Thesis
Proteolipid protein-induced mouse model of multiple sclerosis requires B cell-mediated antigen presentation
University of Iowa
Master of Science (MS), University of Iowa
Summer 2023
DOI: 10.25820/etd.006933
Abstract
The pathogenic role B cells play in multiple sclerosis (MS) is underscored by the success of B cell depletion therapies. Yet, it remains unclear how B cells contribute to disease, although it is increasingly accepted that mechanisms beyond antibody production are involved. Better understanding of pathogenic interactions between B cells and autoreactive CD4 T cells will be critical for novel therapeutics. To focus investigation on B cell:CD4 T cell interactions in vivo and in vitro, we previously developed a B cell-dependent, antibody-independent experimental autoimmune encephalomyelitis (EAE) mouse model driven by the extracellular sequences of myelin proteolipid protein (PLPECD). In this study, we demonstrate that B cell depletion significantly inhibited PLPECD-induced EAE disease, blunted PLPECD-elicited delayed-type hypersensitivity reactions in vivo, and reduced CD4 T cell activation, proliferation, and proinflammatory cytokine production. Further, PLPECD-reactive CD4 T cells sourced from B cell-depleted donor mice failed to transfer EAE to naïve recipients. Importantly, we identified B cell-mediated antigen presentation as the critical mechanism explaining B cell-dependence in PLPECD-induced EAE, where bone marrow chimeric mice harboring a B cell-restricted MHC class II deficiency failed to develop EAE. B cells were ultimately observed to restimulate PLP178-191-reactive CD4 T cell proliferation more efficiently than dendritic cells when provided PLPECD peptide in head to head cultures. We therefore conclude that PLPECD-induced EAE features a required pathogenic B cell-mediated antigen presentation function, providing for investigable B cell:CD4 T cell interactions in the context of autoimmune demyelinating disease.
Details
- Title: Subtitle
- Proteolipid protein-induced mouse model of multiple sclerosis requires B cell-mediated antigen presentation
- Creators
- Connor Wilhelm
- Contributors
- Nitin Karandikar (Advisor)Ashutosh Mangalam (Committee Member)Scott Lieberman (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Pathology
- Date degree season
- Summer 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006933
- Number of pages
- viii, 67 pages
- Copyright
- Copyright 2023 Connor Wilhelm
- Language
- English
- Date submitted
- 07/25/2023
- Description illustrations
- illustrations, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 60-67).
- Public Abstract (ETD)
- Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) where immune cells attack the protective myelin that surrounds neurons. While autoreactive CD4 T cells are thought to be the primary driver of this disease, other immune cell populations play a major role in influencing disease progression. Interest in the pathogenic role B cells play in MS has grown due to the success of B cell depletion therapies in treating MS. Despite this success, it is unclear exactly how B cells contribute to disease progression, though it is increasingly understood that mechanisms beyond antibody production are involved. Given this, we hypothesized B cells contribute to MS development by acting as myelin antigen presenting cells to autoreactive CD4 T cells, thereby enhancing their pathogenicity. To explore B cell:CD4 T cell interactions in this context, we used a novel model of experimental autoimmune encephalomyelitis (EAE), the mouse model of MS, wherein B cells, but not B cell antibodies, are required for disease development. With this novel model, we showed that B cells significantly enhanced the pathogenic character of CD4 T cells in vivo and in vitro. Critically, B cell specific antigen recognition and presentation is required for EAE development in this model. We concluded that this novel model of EAE is a useful tool in characterizing pathogenic B cell:CD4 T cell interactions in the context of demyelinating diseases and content that B cell mediated antigen presentation to CD4 T cells is likely a critical pathologic mechanism in MS.
- Academic Unit
- Pathology
- Record Identifier
- 9984454318402771
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