Lymphocyte Trafficking in Langerhans Cell Histiocytosis
Principal Investigator and Co-Investigator
Kenneth McClain MD, PhD (PI) and Carl Allen MD, PhD
Texas Children’s Cancer Center/Hematology Service – Houston, Texas USA
Date of Award
Amount of Award
Langerhans Cell Histiocytosis is a potentially fatal disease thought to be caused by uncontrolled proliferation of Langerhans cells. Typically, Langerhans cells are located in the skin. The job of these cells is to recognize signals from the environment and to activate the immune system to respond to “danger” signals. When the Langerhans cell is activated it migrates to lymph nodes where it communicates with T-cells. The T-cells then become activated and create an inflammatory response that fights cells with “foreign” material such as viral proteins. Currently there is debate among researchers whether proliferating Langerhans cells arise due to changes in the cell similar to a cancer cell, or whether these cells become activated and divide due to pro-inflammatory signals from the immune system. Preliminary studies in our lab suggest that neither of these models may be accurate. Based on analysis of gene expression in Langerhans cells isolated from LCH lesions, these cells are not proliferating more rapidly than control skin Langerhans cells, nor are they producing pro-inflammatory cytokines at a level higher than control skin Langerhans cells.
We hypothesize that Langerhans cells and other lymphocytes accumulate in skin, bone and other areas due to inappropriate cell trafficking and that accumulation of these cells in lesions gives rise to LCH tumors. We propose to test this theory by validating our preliminary gene expression studies and by testing new tumor samples we collect over the next year. We also propose testing gene expression in cells in blood that give rise to Langerhans cells and Langerhans cells from LCH patients to identify genes that may be involved in inappropriate cell migration. Finally, we propose to re-visit the idea that Langerhans cells in LCH lesions are clonal, meaning that all of the Langerhans cells in a lesion arise from a single progenitor cell. If LCH arises from abnormal cell migration, we expect the accumulation of Langerhans cells in a lesion to arise from many progenitor cells. If LCH does in fact occur because of abnormalities of cell migration rather than from cell proliferation, we may be able to design more effective treatment strategies that target mechanisms involved in regulation of cell trafficking.