Neuroimmunological mysteries of multiple sclerosis: Immune cell dynamics in neurodegeneration

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). MS is thought to be initiated by autoreactive immune cells that infiltrate the brain and generate abnormal responses against CNS autoantigens. In particular, inflammation in MS destroys the myelin sheaths around neuronal axons, also known as demyelination, but also leads to glial activation and neuronal damage, and, eventually, neuronal death. Accordingly, different immune cells partake in this process. This thesis aimed to increase our understanding of the role of different immune cell types in MS. In the first chapters, we investigated B cells in MS and in the later chapters, we focused on NK cells and microglia. B cells B cells are known for their antibody production, but they can also act as antigen-presenting cells and shape the inflammatory responses of other cells. We quantified the immunoglobulin (Ig) levels in the cerebrospinal fluid (CSF) and serum from MS patients and healthy donors and observed an increase of IgM and IgG in the CNS of MS patients, which correlated with markers of neurodegeneration. We further analyzed the peripheral immune landscape of MS patients after a regular or extended interval dosing of ocrelizumab, an anti-B cell therapy, and found that different B cell subsets are repopulating more depending on the interval dosing. We also found that using one or other interval dosing of ocrelizumab did not affect the clinical efficacy of this therapy. Our findings further describe how B cells mainly accumulate in perivascular infiltrates and the leptomeninges during MS, where they can contribute to disease pathogenesis. NK cells NK cells can be classified as CD56bright NK cells and CD56dim NK cells with the first one being considered anti-inflammatory cells and the second one, cytotoxic cells. Regions in close contact with the CSF, such as periventricular regions, are hotspots for MS lesions. In this thesis, we show the specific infiltration of T cells, antibody-secreting B cells and CD56bright NK cells in these brain regions of MS donors. These CD56bright NK cells presented an activated and migratory phenotype suggesting a possible migration over the blood-brain barrier or the blood-CSF barrier in MS patients. Microglia Microglia are CNS-resident immune cells, continuously scanning the brain environment for possible damage or invading pathogens. In MS, microglial functions range from neuroprotective to neurodegenerative, highlighting their dichotomic role in this disease. In this thesis, we studied the phenotype of microglia in the thalamus and the cortex, two regions that are also in close contact with the CSF. We uncovered an altered microglial phenotype in the thalamus that is associated with atrophy in the thalamus in progressive MS donors. Potentially, this indicates an effect of immune cells and mediators in the CSF towards the brain parenchyma. We further identified two MS-specific cortical microglial populations that were associated with meningeal inflammation and neurodegeneration in progressive MS. We hypothesize that microglia initially protect neurons from meningeal inflammation-induced cell death, but eventually lose these neuroprotective properties, thereby leading to neuronal loss. Finally, we expanded our knowledge of meningeal inflammation-mediated pathology and the role of cortical microglia therein by performing different single-cell techniques. Conclusions In sum, this thesis highlights how different immune cells contribute to MS pathology. Further elucidation of the neuroimmunological mysteries of the various immune cell types might improve novel therapies that ameliorate MS pathogenesis.