Immune pathology and bone marrow transplant in disorders of Mecp2 overexpression

Mecp2 过度表达疾病的免疫病理学和骨髓移植

• 批准号: 9118067
• 负责人: JAMES Christopher CRONK
• 金额: $ 4.86万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118067
• 关键词: Accounting; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Appearance; Astrocytes; Binding; Body Weight decreased; Bone Marrow; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell physiology; Cells; Cessation of life; Complex; DNA; Data; Defect; Dendritic Cells; Disease; Ear; Exhibits; Functional disorder; Gene Expression; Genes; Genetic Transcription; Health; ITGAM gene; ITGAX gene; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; Intervention; Knockout Mice; Lead; Life; Link; Lymphocyte; Measures; Mediating; Methyl-CpG-Binding Protein 2; Microglia; Modality; Modeling; Morbidity - disease rate; Mus; Myelogenous; Neurodevelopmental Disorder; Neurologic; Neurons; Neutrophil Infiltration; Organ; Pathologic; Pathology; Patients; Peripheral; Play; Process; Publishing; Recruitment Activity; Recurrence; Respiratory Tract Infections; Rett Syndrome; Risk; Role; Sinus; Site; Syndrome; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Testis Brain; Time; Transplantation; Viral; Virus; Virus Diseases; Wild Type Mouse; Work; X Chromosome; adaptive immunity; base; boys; cytokine; girls; improved; improved outcome; in vitro Assay; in vitro testing; in vivo; influenzavirus; loss of function mutation; mortality; mouse model; neutrophil; overexpression; reconstitution; respiratory; response; treatment strategy

DESCRIPTION (provided by applicant): MeCP2-duplication/triplication syndrome is a devastating neurodevelopmental disorder mostly affecting boys and is caused by duplication (or triplication) of the region in the X-chromosome containing the gene encoding MeCP2 (methyl-CpG-binding protein 2). MeCP2 binds to methylated CpG sites on DNA and recruits transcription complexes to modulate gene expression. Because MeCP2 modulates a multitude of genes, it is not surprising that pinpointing specific functions has proven difficult. In additio to MeCP2-duplication syndrome, loss-of-function mutations in MeCP2 account for about 96% of Rett Syndrome cases, another devastating neurodevelopmental disorder that is typically seen in girls. Because of the strong neurologic component seen in both Rett and MeCP2-duplication syndromes, MeCP2 was long assumed to be primarily important for neurons. However, recent studies have shown that other cells, such as astrocytes and microglia in Rett syndrome, and T cells in MeCP2-duplication syndrome, also play a significant role. This understanding opens up the possibility for treatment modalities beyond direct neuronal intervention, which has been a problematic approach due to the complexity and risk involved in any manipulation of neurons themselves. Here, we propose to test the hypothesis that MeCP2 overexpression causes defects of adaptive immunity that lead to excessive, pathologic innate inflammation, ultimately contributing to morbidity and mortality. Preliminary data in MeCP2Tg3 mice, which overexpress MeCP2 at 3-5 fold normal levels, reveals that as disease progresses, peripheral organs undergo significant weight loss associated with gross pathologic appearance and immune infiltrates. However, immune-privileged organs (brain and testes) are protected from these changes. This suggests that a peripheral destructive immune process is contributing to pathology in MeCP2Tg3 mice. In addition, MeCP2Tg3 mice have significantly increased mortality from influenza infection. In an influenza model, MeCP2Tg3 mice exhibit a deficient CD8+ T cell response and excessive innate inflammation without an apparent defect in viral clearance; we intend to test the hypothesis that CD8+ T cell defects result in a compensatory increased innate response, which causes pathology leading to increased death. The first aim is to test the hypothesis that dendritic cell malfunction contributes to defects of the adaptive immune response using both in vitro and in vivo assessment of antigen presentation and T cell activation. The second aim in this proposal will test the hypothesis that a deficient CD8+ T cell response contributes to increased mortality in MeCP2Tg3 mice via an excessive innate immune response. This will be tested by in vitro assessment of CD8+ T cell function and in vivo assessment of CD8+ T cell response to influenza. The third aim is to ameliorate death from influenza in MeCP2Tg3 mice via either bone marrow transplant or suppression of the excessive innate inflammation. Ultimately, results obtained from this work may lead to immune-based treatment strategies for patients with MeCP2-duplication syndrome.

描述（由申请人提供）：MeCP 2-重复/三重综合征是一种主要影响男孩的破坏性神经发育障碍，由X染色体中含有编码MeCP 2（甲基-CpG结合蛋白2）的基因的区域重复（或三重）引起。MeCP 2与DNA上的甲基化CpG位点结合，并募集转录复合物以调节基因表达。由于MeCP 2调节多种基因，因此确定特定功能已被证明是困难的，这并不奇怪。除了MeCP 2复制综合征之外，MeCP 2中的功能缺失突变占Rett综合征病例的约96%，Rett综合征是另一种通常见于女孩的破坏性神经发育障碍。由于在Rett和MeCP 2复制综合征中观察到的强烈神经学成分，长期以来，MeCP 2被认为对神经元非常重要。然而，最近的研究表明，其他细胞，如Rett综合征中的星形胶质细胞和小胶质细胞，以及MeCP 2-复制综合征中的T细胞，也起着重要作用。这种理解为直接神经元干预之外的治疗方式开辟了可能性，由于神经元本身的任何操纵都涉及复杂性和风险，这一直是一种有问题的方法。 在这里，我们建议测试的假设，MeCP 2过表达导致的适应性免疫缺陷，导致过度的，病理性先天性炎症，最终导致发病率和死亡率。在MeCP 2 Tg 3小鼠中的初步数据显示，随着疾病的进展，外周器官经历与大体病理学外观和免疫浸润相关的显著重量减轻，MeCP 2 Tg 3小鼠以3-5倍正常水平过表达MeCP 2。然而，免疫特权器官（大脑和睾丸）免受这些变化的影响。这表明外周破坏性免疫过程导致MeCP 2 Tg 3小鼠的病理学。此外，MeCP 2 Tg 3小鼠具有显著增加的流感感染的死亡率。在流感模型中，MeCP 2 Tg 3小鼠表现出CD 8 + T细胞应答缺陷和先天性炎症过度，而病毒清除没有明显缺陷;我们打算检验CD 8 + T细胞缺陷导致代偿性先天性应答增加的假设，这会导致导致死亡增加的病理学。第一个目的是测试的假设，树突状细胞功能障碍有助于在体外和体内评估抗原呈递和T细胞活化的适应性免疫应答的缺陷。本提案的第二个目的是检验以下假设：CD 8 + T细胞应答缺陷通过过度的先天免疫应答导致MeCP 2 Tg 3小鼠死亡率增加。这将通过体外评估CD 8 + T细胞功能和体内评估CD 8 + T细胞对流感的应答进行测试。第三个目的是通过骨髓移植或抑制过度的先天性炎症来改善MeCP 2 Tg 3小鼠中流感的死亡。最终，这项工作获得的结果可能会为MeCP 2复制综合征患者带来基于免疫的治疗策略。