Advisor(s)
Ashley Harms
Committee Member(s)
Briana De Miranda
David Standaert
Frances Lund
Laurie Harrington
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Joint Health Sciences
Date of Award
6-3-2025
Abstract
Multiple system atrophy (MSA) is a rare, fast progressing, debilitating and ultimately fatal movement disorder. The pathological hallmark of MSA disease is the aggregation and misfolding of alpha-synuclein (α-syn) protein in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). Accumulation of these GCIs result in progressive demyelination and neurodegeneration of the striatonigral and olivopontocerebellar regions of the brain. Currently, no therapeutics have been approved that slow or halt the progression of this devastating disease. Neuroinflammation, has been increasingly appreciated as a key neuropathological feature of disease, especially activation of tissue resident innate immune cells. Recently, evidence of adaptive immune responses has been discovered, including T cell infiltration into the brain parenchyma and changes in α-syn recognizing antibodies in MSA patients. Studies conducted in the Olig001 viral overexpression mouse model of MSA demonstrate that oligodendrocyte-specific α-syn overexpression induces a T cell response, indicating that α-syn generates an adaptive immune response. B cells are a key cell population in the adaptive immune system, working in tandem with CD4+ T cells to generate a humoral immune response. However, no studies have confirmed if α-syn accumulation in oligodendrocytes results in B cell activation. Using the Olig001 model, we provided evidence of B cell activation in both mice and non-human primates, including B cell infiltration and antibody deposition in areas of α-syn overexpression. Using B cell receptor transgenic mice recognizing hen egg lysozyme (HEL), we reported a reduction in both B cell infiltration and antibody deposition, suggesting that these B cell responses are antigen specific. Finally, we used genetic knockout animals to determine the role these B cells play in MSA disease progression. Interestingly, we found that knocking out B cells does not improve demyelinating pathology and worsens α-syn pathology accumulation. Using HEL BCR transgenic animals, we characterized a protective role of antibody in promoting the clearance of pathological α-syn by myeloid cells. Together, our findings suggest that B cells primarily play a protective role in MSA disease. This supports current therapeutic strategies in development that utilize immunization strategies to block accumulation and facilitate the clearance of α-syn pathology.
ProQuest ID
Recommended Citation
Childers, Gabrielle, "The Role Of B Cells In A Mouse Model Of Multiple System Atrophy" (2025). All ETDs from UAB. 7329.
https://digitalcommons.library.uab.edu/etd-collection/7329
