PhD defence S.C. (Steven) Koetzier

Summary:

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T and B cells (immune cells) inflict damage to neurons that can result in neurological deficits. Till date, it remains unclear how T and B cells get triggered to migrate from the blood into the CNS of these patients. In this thesis, the role of genetic and hormonal factors driving the formation of brain-infiltrating T and B cells in MS was explored. In the first part of this thesis, it was investigated whether the MS-associated genetic risk variant of RUNX3 influences the function of cytotoxic T cells. Here, it was shown that this variant drives the formation of CD8+ T-cells with an early brain-infiltrating phenotype. In the second part of this thesis, it was demonstrated that a brain-infiltrating CD4+ T cell termed Th17.1 was resistant to synthetic glucocorticoids, which is routinely used to treat acute MS relapses. In the laboratory, this glucocorticoid-resistant phenotype was reversed when these cells were co-supplemented with high dosages of vitamin D and progesterone. These hormones are increased within the human body during pregnancy and strongly decrease after delivery. This respectively associates with a decreased or increased risk of getting a relapse after delivery in MS patients. In the third part of this thesis, we show that the suppression of Th17.1 and not B cells during pregnancy was predictive for a relapse after delivery in MS. Together, this research contributed to a better understanding of MS pathology and treatment.