LCH lesions are characterized by accumulating LCH-cells, which are related to Langerhans and/or Dendritic cells, and the presence of other elements of the immune system. A significant proportion of... Show moreLCH lesions are characterized by accumulating LCH-cells, which are related to Langerhans and/or Dendritic cells, and the presence of other elements of the immune system. A significant proportion of LCH-cells display somatic mutations in proteins that drive the constitutive activation of the MAPK-pathway. Outcome is heterogeneous and unpredictable. The main goal of this thesis was to gain insight to the pathogenesis of Langerhans Cell Histiocytosis (LCH) by studying the genetic and immunologic ‘finger-prints’ of therapy-naive LCH lesions. We found a few biomarkers that could predict the outcome of LCH. These include the expression of a chemokine receptor, CXCR4, on LCH-cells and the degree of lymphoid aggregation within the LCH lesions. We found an ever functionally intact IFN-γ-signalling loop in LCH patients and the presence of activated and regulatory T-cells. However, neither an activated or immunosuppressive environment in LCH lesions was associated with a particular LCH manifestation form or outcome. We found another MAPK-pathway activating mutation in LCH-cells which was sensitive towards the FDA approved BRAF-inhibitor vemurafenib. The research described in this thesis support the concept that LCH lesions should be seen as a ‘cocktail’ of genetically aberrant LCH-cells which accumulate at sites with a mixed immunological background. Show less
The aim of this thesis was to work towards pre-clinical proof-of-concept for NOTCH3 cysteine corrective exon skipping as a rational therapeutic approach for CADASIL. To address all aspects required... Show moreThe aim of this thesis was to work towards pre-clinical proof-of-concept for NOTCH3 cysteine corrective exon skipping as a rational therapeutic approach for CADASIL. To address all aspects required for therapeutic development, the work performed for this thesis included not only in vitro testing of NOTCH3 exon skipping in CADASIL patient derived vascular smooth muscle cells and studies into the function of the cysteine corrected proteins, but also the generation of a relevant humanized in vivo model, pre-clinical biomarker development, and studies defining prevalence, spectrum and characteristics of NOTCH3 mutations worldwide. Show less
