Collagen XVII unmasking in Parkinson's disease and scratching

帕金森病和抓挠中的 XVII 胶原蛋白揭秘

• 批准号: 10488279
• 负责人: Kyle T. Amber
• 金额: $ 19.63万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488279
• 关键词: Address; Aging; Animal Model; Animals; Antibodies; Antigen Presentation; Antigens; Applications Grants; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Basement membrane; Behavior; Birth; Bulla; Bullous Pemphigoid; Bypass; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Chronic; Clinical; Code; Collagen; Collagen Type XVII; Cre-LoxP; Cutaneous; Deposition; Dermatitis; Development; Disease; Elderly; Epitope spreading; Epitopes; Exons; Experimental Parkinsonism; Genes; High Prevalence; Homologous Gene; Human; Immune Tolerance; Immune response; Immune system; Immunization; Immunosuppression; Inflammation; Inflammatory Response; Knock-out; Knockout Mice; Lead; MPTP model; Medical; Modeling; Monitor; Multiple Sclerosis; Mus; Neurons; Organ; Oxazolone; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Physiological; Predisposition; Process; Pruritus; Recombinants; Reporting; Risk; Role; Scabies; Self Tolerance; Serology; Serum; Skin; Study models; T-Cell Development; T-Lymphocyte; TNFSF5 gene; Tamoxifen; Testing; Tyrosine 3-Monooxygenase; antigen-specific T cells; body system; clinical phenotype; comorbidity; emerging adult; experimental study; genetic approach; high risk; in vivo; in vivo Model; innovation; insight; mortality; mouse model; neoantigens; nervous system disorder; neuroinflammation; novel; novel strategies; promoter; restoration; skin barrier; skin lesion; tool; translational potential

PROJECT SUMMARY Bullous pemphigoid (BP) is an autoimmune disease that results in the development of severe itch and blisters. It is the most common form of autoimmune blistering disease and is overrepresented in the elderly. Treatment for bullous pemphigoid relies on the use of immunosuppression, which given the high prevalence of medical comorbidities in this group, results in one-year mortality rates ranging from 13% to 27%. Bullous pemphigoid is caused by the development of antibodies against collagen XVII leading to blister formation and the development of inflammation. Loss of self-tolerance to collagen XVII, especially in the aging immune system, is thought to lead to development of BP. Parkinson's disease and pre-existing pruritus both independently impose strong predisposition towards the development of bullous pemphigoid, likely through autoinoculation with collagen XVII. Understanding the mechanism of collagen XVII autoinoculation not only provides insight into the pathogenesis of bullous pemphigoid, but offers significant insight into the immune response in Parkinson's disease. We propose two discrete hypotheses, 1) that scratching induced skin barrier damage or 2) neuroinflammation seen in Parkinson's disease are sufficient to autoinoculate collagen XVII in a tolerant with minimal T-cell tolerance. To test this hypothesis, we propose utilizing a novel animal model. We have used CRISPR-Cas9 to develop a mouse expressing a LoxP-PolyA-LoxP sequence upstream of exon 18, the coding region of the NC15a domain of collagen XVII. This domain corresponds with the human NC16a domain, which serves as the principle autoantigen in BP. When crossed to a tamoxifen inducible Cre-Lox mouse model, restoration of collagen XVII expression occurs in early adulthood, bypassing T-cell tolerance once unmasked. With inflammation and antigen unmasking through scratching or experimentally induced Parkinson's disease, we anticipate development of antigen-specific CD4+ T-cells and autoantibodies against collagen XVII. Two specific aims are proposed: 1) Determine the impact of scratching behaviors on the development of anti- collagen XVII autoantibodies, antigen-specific CD4+ T-cells, and the development of BP. 2) Determine the effect of neuroinflammation in experimental Parkinsonism in inducing cutaneous autoimmunity against collagen XVII. This project will provide significant insight into both the role of scratching and neuroinflammation in antigen unmasking. This proposal is likely to have strong translational potential across several disease processes and organ systems. Our novel approach provides a valuable tool for studying the immune response in Parkinson's disease, as well as for studying other autoimmune diseases with well-characterized autoantigens.

