Investigating Chemokine Receptor Dysregulation in Langerhans Cell Histiocytosis

Directed cell migration is central to many physiological processes as well as to pathologies such as chronic inflammatory diseases, cancer and immunologic disorders. The main navigators of directed cell migration in both innate and adaptive immune responses are chemokine receptors and their ligands. Langerhans cell histiocytosis (LCH) is a rare immunological disease with unknown pathogenesis. It predominantly occurs in the early childhood and shows characteristics of both inflammation and neoplasia. The cardinal feature of LCH is migration and accumulation of abnormal, semi-mature Langerhans cells (LCs) into specific organs causing tissue destruction. Normal immature LCs in epithelia express only the chemokine receptor CCR6, and, upon antigen uptake and maturation, switch to only expressing the chemokine receptor CCR7. Pathologic LCs in lesions of LCH patients were found to express both receptors simultaneously, which might prompt their aberrant migration. To investigate the biological relevance of chemokine receptor dysregulation to LCH pathophysiology I have generated a transgenic mouse model mimicking this chemokine receptor co-expression in LCs. I will characterize LC trafficking and organ infiltration in these genetically engineered mice which over-express either CCR6, CCR7 or both chemokine receptors together. Flow cytometry and immunofluorescence methods will be used to track LCs in both steady-state and in inflammatory conditions. In this study I will investigate the mechanism of abnormal LC migration and accumulation, which will provide crucial insight into the pathobiology of LCH and related histiocytic disorders. The results will also further our understanding of normal immunological behavior of dendritic cells. Because there are no LCH-derived cell lines nor an in vivo model of LCH this mechanistic model of aberrant LC migration will be a valuable tool to study the progression of LCH. If chemokine receptor dysregulation proves to be necessary and sufficient for aberrant LC trafficking, chemokine receptors may be suitable targets for intervention. In particular, LCH patients in the high- risk group might strongly benefit from a symptomatic treatment, e.g. with chemokine receptor antagonists, that could stimulate the emigration of LCs from the affected organs.