Langerhans cell histiocytosis : genetic and immunologic fingerprinting

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

Regulatory T cell subsets in Langerhans Cell Histiocytosis

Transplantation and immunomodulatio

Activated Conventional T-Cells Are Present in Langerhans Cell Histiocytosis Lesions Despite the Presence of Immune Suppressive Cytokines

Transplantation and immunomodulatio

Activated Conventional T-Cells Are Present in Langerhans Cell Histiocytosis Lesions Despite the Presence of Immune Suppressive Cytokines

Transplantation and immunomodulatio

ANALYSIS OF IFN-gamma R1 GENE EXPRESSION AND FUNCTION CAN DISTINGUISH LANGERHANS CELL HISTIOCYTOSIS PATIENTS FROM PATIENTS WITH MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASE

Immunogenetics and cellular immunology of bacterial infectious disease

The presence of CXCR4(+) CD1a(+) cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome

Transplantation and immunomodulatio

Intact IFN-gammaR1 Expression and Function Distinguishes Langerhans Cell Histiocytosis From Mendelian Susceptibility to Mycobacterial Disease

Poly-ostotic Langerhans Cell Histiocytosis (LCH) can be difficult to distinguish clinically and histologically from disseminated infection in manifesting specific subtypes of Mendelian Susceptibility to Mycobacterial Disease (MSMD). In MSMD-patients, dominant negative germline mutations in the IFN-gamma R1 gene, in particular in exon 6, lead to autosomal dominant IFN-gamma receptor 1 deficiency (ADIFNGR1) and can mimic LCH. We hypothesized that similar defects might underlie the pathogenesis of LCH. IFN-gamma R1 expression was immunohistochemically determined at disease onset in biopsies from 11 LCH-patients and four ADIFNGR1-patients. IFN-gamma R1 function was analyzed in 18 LCH-patients and 13 healthy controls by assessing the IFN-gamma-induced upregulation of Fc-gamma-receptor I (Fc gamma RI) expression on monocytes. Pro-inflammatory cytokine production was measured after stimulation of whole blood with LPS and IFN-gamma. Exon 6 of the IFN-gamma R1 gene was sequenced in 67 LCH-patients to determine whether mutations were present. IFN-gamma R1 expression was high in three LCH-affected biopsies, similar to ADIFNGR1-affected biopsies, but varied from negative to moderate in eight other LCH-affected biopsies. No functional differences in IFN-gamma signaling were detected between LCH-patients with active or non-active disease and healthy controls. No germline mutations in exon 6 of the IFN-gamma R1 gene were detected in any of the 67 LCH-patients. In contrast to ADIFNGR1-patients, IFN-gamma signaling is fully functional in LCH-patients. Either performed before, during or after treatment, these non-invasive functional assays can distinguish LCH-patients from ADIFNGR1-patients and thereby facilitate correct therapy regimens for patients with recurrent osteolytic lesions

Intact IFN-gamma R1 Expression and Function Distinguishes Langerhans Cell Histiocytosis From Mendelian Susceptibility to Mycobacterial Disease (vol 34, pg 84, 2014)

Immunogenetics and cellular immunology of bacterial infectious disease

Intact IFN-gamma R1 Expression and Function Distinguishes Langerhans Cell Histiocytosis From Mendelian Susceptibility to Mycobacterial Disease (vol 34, pg 84, 2014)

Transplantation and immunomodulatio