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