Contribution of the effector Treg-B-antibody nexus to the regulation of CNS autoimmunity

效应 Treg-B-抗体关系对中枢神经系统自身免疫调节的贡献

• 批准号: 10804754
• 负责人: Jianmei Wu Leavenworth
• 金额: $ 13.89万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10804754
• 关键词: Ablation; Adopted; Affect; Animal Model; Antibodies; Antibody Affinity; Antibody Response; Antigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biological Assay; Biology; CNS autoimmunity; Cells; Central Nervous System; Data; Deposition; Development; Disease; Disease Progression; Ensure; Epigenetic Process; Eragrostis; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Generations; Genetic; Glycolysis; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; IL17 gene; IgE; Immune response; Impairment; Infection; Inflammatory; Inflammatory Response; Interleukin-10; Maintenance; Mediating; Metabolic; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Nature; Paralysed; Pathogenesis; Phenotype; Publications; Recovery; Regulation; Regulatory T-Lymphocyte; Role; Secondary to; Serum; Shapes; Structure of germinal center of lymph node; T-Lymphocyte Subsets; TFRC gene; Testing; Tissues; Vaccination; anergy; comparison control; defined contribution; disorder control; effector T cell; epigenomics; glial activation; insight; metabolic fitness; microbial; multiple sclerosis patient; neuroinflammation; novel therapeutic intervention; oligodendrocyte-myelin glycoprotein; prevent; programs; response; restraint; tertiary lymphoid organ; transcription factor; transcriptomics

PROJECT SUMMARY: Multiple sclerosis (MS) is a debilitating autoimmune inflammatory disease that affects the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model of MS. Although emerging data have suggested the contribution of TFR-TFH-GC B-antibody (Ab) responses to EAE and MS, the contribution of TFR cells to the disease pathogenesis and the nature of Ab response remain largely unknown. Effector Tregs (eTregs) including TFR cells must maintain their suppressive anergic phenotype at non-lymphoid tissues, including the CNS, and during ongoing inflammatory responses. However, the mechanisms that ensure maintenance of anergy, lineage identity and expression of regulatory activity by eTregs are not well defined. Our recent publication has revealed that expression of the transcription factor Blimp1 in eTregs, including the TFR subset, is essential for maintenance of FoxP3 expression and stable eTreg suppressive activity. The pro-inflammatory potential of Blimp1-deficient eTregs has prompted us to examine their impact on the CNS autoimmunity using the myelin oligodendrocyte glycoprotein (MOG)-induced EAE model. We observed that mice with a FoxP3-specific ablation of Blimp1 developed severe EAE, failed to recover and all succumbed to paralysis compared to controls, which reflected conversion of unstable Blimp1- deficient eTregs into IL-17A/GM-CSF-producing effector T-cells (Teff) associated with enhanced glycolysis and loss of suppression on TFH-Ab responses as well as aberrant microglial activation. Surprisingly, serum IgE titers were positively correlated with EAE scores and these mice had more IgE deposition in the CNS. Moreover, compared to healthy controls (HC), MS patients had reduced circulating Blimp1+ Tregs and TFR cells expressing lower levels of Blimp1 and IL-10, associated with elevated IgE levels. We hypothesize that Blimp1 expression enforces eTreg stability under CNS autoimmunity by preventing acquisition of effector activity and metabolic skewing as well as restraining TFH-Ab response. Using combined transcriptomic, epigenomic and metabolic assays, we will delineate the mechanisms by which eTregs, TFR cells and Ab responses regulate neuroinflammation and how loss of Blimp1 in eTregs re-shape the CNS microenvironment. The proposed study will uncover Blimp1 as a new regulator that is important for eTreg stability and for mediating disease recovery during CNS autoimmunity. Our findings point to a previously unrecognized mechanism enforcing eTreg stability by coordinating response to the autoimmune milieu and maintaining metabolic fitness via regulation of Blimp1. This study also has the potential to reveal the unappreciated role of TFR cells, and to clarify the role of B-cells and Ab responses (particularly IgE) in the regulation of CNS autoimmunity. Insights from these studies may provide critical strategies to formulate novel therapeutic approaches to MS by exploiting a surprising aspect of the biology of a critical T-cell subset.

项目概要： 多发性硬化症 (MS) 是一种影响中枢神经的衰弱性自身免疫炎症性疾病 系统（CNS），而实验性自身免疫性脑脊髓炎（EAE）是最常用的动物 MS 模型。尽管新出现的数据表明 TFR-TFH-GC B 抗体 (Ab) 的贡献 对 EAE 和 MS 的反应、TFR 细胞对疾病发病机制的贡献以及抗体的性质 反应仍然很大程度上未知。包括 TFR 细胞在内的效应 Treg (eTreg) 必须保持其抑制性 非淋巴组织（包括中枢神经系统）以及持续炎症反应期间的无反应表型。 然而，确保维持无反应性、谱系特性和调节表达的机制 eTreg 的活动尚未明确定义。我们最近的出版物揭示了转录的表达 eTregs（包括 TFR 子集）中的因子 Blimp1 对于维持 FoxP3 表达和稳定至关重要 eTreg 抑制活性。 Blimp1 缺陷的 eTregs 的促炎潜力促使我们 使用髓鞘少突胶质细胞糖蛋白 (MOG) 诱导检查它们对中枢神经系统自身免疫的影响 EAE模型。我们观察到，具有 FoxP3 特异性消融 Blimp1 的小鼠出现了严重的 EAE，但未能 与对照组相比，恢复并全部死于瘫痪，这反映了不稳定的 Blimp1- 的转变 将缺陷的 eTreg 转化为产生 IL-17A/GM-CSF 的效应 T 细胞 (Teff)，与增强的糖酵解和 对 TFH-Ab 反应的抑制丧失以及小胶质细胞的异常激活。令人惊讶的是，血清IgE 滴度与 EAE 评分呈正相关，并且这些小鼠的中枢神经系统中有更多的 IgE 沉积。 此外，与健康对照 (HC) 相比，MS 患者的循环 Blimp1+ Tregs 和 TFR 细胞减少 表达较低水平的 Blimp1 和 IL-10，与升高的 IgE 水平相关。我们假设 Blimp1 表达通过阻止效应子活性的获得来增强中枢神经系统自身免疫下 eTreg 的稳定性 代谢偏差以及抑制 TFH-Ab 反应。结合转录组学、表观基因组学和 代谢测定，我们将描述 eTregs、TFR 细胞和 Ab 反应调节的机制 神经炎症以及 eTreg 中 Blimp1 的缺失如何重塑 CNS 微环境。拟议的 研究将发现 Blimp1 作为一种新的调节因子，对于 eTreg 稳定性和介导疾病非常重要 中枢神经系统自身免疫期间的恢复。我们的研究结果指出了一种以前未被认识到的强制机制 eTreg 的稳定性通过协调对自身免疫环境的反应并通过以下方式维持代谢健康 Blimp1 的调节。这项研究还有可能揭示 TFR 细胞未被认识到的作用，并 阐明 B 细胞和抗体反应（特别是 IgE）在中枢神经系统自身免疫调节中的作用。见解 这些研究可能为制定多发性硬化症的新治疗方法提供关键策略 利用关键 T 细胞亚群生物学的一个令人惊讶的方面。