Leukocyte Activation and Migration in Autoimmune Encephalomyelitis

自身免疫性脑脊髓炎中的白细胞激活和迁移

• 批准号: 9424637
• 负责人: Youhai H Chen
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9424637
• 关键词: Antigen Receptors; Antigens; Autoimmune Diseases; Binding; Biochemical; Blood - brain barrier anatomy; Cells; Complex; Cytoskeleton; Defect; Development; Disease; Environmental Risk Factor; Enzymes; Experimental Autoimmune Encephalomyelitis; Family; Gene Expression; Generations; Genes; Genetic; Guanosine Triphosphate Phosphohydrolases; Human; Hydrophobicity; Hyperactive behavior; Hypersensitivity; Immunologics; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Integrins; Knowledge; Leukocytes; Ligands; Lipids; Location; Malignant Neoplasms; Mediating; Membrane; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Mus; Myelin; Neuraxis; PDPK1 gene; PTP4A2 gene; Pathogenicity; Pathway interactions; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Play; Protein Family; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Receptor Activation; Receptor Signaling; Regulatory Pathway; Regulatory T-Lymphocyte; Research; Resistance; Risk Factors; Role; Second Messenger Systems; Signal Transduction; Site; Spinal Cord; System; T cell differentiation; T-Cell Activation; T-Lymphocyte; TCR Activation; TNF gene; Testing; Tissues; Water; base; cell motility; chemokine; chemokine receptor; clinical practice; experimental study; extracellular; human disease; leukocyte activation; migration; multiple sclerosis patient; natalizumab; phosphatidylinositol 3,4,5-triphosphate; prevent; programs; public health relevance; receptor; receptor binding; recruit; theories

 DESCRIPTION (provided by applicant): The overall objective of our research program is to understand the molecular mechanisms of leukocyte activation and migration during autoimmune diseases such as multiple sclerosis (MS). A large number of membrane receptors can initiate leukocyte activation and/or migration, which include antigen receptors, chemokine receptors, and integrins. While these receptors bind to a diverse array of extracellular ligands (first messengers), a common intracellular second messenger generated by them is PIP3 (phosphatidylinositol 3,4,5-trisphosphate); PIP3 in turn directs leukocyte activation and migration by binding to dozens of effector proteins (such as protein kinases AKT, BTK, and PDK1) that regulate gene expression and/or cytoskeleton remodeling. This application is inspired by our recent discovery that the genesis and function of the common lipid second messenger PIP3 are controlled by its "professional" transfer proteins of the TNFAIP8 (tumor necrosis factor-α-induced protein 8) family. The TNFAIP8 family possesses a specific hydrophobic cavity that is constitutively occupied by the acyl chains of phosphoinositides such as PIP3, and it is the only known transfer protein family of PIP3. We initially cloned the TIPE2 (TNFAIP8-like 2) gene from spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) and found that it was preferentially expressed by leukocytes. We then generated TIPE2-deficient mice and found that they were significantly resistant to EAE. Unexpectedly, TIPE2-deficient myelin-specific TH1 and TH17 cells were hyper-sensitive to myelin antigens but had an intrinsic defect in migration into CNS. We therefore hypothesize that TNFAIP8 family confers the encephalitogenicity of myelin-specific T cells by controlling the genesis and function of common lipid second messengers that mediate both activation and migration. In its absence, the activation-induced surge of lipid second messengers destroys the internal PIP3 "compass" that guides cell migration, leading to the generation of hyper-active non-encephalitogenic TH1 and TH17 cells not capable of directional migration. This theory will be tested in both murine and human systems (including MS) using genetic, immunological, and biochemical approaches. Specifically, we will determine (I) the mechanism through which TIPE2 and TNFAIP8 regulate myelin-specific T cell activation, and (II) the mechanism through which TIPE2 and TNFAIP8 regulate leukocyte migration during autoimmune encephalomyelitis.

 描述（由申请人提供）：我们研究项目的总体目标是了解多发性硬化症（MS）等自身免疫性疾病期间白细胞激活和迁移的分子机制。大量的膜受体可以启动白细胞活化和/或迁移，其中包括抗原受体、趋化因子受体和整合素。虽然这些受体与多种细胞外配体（第一信使）结合，但它们产生的常见细胞内第二信使是 PIP3（磷脂酰肌醇 3,4,5-三磷酸）； PIP3 反过来通过与数十种调节基因表达和/或细胞骨架重塑的效应蛋白（例如蛋白激酶 AKT、BTK 和 PDK1）结合来指导白细胞激活和迁移。该应用的灵感来自于我们最近的发现，即常见脂质第二信使 PIP3 的起源和功能是由 TNFAIP8（肿瘤坏死因子-α 诱导蛋白 8）家族的“专业”转移蛋白控制的。 TNFAIP8家族具有特定的疏水空腔，该空腔被PIP3等磷酸肌醇的酰基链组成组成型占据，是唯一已知的PIP3转移蛋白家族。我们最初从实验性自身免疫性脑脊髓炎（EAE）小鼠的脊髓中克隆了TIPE2（TNFAIP8-like 2）基因，发现它优先由白细胞表达。然后我们培育了 TIPE2 缺陷小鼠，发现它们对 EAE 具有显着的抵抗力。出乎意料的是，TIPE2 缺陷的髓磷脂特异性 TH1 和 TH17 细胞对髓磷脂抗原高度敏感，但在迁移到 CNS 方面存在内在缺陷。因此，我们假设 TNFAIP8 家族通过控制介导激活和迁移的常见脂质第二信使的发生和功能，赋予髓磷脂特异性 T 细胞致脑炎性。如果没有它，激活诱导的脂质第二信使激增会破坏指导细胞迁​​移的内部 PIP3“指南针”，导致产生高度活跃的非脑炎性 TH1 和 TH17 细胞，无法定向迁移。该理论将使用遗传、免疫学和生化方法在小鼠和人类系统（包括多发性硬化症）中进行测试。具体来说，我们将确定（I）TIPE2和TNFAIP8调节髓磷脂特异性T细胞活化的机制，以及（II）TIPE2和TNFAIP8在自身免疫性脑脊髓炎期间调节白细胞迁移的机制。