Heterogeneity of the immunopathology in advanced multiple sclerosis An autopsy cohort analysis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which mostly presents in young adults. The disease often starts with a relapsing-remitting phase where patients show acute onset of neurological symptoms with spontaneous remission. Over time most MS patients accumulate disability and enter a progressive disease phase. The current available immunomodulatory therapies for MS directed at peripheral T or B-cells show an effect on the relapse rate in the early disease phase, however they do not halt the progression of the disease in advanced stages. This led to the concept that circulating immune cells contribute to the onset and early phase of the disease, while they are not involved in disease progression in advanced MS. In this thesis we show that advanced progressive MS is characterized by substantial inflammatory lesion activity which is correlated with the rate of clinical disability progression. This suggests that inflammatory lesion activity is involved in the clinical disease progression in advanced MS. Brain specific tissue-resident memory T-cells, that under non-inflammatory conditions reside in the perivascular space, are reactivated and invade the brain parenchyma in advanced progressive MS white matter lesions. These observations suggest that resident brain immune cells contribute to the ongoing inflammatory lesion activity in advanced MS. Finally, by analysing the heterogeneity of the immunopathology of MS in an autopsy cohort in relation with the clinical disease course, sex and genetic factors, we identified pathophysiological mechanisms that potentially contribute to the heterogeneity in the clinical disease course of MS patients.