Pathogenic B cell:CD4 T cell interactions in a novel B cell-dependent EAE mouse model of multiple sclerosis

致病性 B 细胞：CD4 T 细胞在新型 B 细胞依赖性多发性硬化症 EAE 小鼠模型中的相互作用

• 批准号: 10718277
• 负责人: Alexander Boyden
• 金额: $ 47.24万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718277
• 关键词: Affect; American; Animal Model; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune; Autopsy; B cell therapy; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Blood; Bone Marrow; Brain; CD4 Positive T Lymphocytes; CXCR3 gene; Cell Communication; Cell Shape; Cells; Central Nervous System Diseases; Cephalic; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Disease Progression; Economic Burden; Evaluation; Exhibits; Experimental Autoimmune Encephalomyelitis; Extracellular Domain; Flow Cytometry; Health; Helper-Inducer T-Lymphocyte; Histologic; Homing; Human; IL17 gene; Immune; Immunization; Immunize; Inflammation; Integrin alpha Chains; Integrin alpha4beta1; Interleukin-6; Investigation; Kinetics; Lesion; MHC Class II Genes; MS4A1 gene; Manuscripts; Mediating; Meningeal; Meninges; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Mus; Myelin; Myelin Proteolipid Protein; Nature; Pathogenicity; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Population; Positioning Attribute; Prevalence; Production; Proliferating; Research Personnel; Role; Shapes; Spinal Cord; Supporting Cell; Surface; Symptoms; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Tissues; United States; Visualization; Work; autoreactivity; central nervous system demyelinating disorder; cytokine; early onset; human model; immunoreactivity; in vivo; insight; interest; intravital imaging; mouse model; multiple sclerosis patient; neuroinflammation; novel; polarized cell; response; success; transcription factor; transcriptome

PROJECT ABSTRACT MS is an immune-mediated demyelinating disease of the CNS, and despite first line drugs that limit symptoms, disease progresses over time and is incurable. Given its early onset and rise in prevalence for nearly 1 million Americans, MS presents immense health and economic burdens on the United States. Given the success of B cell depletion therapy (BCDT), understanding the pathogenic roles of B cells during disease is of high interest. Because of the CD20-targeted nature of BCDT, it is understood that B cells contribute to MS pathology through mechanisms beyond antibody production, likely through support of autoreactive CD4 T cells. Most animal models of MS (experimental autoimmune encephalomyelitis or EAE) are B cell-independent, which limits impactful insights into pathogenic B:T interactions in vivo. To circumvent this, we have recently developed a B cell-dependent, antibody-independent animal model of MS featuring CD4 T cell immunoreactivity to the extracellular domain sequences of the highly abundant and 100% conserved myelin proteolipid protein (PLPECD). Through rigorous preliminary studies, we have identified B cell-mediated antigen presentation to CD4s through MHC class II as the required pathogenic B cell mechanism in PLPECD-induced EAE, where B cells engage PLPECD through the B cell receptor and are superior vs. non-B cell antigen presenting cells at processing and presenting immunodominant residues from within PLPECD to PLP178-191-reactive CD4 T cells. Further mimicking the sustained pathogenic B cell involvement seen in MS and unlike B cell- independent EAE driven by PLP178-191, BCDT robustly ameliorates established PLPECD disease. B cells’ role in supporting CD4s during neuroinflammation and shaping the diverse T helper cell (Th) profiles observed in MS remains unclear. Understanding these dynamics in MS may prove significant in identifying which patients will respond to BCDT and thus modeling pathogenic B cell involvement in vivo is becoming increasingly important. Our objective is to use this powerful B cell-dependent EAE model to understand how B cells shape the CD4 response and to investigate B cell-mediated support of CD4s in the CNS. These are key aspects of B cell-mediated pathology that are not currently understood and difficult to model appropriately in vivo. Our model put us in a unique position to answer these questions. We hypothesize that B cell-provided cytokines shape a biased Th profile and that CNS B cell:CD4 interactions are critical in promoting demyelination in PLPECD EAE. Specific Aim 1 will determine how B cells shape pathogenic CD4 T cells by testing B cell-provided cytokines’ impact on Th1/17 bias. Specific Aim 2 will determine CNS B cells’ role in PLPECD-induced EAE and visualize B cell-supported neuroinflammation.

项目摘要 MS是一种免疫介导的CNS脱髓鞘疾病，尽管一线药物 限制症状，疾病随着时间的推移而发展，并且无法治愈。鉴于其早期发病和上升， 近100万美国人患病，MS带来了巨大的健康和经济负担 关于美国。鉴于B细胞耗竭疗法（BCDT）的成功，了解 B细胞在疾病中的致病作用受到高度关注。由于CD 20靶向性质， 对于BCDT，应理解B细胞通过除 抗体产生，可能通过支持自身反应性CD 4 T细胞。大多数动物模型 MS（实验性自身免疫性脑脊髓炎或EAE）是B细胞非依赖性的，这限制了 对体内致病性B：T相互作用的深刻见解。为了避免这种情况，我们最近 开发了一种B细胞依赖性、抗体非依赖性的MS动物模型，其特征在于CD 4 T细胞 免疫反应性的细胞外结构域序列的高度丰富和100% 保守髓鞘蛋白脂质蛋白（PLPECD）。通过严格的初步研究，我们 鉴定了B细胞介导的抗原通过MHC II类呈递给CD 4 s， PLPECD诱导的EAE中的致病性B细胞机制，其中B细胞通过 B细胞受体，并且在加工和免疫应答方面优于非B细胞抗原呈递细胞。 将来自PLPECD内的免疫显性残基呈递给PLP 178 -191反应性CD 4 T细胞。 进一步模拟在MS中观察到的持续致病性B细胞参与，而不像B细胞， 在由PLP 178 -191驱动的独立EAE中，BCDT稳健地改善已建立的PLPECD疾病。 B细胞在神经炎症期间支持CD 4 s和形成多样化T辅助细胞中的作用 (Th)在MS中观察到的特征仍不清楚。了解MS中的这些动态可能会证明 在鉴定哪些患者将对BCDT有反应并因此对致病性B细胞建模方面具有重要意义 体内参与变得越来越重要。我们的目标是利用这个强大的B 细胞依赖性EAE模型，以了解B细胞如何塑造CD 4反应，并研究 CNS中B细胞介导的CD 4支持。这些是B细胞介导的病理学的关键方面 目前尚不清楚并且难以在体内适当建模。我们的模型把我们 一个独特的位置来回答这些问题我们假设B细胞提供的细胞因子形状 偏向性Th分布和CNS B细胞：CD 4相互作用在促进脱髓鞘中是关键的 在PLPECD EAE中。特异性目的1将通过测试来确定B细胞如何形成致病性CD 4 T细胞。 B细胞提供的细胞因子对Th 1/17偏倚的影响。特异性目的2将决定CNS B细胞的作用 在PLPECD诱导EAE和可视化B细胞支持的神经炎症中。