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.

项目摘要/摘要 在全身性红斑狼疮（SLE）中，女性的男性约为9：1。之前， 免疫过程中的性二态性是通过免疫基因在性别上的位置来解释的 染色体或性激素的作用。但是，正如我们小组所证明的，有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 与自身免疫性疾病的敏感性相关，并且在体外和体内与性激素水平无关。 因此，妇女自身免疫性倾向涉及的机制尚不清楚。 该应用的重点是阐明河马途径调节器VGLL3促进的机制 自身免疫性，但我们以前的工作将这一因素确定为性二态免疫的关键决定因素 回答。因此，VGLL3靶基因富含与与之相关的多种免疫反应元件 多种自身免疫性疾病，包括SLE和最近开发的鼠标模型，其中VGLL3为 在小鼠表皮中组成型表达，形成了强大的SLE样炎症表型 通过增加的I型IFN激活，以及SLE相关的细胞因子在内的表达，包括TNFS13B（BAFF）， TNFSF4，I型IFN，以及伴有自身抗体的体液免疫反应的强大激活 （抗DSDNA）和皮肤和肾脏中的免疫复合物沉积。令人惊讶的是，转基因VGLL3小鼠的穿越 IL-7受体缺乏小鼠阻止了这种自身免疫表型的发展，这表明至关重要 对于SLE发病机理中的IL-7。 这些观察结果是我们假设的基础，即VGLL3核贩运和调节 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 提出：阐明VGLL3诱导的IL7表达的机制（AIM 1）。确定依赖性 VGLL3和干扰素在促进IL7的性别偏见表达（AIM 2）中，并确定机制 IL-7驱动的系统自身免疫反应（AIM 3）。 该建议将重点介绍由VGLL3调制驱动的性偏见自身免疫的新机制 IL-7的河马途径信号传导和激活，其作用于驱动下游的目标细胞类型 自身免疫反应。它将阐明在SLE发病机理和 为这种毁灭性疾病的未来治疗靶向提供新颖的方法。

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