项目概要 大疱性类天疱疮 (BP) 是一种自身免疫性疾病，会导致严重瘙痒和水疱。 它是最常见的自身免疫性水疱病，在老年人中发病率较高。治疗 大疱性类天疱疮的治疗依赖于免疫抑制的使用，考虑到医疗的高患病率 该组的合并症导致一年死亡率为 13% 至 27%。大疱性类天疱疮是 由针对 XVII 胶原蛋白的抗体的产生导致水泡形成和 炎症的发展。对胶原蛋白 XVII 的自我耐受性丧失，尤其是在衰老的免疫系统中， 思想导致 BP 的发展。帕金森病和已有的瘙痒症都是独立的 可能通过自身接种，对大疱性类天疱疮的发展产生强烈的倾向 与胶原蛋白XVII。了解 XVII 胶原蛋白自体接种机制不仅提供了见解 研究大疱性类天疱疮的发病机制，但提供了对大疱性类天疱疮的免疫反应的重要见解 帕金森病。我们提出两个独立的假设，1）抓挠会引起皮肤屏障损伤或 2) 帕金森病中出现的神经炎症足以在耐受的情况下自动接种胶原蛋白 XVII 最小的 T 细胞耐受性。为了检验这一假设，我们建议使用一种新颖的动物模型。我们已经用过 CRISPR-Cas9 培育出表达外显子 18（编码基因）上游 LoxP-PolyA-LoxP 序列的小鼠 XVII 胶原蛋白 NC15a 结构域的区域。该结构域对应于人类 NC16a 结构域， 是 BP 中的主要自身抗原。当与他莫昔芬诱导的 Cre-Lox 小鼠模型杂交时， XVII 胶原蛋白表达的恢复发生在成年早期，一旦暴露，就绕过了 T 细胞耐受性。 通过抓挠或实验诱发的帕金森氏病而导致炎症和抗原暴露， 我们预计会开发出抗原特异性 CD4+ T 细胞和针对 XVII 胶原蛋白的自身抗体。二 提出了具体目标：1）确定抓挠行为对抗抓能力发展的影响 XVII 胶原蛋白自身抗体、抗原特异性 CD4+ T 细胞以及 BP 的发展。 2）确定 实验性帕金森病神经炎症诱导皮肤胶原自身免疫的作用 十七．该项目将提供对抓挠和神经炎症在神经炎症中的作用的重要见解。 抗原揭开。该提议可能对多种疾病具有强大的转化潜力 过程和器官系统。我们的新方法为研究免疫反应提供了一个有价值的工具 帕金森病，以及研究其他具有良好特征的自身免疫性疾病 自身抗原。

项目成果

C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita.

• DOI: 10.3389/fimmu.2023.1266359
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Guerrero-Juarez, Christian F.;Schilf, Paul;Li, Jing;Zappia, Maria Paula;Bao, Lei;Patel, Payal M.;Gieseler-Tillmann, Jenny;Murthy, Sripriya;Cole, Connor;Sverdlov, Maria;Frolov, Maxim V.;Hashimoto, Takashi;Ishii, Norito;Ruelicke, Thomas;Bieber, Katja;Ludwig, Ralf J.;Sadik, Christian D.;Amber, Kyle T.
• 通讯作者: Amber, Kyle T.

Targeting interleukin (IL)-4/IL-13 in immune checkpoint inhibitor-induced bullous pemphigoid: a cautionary note on the beneficial effect of T helper 2 immunity in melanoma and immunotherapy.

在免疫检查点抑制剂诱导的大疱性类天疱疮中靶向白细胞介素 (IL)-4/IL-13：关于 T 辅助细胞 2 免疫在黑色素瘤和免疫治疗中的有益作用的警告。

• DOI: 10.1093/bjd/ljad324
• 发表时间: 2023
• 期刊: The British journal of dermatology
• 作者: Guerrero-Juarez,ChristianF;Goyal,ParulK;Amber,KyleT
• 通讯作者: Amber,KyleT

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms.

• DOI: 10.3389/fimmu.2022.912876
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Cole, Connor;Vinay, Keshavamurthy;Borradori, Luca;Amber, Kyle T.
• 通讯作者: Amber, Kyle T.