Autoimmune Mechanisms in Peripheral Neuropathy

周围神经病变的自身免疫机制

• 批准号: 9792291
• 负责人: STEVEN Simon Scherer
• 金额: $ 50.77万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792291
• 关键词: Adoptive Transfer; Adrenal Cortex Hormones; Affect; Antibodies; Antigen Presentation; Antigens; Autoimmune Process; Autoimmunity; Binding; Biology; Biopsy; Blood Component Removal; Bone Marrow; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular biology; Chemotaxis; Chronic; Chronic Inflammatory Demyelinating Polyneuropathy; Classical Complement Pathway; Complement; Complement 1q; Complement Activation; Data; Defect; Dependovirus; Deposition; Development; Disease; Expression Profiling; Extracellular Matrix Proteins; Gene Expression; Histocompatibility Antigens Class II; Immune; Immune Tolerance; Immune system; Immunotherapeutic agent; In Vitro; In complete remission; Infiltration; Inflammation; Inflammatory Response; Integrin Binding; Integrin alpha Chains; Integrins; Intervention; Intravenous; Intravenous Immunoglobulins; Knockout Mice; Lead; MHC Class II Genes; Mediating; Modeling; Mus; Nerve; Neuropathy; Pathogenesis; Pathogenicity; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Polyneuropathy; Process; Proteins; Role; Schwann Cells; T-Cell Activation; Testing; Up-Regulation; Virulence Factors; Work; base; insight; macrophage; mouse model; new therapeutic target; novel; periostin; prevent; recruit; vector

Abstract Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is the most common acquired chronic autoimmune neuropathy. Current treatments for CIDP are non-specific, ineffective in one-third of patients, and do not result in complete remission in most patients. Thus, more effective, mechanism-based therapies are needed, and understanding the immune tolerance defects that result in PNS autoimmunity will enable their development. Studies to date suggest a model in which CD4+ T cells, macrophages, and complement lead to the autoimmune destruction of Schwann cells in the PNS. Our data indicate that Schwann cells unexpectedly undergo changes during autoimmune attack that may expand the inflammatory response. Schwann cells turn on expression of Periostin, a secreted extracellular matrix protein important in chemotaxis of pathogenic macrophages; increase expression of CD49b, an integrin important in binding complement protein C1q; and induce expression of MHC Class II, a molecule required for antigen-presentation to CD4+ T cells. Thus, we hypothesize that Schwann cell-associated changes may promote autoimmunity through increased macrophage recruitment, complement deposition, and CD4+ T cell activation. To test this, we propose to determine whether: i) Schwann cell-specific Periostin expression is sufficient to drive macrophage recruitment and neuropathy development; ii) loss of CD49b in Schwann cells and/or C1q prevents complement activation and protects from neuropathy; and iii) Schwann cell-specific MHCII deficiency dampens CD4+ T cell stimulation and protects against PNS autoimmunity. These Aims will be tested in CIDP mouse models and patient nerve biopsies. This project takes advantage of complementary expertise of the multiple PI's (Dr. Su in PNS autoimmunity and Dr. Scherer in Schwann cell biology) to elucidate the role of Schwann cells in promoting demyelinating neuropathy. Successful completion of the Aims of this project will pave the way to identifying new targets for mechanism-based immunotherapeutic interventions for CIDP. Additionally, findings from these studies will contribute to a broader understanding of how Schwann cells may amplify inflammation in immune- mediated diseases of the PNS.

摘要 慢性炎症性脱髓鞘性多发性神经病（CIDP）是最常见的获得性慢性 自身免疫性神经病目前CIDP的治疗是非特异性的，在三分之一的患者中无效， 在大多数患者中不会导致完全缓解。因此，更有效的，基于机制的疗法是 需要，并了解导致PNS自身免疫的免疫耐受缺陷将使他们能够 发展迄今为止的研究提出了一种模型，其中CD 4 + T细胞、巨噬细胞和补体导致 PNS中雪旺细胞的自身免疫性破坏。我们的数据表明雪旺细胞出乎意料地 在自身免疫攻击期间发生变化，可能会扩大炎症反应。雪旺氏细胞 对骨膜蛋白表达的影响，骨膜蛋白是一种分泌的细胞外基质蛋白，在致病性 增加CD 49 b的表达，CD 49 b是一种在结合补体蛋白C1 q中重要的整联蛋白;和 诱导MHC II类分子表达，MHC II类分子是向CD 4 + T细胞呈递抗原所需的分子。因此我们 假设雪旺细胞相关变化可能通过增加巨噬细胞 募集、补体沉积和CD 4 + T细胞活化。为了验证这一点，我们建议确定 i）雪旺细胞特异性骨膜蛋白表达是否足以驱动巨噬细胞募集， 神经病发展; ii）雪旺细胞中CD 49 b和/或C1 q的丧失阻止补体激活， iii）施旺细胞特异性MHCII缺陷抑制CD 4 + T细胞刺激 并防止PNS自身免疫。这些目标将在CIDP小鼠模型和患者神经中进行测试 活组织检查该项目利用了多个PI的互补专业知识（PNS的Su博士 自身免疫和谢勒博士在雪旺细胞生物学），以阐明雪旺细胞在促进 脱髓鞘神经病。成功完成本项目的目标将为确定 CIDP机制免疫干预的新目标。此外，这些调查结果 这些研究将有助于更广泛地了解雪旺细胞如何在免疫系统中放大炎症， 介导的PNS疾病。