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: 10621378
• 负责人: Jianmei Wu Leavenworth
• 金额: $ 36.58万
• 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/10621378
• 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.

项目摘要： 多发性硬化症（MS）是一种令人衰弱的自身免疫性炎症性疾病，会影响中枢神经 系统（CNS）和实验性自身免疫性脑脊髓炎（EAE）是最常用的动物 MS的模型。尽管新兴数据表明TFR-TFH-GC B抗体（AB）的贡献 对EAE和MS的反应，TFR细胞对疾病发病机理的贡献和AB的性质 响应在很大程度上未知。包括TFR细胞在内的效应tregs（ETREGS）必须保持其抑制作用 包括CNS在内的非淋巴组织和持续炎症反应期间的非淋巴组织中的厌氧表型。 但是，确保维持厌食，谱系身份和调节表达的机制 ETREG的活动不是很好的定义。我们最近的出版物揭示了转录的表达 ETREG中的因子Blimp1（包括TFR子集）对于维持FOXP3表达和稳定至关重要 ET抑制活性。 Blimp1缺陷ETREGS的促炎潜力促使我们提出 使用髓磷脂少突胶质细胞糖蛋白（MOG）诱导的，检查它们对CNS自身免疫的影响 EAE模型。我们观察到用Blimp1的Foxp3特异性消融的小鼠发展出严重的EAE，未能 与对照组相比，恢复并屈服于瘫痪，这反映了不稳定的Blimp1-的转化 缺乏与IL-17A/GM-CSF产生效应子T细胞（TEFF）的缺陷，与增强的糖酵解和 对TFH-AB反应以及异常小胶质细胞激活的抑制丧失。令人惊讶的是，血清Ige 滴度与EAE分数呈正相关，这些小鼠在中枢神经系统中具有更多的IgE沉积。 此外，与健康对照组（HC）相比，MS患者减少了循环Blimp1+ Treg和TFR细胞 表达较低水平的Blimp1和IL-10，与IgE升高有关。我们假设Blimp1 通过防止获得效应子活动和 代谢偏斜以及限制TFH-AB反应。使用转录组，表观基因组和 代谢测定法，我们将描述ETREG，TFR细胞和AB反应调节的机制 神经炎症以及ETREGS中Blimp1的损失如何重塑CNS微环境。提议 研究将发现Blimp1是一种对ETREG稳定性和介导疾病很重要的新调节剂 CNS自身免疫期间的恢复。我们的发现指出了先前无法识别的机制 通过协调对自身免疫环境的反应并维持代谢适应性，通过 Blimp1的调节。这项研究还有可能揭示TFR细胞的未引起的作用，并 阐明B细胞和AB反应（尤其是IgE）在CNS自身免疫调节中的作用。见解 从这些研究中，可以提供关键策略，以通过 利用关键T细胞子集生物学的令人惊讶的方面。