ABSTRACT In Systemic Lupus Erythematosus (SLE) women outnumber men in approximately 9:1 ratio. Previously, sexual dimorphism in immune processes has been explained by the location of immune genes on the sex chromosomes, or by the effects of sex hormones. However, as demonstrated by our group, 87.8% of sex-biased genes in skin lie on the autosomes, including interferon (IFN)-response genes (IRGs), as well as other genes associated with autoimmune disease susceptibility, and are unrelated to sex hormone levels in vitro and in vivo. Therefore, the mechanisms involved in autoimmune predisposition in women remain unclear. This application is focused on elucidating the mechanism by which the Hippo pathway regulator Vgll3 promotes autoimmunity, but our previous work identified this factor as a key determinant of sexually dimorphic immune responses. Thus, VGLL3 target genes are enriched for multiple immune response elements associated with multiple autoimmune diseases, including SLE, and a recently developed mouse model, where Vgll3 was expressed constitutively in mouse epidermis develop a robust SLE-like inflammatory phenotype characterized by increased type I IFN activation, and expression of SLE-associated cytokines including Tnfs13b (BAFF), Tnfsf4, type I IFNs, along with robust activation of humoral immune response accompanied by autoantibodies (anti-dsDNA) and immune complex deposition in skin and kidneys. Strikingly, crossing of transgenic Vgll3 mice with Il-7 receptor deficient mice prevented development of this autoimmune phenotype, suggesting a critical role for IL-7 in SLE pathogenesis. These observations form the basis of our hypothesis that VGLL3 nuclear trafficking and modulation of TEAD transcription factor activity promotes an IL-7 dependent autoimmune phenotype. Three aims are proposed to: Elucidate the mechanisms of VGLL3-induced IL7 expression (Aim 1). Determine the dependency of VGLL3 and interferons in promoting sex-biased expression of IL7 (Aim 2), and to determine the mechanism of IL-7-driven systemic autoimmune responses (Aim 3). This proposal will focus on a novel mechanism of sex-biased autoimmunity driven by VGLL3 modulation of Hippo pathway signaling and activation of IL-7, and the target cell type it acts on to drive the down-stream autoimmune response. It will elucidate a novel VGLL3-IL7-autoimmunity pathway in SLE pathogenesis and provide novel approaches for future therapeutic targeting of this devastating disease.

项目总结/摘要 在系统性红斑狼疮（SLE）中，女性人数超过男性，比例约为9：1。在此之前， 免疫过程中的性别二型性可以用免疫基因在性别上的位置来解释。 染色体，或者性激素的影响。然而，正如我们的小组所证明的那样，87.8%的性别偏见 皮肤中的基因位于常染色体上，包括干扰素（IFN）反应基因（IRGs）以及其他基因 与自身免疫性疾病易感性相关，与体外和体内的性激素水平无关。 因此，女性自身免疫易感性的机制仍不清楚。 本申请集中于阐明Hippo途径调节剂Vgll 3促进细胞凋亡的机制。 自身免疫，但我们以前的工作确定了这个因素作为一个关键的决定因素，性二型免疫 应答因此，VGLL 3靶基因富集了与以下相关的多种免疫应答元件： 多种自身免疫性疾病，包括SLE，以及最近开发的小鼠模型，其中Vgll 3被 在小鼠表皮中组成性表达的IL-10产生了一种稳健的SLE样炎症表型，其特征在于 通过增加I型IFN活化，和SLE相关细胞因子包括Tnfs 13 b（BAFF）的表达， TNFSF 4，I型IFN，沿着伴随有自身抗体的体液免疫应答的强烈激活 （抗dsDNA）和免疫复合物沉积在皮肤和肾脏中。引人注目的是，转基因Vgl 13小鼠的杂交 IL-7受体缺陷小鼠阻止了这种自身免疫表型的发展，这表明IL-7受体缺陷小鼠在预防这种自身免疫表型的发展中发挥了关键作用。 IL-7在SLE发病机制中的作用。 这些观察结果构成了我们假设的基础，即VGLL 3核运输和对细胞增殖的调节可能与VGLL 3的表达有关。 TEAD转录因子活性促进IL-7依赖性自身免疫表型。三个目标是 目的：阐明VGLL 3诱导IL 7表达的机制（目的1）。确定依赖关系 VGLL 3和干扰素在促进IL 7性别偏向性表达中的作用（目的2），并确定其机制。 IL-7驱动的全身性自身免疫应答（Aim 3）。 这项提案将集中在一个新的机制，性别偏见的自身免疫驱动的VGLL 3调节， Hippo通路信号传导和IL-7的激活，以及其作用于驱动下游的靶细胞类型 自身免疫反应它将阐明SLE发病机制中的一种新的VGLL 3-IL 7-自身免疫途径， 为未来治疗这种毁灭性疾病提供了新的方法。

项目成果

Sex bias in autoimmunity.

• DOI: 10.1097/bor.0000000000000564
• 发表时间: 2019-01
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1
• 作者: Billi AC;Kahlenberg JM;Gudjonsson JE
• 通讯作者: Gudjonsson JE

IL-17 integrates multiple self-reinforcing, feed-forward mechanisms through the RNA binding protein Arid5a.

• DOI: 10.1126/scisignal.aat4617
• 发表时间: 2018-10-09
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Amatya N;Childs EE;Cruz JA;Aggor FEY;Garg AV;Berman AJ;Gudjonsson JE;Atasoy U;Gaffen SL
• 通讯作者: Gaffen SL

Psoriasis: a mixed autoimmune and autoinflammatory disease.

• DOI: 10.1016/j.coi.2017.07.007
• 发表时间: 2017-12
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Liang Y;Sarkar MK;Tsoi LC;Gudjonsson JE
• 通讯作者: Gudjonsson JE