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 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
