Foxp3 isoforms and IgE-mediated UVB-induced skin inflammation expression

Foxp3亚型和IgE介导的UVB诱导的皮肤炎症表达

• 批准号: 10728256
• 负责人: Steven F Ziegler
• 金额: $ 26万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-22 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728256
• 关键词: Age; Alternative Splicing; Amino Acid Sequence; Animal Model; Animals; Antibodies; Antigens; Atmosphere; Autoantibodies; Autoimmune Diseases; Autoimmunity; Basophils; Binding; Bone Marrow; Carcinogen exposure; Cells; Chimera organism; Complex; Cutaneous; DNA; Data; Deposition; Development; Disease; Exons; Exposure to; FOXP3 gene; Flare; Frequencies; Gene Structure; Geographic Locations; Homeostasis; Human; IgE; Immune response; Immune system; Infiltration; Inflammation; Inflammatory; Keratin; Kidney; Length; Light; Link; Lupus; Mediating; Mixed Connective Tissue Disease; Modeling; Mouse Strains; Mus; Mutation; Nuclear; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phototoxic Dermatitis; Play; Production; Protein Isoforms; Regulatory T-Lymphocyte; Role; Skin; Structure of germinal center of lymph node; Syndrome; Systemic Lupus Erythematosus; TNFSF5 gene; Testing; Therapeutic Intervention; UV Radiation Exposure; UVB induced; Work; autoreactivity; immunoregulation; insight; irradiation; keratinocyte; light intensity; novel; response; skin disorder; ultraviolet; ultraviolet irradiation

PROJECT SUMMARY Ultraviolet B light (UVB; 280-315nm) is a common environmental trigger that can induce skin inflammation and flares in several autoimmune diseases. UVB light is an established trigger for skin flares in SLE patients, and regional spikes in atmospheric UVB intensity correlate with flare frequency among SLE patients within that geographic region. In mice, IgE antibodies are elevated after UVB exposure, and previous work shows that skin-reactive IgE also plays a key role in removing damaged keratinocytes after carcinogen exposure. However, the role of self-reactive IgE has not been studied in photosensitivity reactions in autoimmunity. Regulatory T (Treg) cells play a central role in maintaining immune system homeostasis and modulating immune responses. Foxp3 is a master regulator of Treg development and function. FOXP3 mutations in patients with IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), which result in a deficiency in Tregs, result in lethal autoimmunity, similar to the disease observed in Foxp3 deficient mice. While highly conserved in both amino acid sequence and gene structure, one difference between humans and mice is that the human FOXP3 gene encodes two major alternatively spliced isoforms: a full-length version that uses all 10 exons (FOXP3FL, the only isoform in mice) and a shorter isoform lacking exon 2 (FOXP3∆E2). Recent studies have shown that Tregs from patients with some autoimmune diseases express increased levels of the ∆E2 isoform compared to those from healthy donors. Consistent with this finding, we have found that Tregs from SLE patients have increased expression of the FOXP3∆E2 isoform. To study the role of the ∆E2 isoform in Treg function we generated a new mouse strain with Foxp3 exon 2 deletion. Interestingly, we found that Foxp3∆E2 mice develop hallmark features of SLE, including anti-DNA and anti-nuclear autoantibodies, increased number and size of spontaneous germinal centers and kidney deposition of antibody complexes, by 4-5 weeks of age. Importantly, these mice display a marked increase in circulating IgE and develop IgE-specific autoantibodies against skin antigens, including Keratins 2 and 14. In addition, these mice have IgE deposits in the skin, which increase dramatically following UVB irradiation. Our central hypothesis is Foxp3DE2-expressing Tregs fail to regulate germinal center responses and promote IgE autoantibodies. To test this hypothesis, we will first determine the role of Foxp3∆Ex2-expressing Tregs in germinal center function, focusing on the relationship between Tfh and Tfr cells. Next, we will assess the role of autoreactive IgE in UVB-mediated skin inflammation in these mice. These studies will provide insights into the role of Foxp3∆E2 Treg function and the development and progression of inflammatory skin disease.

项目摘要 紫外线B光（UVB; 280- 315 nm）是一种常见的环境触发物，可诱导皮肤 炎症和耀斑在一些自身免疫性疾病。UVB光是一个既定的触发皮肤耀斑， SLE患者中，大气UVB强度的区域峰值与SLE患者中的耀斑频率相关 这个地理区域内的病人。在小鼠中，IgE抗体在UVB暴露后升高，而先前的IgE抗体在UVB暴露后升高。 研究表明，皮肤反应性IgE在去除致癌物质后受损的角质形成细胞中也起着关键作用。 exposure.然而，自身反应性IgE的作用还没有被研究在光敏反应中， 自身免疫 调节性T（Treg）细胞在维持免疫系统稳态和调节免疫应答中起核心作用。 免疫反应。Foxp 3是Treg发育和功能的主要调节因子。患者中的FOXP 3突变 与IPEX（免疫失调，多内分泌病，肠病，X连锁综合征），这导致一个 TcP缺乏导致致死性自身免疫，类似于在Foxp 3缺陷小鼠中观察到的疾病。而 在氨基酸序列和基因结构上高度保守，人类和小鼠之间的一个区别是 人类FOXP 3基因编码两种主要的选择性剪接异构体：一种全长版本， 所有10个外显子（FOXP 3FL，小鼠中唯一的同种型）和缺少外显子2的较短同种型（FOXP 3 E2）。最近 研究表明，来自某些自身免疫性疾病患者的T细胞表达水平增加， 与来自健康供体的那些相比，E1 E2亚型。与这一发现一致，我们发现， SLE患者FOXP 3 β E2亚型表达增加。 为了研究Foxp 2同种型在Treg功能中的作用，我们产生了具有Foxp 3外显子的新小鼠品系 2删除。有趣的是，我们发现Foxp 3/E2小鼠出现了SLE的标志性特征，包括抗DNA 和抗核自身抗体，自发性生殖中心和肾脏的数量和大小增加 4-5周龄时抗体复合物沉积。重要的是，这些小鼠显示出显著增加， 循环IgE并产生针对皮肤抗原的IgE特异性自身抗体，包括角蛋白2和14。在 此外，这些小鼠在皮肤中具有IgE沉积物，其在UVB照射后显著增加。我们 中心假设是表达Foxp 3DE 2的TcR不能调节生发中心反应， 促进IgE自身抗体。为了验证这一假设，我们将首先确定Foxp 3基因外显子2表达的作用。 Tfh在生殖中枢中的作用，重点研究Tfh和Tfr细胞之间的关系。接下来，我们将评估 自身反应性IgE在UVB介导的皮肤炎症中的作用。这些研究将提供 深入了解Foxp 3/E2 Treg功能的作用以及炎症性皮肤的发展和进展 疾病