Autoimmune Mechanisms in Peripheral Neuropathy

摘要 慢性炎症性脱髓鞘多神经病(CIDP)是最常见的获得性慢性疾病 自身免疫性神经病。目前对CIDP的治疗是非特异性的，对三分之一的患者无效， 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 并了解导致三叉神经痛自身免疫的免疫耐受缺陷将使他们的 发展。到目前为止的研究表明，CD4T细胞、巨噬细胞和补体导致 PNS中雪旺细胞的自身免疫破坏。我们的数据表明，雪旺细胞出人意料地 在自身免疫攻击期间发生变化，这可能会扩大炎症反应。雪旺细胞转向 致病菌趋化作用重要的分泌型细胞外基质蛋白Periostin的表达 巨噬细胞；增加CD49b的表达，CD49b是与补体蛋白C1q结合的重要整合素；以及 诱导MHC第二类分子的表达，这是一种将抗原呈递给CD4T细胞所需的分子。因此，我们 假设雪旺细胞相关变化可能通过巨噬细胞增加促进自身免疫 募集、补体沉积和CD4T细胞激活。为了测试这一点，我们建议确定 雪旺细胞特异性Periostin的表达是否足以驱动巨噬细胞的募集和 神经病变的发展；ii)雪旺细胞和/或C1q中CD49b的丢失阻止补体激活和 防止神经病变；以及iii)雪旺细胞特异性MHCII缺陷抑制CD4T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中的Su博士 自身免疫和雪旺细胞生物学中的谢勒博士)，以阐明雪旺细胞在促进 脱髓鞘神经病。成功完成该项目的目标将为确定 CIDP基于机制的免疫治疗干预新靶点。此外，这些发现 研究将有助于更广泛地理解雪旺细胞如何放大免疫系统中的炎症。 中介疾病的三叉神经节。

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.