Langerhans Cell Histiocytosis (LCH) is the most common of histiocytosis, a group of rare diseases that involve tissue-resident macrophages and dendritic cells. Patients with single system disease require minimal treatment, but even in these patients there may be permanent, mainly orthopaedic consequences. At the other extreme and most often in young infants, the presentation is multisystemic with organ failure and can be fatal in 25% of the cases. LCH results from the accumulation of Langerhans cell-like cells also called the LCH cells. LCH cells are always associated with a local cytokine storm and a large T cell infiltrate leading to irreversible damage to several organs that include the lungs, liver, central nervous system and the skin. LCH research has been hampered by problems related to rare diseases of childhood. Individual physicians see few cases and fresh material are hard to collect. The two central questions that remain unresolved and prevent adequate therapy are: 1) what is the origin of the LCH cell and 2) is LCH a true neoplastic or a reactive disorder. Answering these questions would change the way we diagnose and treat the disease. The current paradigm suggests that LCH results from an accumulation of epidermal dendritic cells (DCs) also called "Langerhans cells" (LCs).This concept is based on observations showing that LCH lesions are infiltrated by langerin+ cells and it associated Birbeck granules, features thought to be restricted to epidermal LCs. However, it has been difficult to understand how LCs, which is normally restricted to stratified epithelia, could give rise to such a multi-focal disorder. We recently identified the presence of interstitial langerin+ DCs, independent of LCs, in most non-lymphoid tissue in mice and in human lung and dermis (Fig. 5). In contrast to langerin- DCs that derive from circulating monocytes, we found that langerin+ DCs derive from a circulating DC restricted progenitor in a Flt3 ligand dependent manner. In addition, we found that inhibition of the receptor Flt3 leads to the specific depletion of langerin+ DCs whereas langerin- DCs and LCs remain unaffected. Our preliminary data also suggest that LCH cells have a phenotype that resemble interstitial langerin+ DCs, and express high levels of Flt3. Based on these findings, we hypothesize that LCH is due to an accumulation of interstitial langerin+ DCs, and not LCs, and can be characterized by dysregulated molecular pathways in the former. We also hypothesize that the receptor Flt3 may represent a novel therapeutic target for the treatment of LCH patients. To address this hypothesis we propose in aim 1 to characterize langerin+ DCs that populate in healthy tissues in humans.
In aim 2, we propose to identify the precursors and the mechanisms that control the development of human langerin+, while in Aim 3 we propose to characterize the circulating precursors and langerin+ DCs that accumulate in LCH lesions.
Langerhans cell histiocytosis (LCH) research has been handicapped by the difficult access to fresh material and by the lack of a comparative population;here we propose to perform detailed characterization of LCH at the cellular and molecular level and to use highly purified cell populations for comparative analysis. These results should lead to a better understanding of the disease and have important implications for this condition. Future studies will be aimed at utilizing the data acquired here to build mouse models of the disease, and to expand our approach to a larger cohort of patients.
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