Major cell, cytokine, and protease players in LCH lesion. This simplified overview indicates the main cytokines, chemokines, and proteases found in an LCH lesion that may play a major role in cell recruitment, survival, fusion, and inflammatory and tissue-aggressive activities, supported by proinflammatory cytokines and matrix metalloproteinases (MMPs), respectively. The origin of the pathogenic DC in an LCH lesion is still a matter of debate. Recent results argue that pathogenic DCs do not arise from Langerhans cells but from accumulation of bone marrow–derived immature myeloid cells able to differentiate into DCs such as monocytes, macrophage and DC precursor (MDP), or CD135⁺ lympho-myeloid progenitor (LMP). CCL, chemokine (C-C motif) ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; RANKL, receptor activator of nuclear factor κ-B ligand; TNF, tumor necrosis factor; Treg, regulatory T cell.