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是一种免疫介导的中枢神经系统的脱髓鞘疾病，并希望一线药物 限制符号，疾病会随着时间的流逝而进展，并且是无法治愈的。鉴于它的早期发作和上升 近100万美国人的患病率是巨大的健康和经济伯恩斯 在美国。考虑到B细胞部署疗法（BCDT）的成功，了解 B细胞在疾病中的致病作用很高。由于CD20靶向的性质 BCDT的据了解，B细胞通过以外的机制有助于MS病理 抗体产生，可能是通过支持自动反应性CD4 T细胞的。大多数动物模型 MS（实验性自身免疫性脑脊髓炎或EAE）是B细胞独立的，它限制了 对病原B：T体内相互作用的有影响力的见解。为了解决这个问题，我们最近有 开发了B细胞依赖性的，抗体独立的MS动物模型，具有CD4 T细胞 对高度丰富的细胞外域序列的免疫反应性和100％ 保守的髓磷脂蛋白脂蛋白（PLPECD）。通过严格的初步研究，我们有 通过MHC II确定了B细胞介导的抗原呈现给CD4S的抗原呈递 PLPECD诱导的EAE中的致病B细胞机制，B细胞通过PLPECD通过 B细胞受体，是在加工和 从PLPECD内到PLP178-191反应性CD4 T细胞呈现免疫主导残留物。 进一步模仿在MS中看到的持续致病B细胞受累，与B细胞不同 由PLP178-191驱动的独立EAE，BCDT可靠地缓解已建立的PLPECD疾病。 B细胞在神经炎症过程中支持CD4和塑造潜水员T辅助细胞的作用 （Th）在MS中观察到的轮廓尚不清楚。了解MS中的这些动态可能证明 对于确定哪些患者对BCDT的反应，从而对致病性B细胞进行建模很重要 参与体内变得越来越重要。我们的目标是使用这种强大的B 依赖细胞的EAE模型，以了解B细胞如何塑造CD4响应并研究 B细胞介导的CD4在中枢神经系统中的支持。这些是B细胞介导的病理学的关键方面 目前尚不理解且难以在体内进行适当的建模。我们的模型使我们加入了 回答这些问题的独特位置。我们假设B细胞提供的细胞因子形状 TH的偏见和CNS B细胞：CD4相互作用对于促进脱髓鞘至关重要 在PLPECD EAE中。特定的目标1将通过测试如何确定B细胞如何塑造致病性CD4 T细胞 B细胞的细胞因子对Th1/17偏置的影响。特定的目标2将确定CNS B细胞的作用 在PLPECD诱导的EAE中，可视化B细胞支持的神经炎症。