Notch is active in Langerhans Cell Histiocytosis and confers pathognomonic features on dendritic cells

Langerhans cell histiocytosis (LCH) is an enigmatic disease defined by the accumulation of Langerhans-cell-like dendritic cells (DC). Here we demonstrate that LCH cells exhibit a unique transcription profile that separates them not only from plasmacytoid and myeloid DC but also from epidermal Langerhans cells, indicating a distinct DC entity. Molecular analysis revealed that isolated as well as tissue bound LCH-cells selectively express Notch ligand Jagged 2 (JAG2) and are the only DC that express both Notch ligand and its receptor. We further show that JAG2 signaling induces key LCH-cell markers in monocyte-derived DC, suggesting a functional role of Notch signaling in LCH ontogenesis. Notably, JAG2 also induced matrix-metalloproteinases 1 and 12, which are highly expressed in LCH and may account for tissue destruction in LCH lesions. This induction was selective for DC and not recapitulated in monocytes. Together these findings suggest that JAG2 mediated Notch activation confers phenotypic and functional aspects of LCH to DC. Thus, interference with Notch signaling may prove an attractive strategy to combat this disease