Mechanisms of accumulation of LCH pathogenic DCs through proliferation and prolonged survival. (A) DC survival is basically regulated by exogenous concentration of GM-CSF on CSF2R. Low GM-CSF concentration (black) stimulates the selective activation of Ser⁵⁸⁵/14-3-3/PI-3 kinase (PI3K), the “survival only” pathway, and high GM-CSF concentration (red) can give rise to assembling of CSF2R chains⁴⁰  in dodecamer, thus involving the Jak/STAT, Ras/mitogen-activated protein kinase (MAPK), and PI3K pathways (middle) downstream of Ser⁵⁸⁵ and Tyr⁵⁷⁷ phosphorylation (red bullet). In the IL-17A inflammatory microenvironment (green), monocyte-derived DC survival can be prolonged for weeks by IL-17A treatment.³³  The TRAF6-dependent IL-17R transduction is able to activate both PI3K/Akt and nuclear factor κB (NF-κB) pathways.⁴¹  S, serine; Y, tyrosine. (B) In LCH patients, although low concentration of GM-CSF will normally induce PI3K/Akt (black), other molecular specificities turn DC survival and phenotype into aggressive myeloid cells: the presence of IL-17A activates both PI3K/Akt and NF-κB pathways (green), leading to increased survival, inflammation, and DC fusion. In addition, pathogenic LCH DCs express JAG2 and activate transduction downstream of its receptor NOTCH (brown),³²  which may account for tissue destruction via MMP expression. BRAF^V600E mutation will ensure constitutive activation of the MAPK pathway (red). It will be important in the future to explore the Jak2/Stat5 pathway, which may be absent in LCH DCs. From this recent knowledge, new therapeutic interventions in LCH may neutralize IL-17A, inhibit NOTCH and BRAF^V600E/MAPK pathways, and possibly activate the Jak2/Stat5 pathway to reverse LCH DC phenotype toward normal DC phenotype until we better understand the origin of this impairment of DC differentiation.