טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKorin Ben
SubjectThe Brain's Immune Compartment and How it is Affected by
Changes in Brain Activity
DepartmentDepartment of Medicine
Supervisor Professor Asya Rolls
Full Thesis textFull thesis text - English Version


Abstract

The brain and its border tissues create a highly dynamic microenvironment comprised of multiple cell types that constantly interact with each other. Some of these cells are immune cells that are located in the brain parenchyma, and others are immune cells that migrate from the blood and are mainly found in the borders of the brain. Increasing evidence indicates the importance of these collective immune populations in the brain function and homeostasis. However, most studies have been focused on the crosstalk between the immune system and the brain in various neurodegenerative and neuroinflammatory disorders. Thus, in the first part of my thesis, we explored and characterized the naïve brain immune compartment. We used mass cytometry, which enables a high-dimensional description of tens of markers at the single-cell level, providing a broad view of the immune system. We showed that the healthy mouse brain is populated by a variety of immune cells that originate from the blood circulation; for example, mature natural killer cells, dendritic cells, T cell subsets, B cells, and others that were not described before in the naïve brain compartment, and were mostly considered as a part of an evident pathology. We further described the phenotype of these immune cells, that although originate from the blood, have distinct features in the brain compartment, emphasizing the selectivity for its immune cells. Following a high-dimensional analysis of the brain’s resident myeloid cells (i.e., microglia), we detected that CD44, a hyaluronic acid receptor, is exclusively expressed in infiltrating and not in resident myeloid cells, which may point to the receptor’s importance in cell migration to the brain compartment. This result provides an additional approach to the essential distinction between resident microglia and blood-derived myeloid cells. Our research, published in Nature Neuroscience (2017) and Nature Protocols (2018), introduced a new perspective to our understanding of the involvement of immune cells in normal brain function, and further support the importance of a broad and in-depth immune characterization of the brain. In the second part of my research thesis, we applied this platform for immune cell analysis, to determine whether and how short-term sleep deprivation affects the brain’s immune compartment. We identified that depriving sleep for 6 hours increased the abundance of B cells in the brain compartment. Mechanistically, this effect can be accounted for, at least in part, by elevated expression of the migration-related receptor, CXCR5, on B cells, and its ligand, cxcl13, in the meninges following sleep deprivation. As many brain disorders are accompanied by sleep and immune alterations, our study, published in Sleep (2019), proposes new insights on how sleep dysfunction can affect immune cells in the brain and promote pathology. Taken together, my thesis provided novel tools and venues in neuroimmunology research, and a broad perspective of the naïve brain compartment and how it is affected by intrusions in homeostasis. Further exploring the brain’s immunological environment in numerous conditions and disorders will allow us to identify potential targets for manipulation and new neuroimmune-based paths for intervention.