Advisory Committee Chair
David G Standaert
Advisory Committee Members
Chander Raman
Etty T Benveniste
Matthew S Goldberg
Document Type
Dissertation
Date of Award
2021
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Parkinson disease (PD) is a neurodegenerative movement disorder that is characterized by aggregated alpha-synuclein (a-syn), loss of dopaminergic neurons, and neuroinflammation. This neuroinflammation includes the activation of immune cells that reside in the CNS, such as microglia and border associated macrophages (BAMs), in addition to the infiltration of peripheral leukocytes and increased cytokine and chemokine production. Because of the involvement of both the innate and adaptive immune systems, we sought to investigate their interaction through antigen presentation and determine what role this played in disease progression. Using an a-syn based mouse model of PD, our studies have provided evidence via knock-out and CNS-targeted silencing of Ciita, the class II transactivator, that class II antigen presentation to CD4+ T cells within the ventral midbrain drives further neuroinflammation and neurodegeneration. Additionally, we closely investigated a small group of CNS resident macrophages called BAMs. These cells have high expression of class II-related genes and the population expands in response to a-syn. Furthermore, we determined that a subset of BAMs is highly active in response to disease, and we thus termed them “disease-activated BAMs.” Specific BAM depletion indicated that they are responsible for the recruitment of and interaction with infiltrating immune cells at the borders of the CNS. Collectively, this work highlights the importance of interactions between the innate and adaptive immune system via antigen presentation in neuroinflammatory disease. Furthermore, for the first time, we highlight the importance of BAMs at the borders of the CNS, as opposed to microglia or meningeal dendritic cells, in driving neuroinflammation. Broadly, targeting these interactions or specific cells could provide potential targets for new disease modifying therapies that halt the neuroinflammatory process and protect neurons.
Recommended Citation
Schonhoff, Aubrey Michelle, "Cns Antigen Presentation And Immune Cell Infiltration In An Α-Syn Model Of Parkinson Disease" (2021). All ETDs from UAB. 911.
https://digitalcommons.library.uab.edu/etd-collection/911