Circulating CD1c⁺ myeloid dendritic cells are potential precursors to LCH lesion CD1a⁺CD207⁺ cells

Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder that is characterized by the inflammatory lesionswith pathogenic CD1a⁺CD207⁺ dendritic cells (DCs). BRAFV600E and other somatic activating MAPK gene mutations have been identified in differentiating bone marrow and blood myeloid cells, but the origin of the LCH lesion CD1a⁺CD207⁺ DCs and mechanisms of lesion formation remain incompletely defined. To identify candidate LCH CD1a⁺CD207⁺ DC precursor populations, gene-expression profiles of LCH lesion CD1a⁺ CD207⁺ DCs were first compared with established gene signatures from human myeloid cell subpopulations. Interestingly, the CD1c⁺ myeloid DC (mDC) gene signature wasmost enriched in the LCH CD1a⁺CD207⁺ DC transcriptome. Additionally, the BRAFV600E allele was not only localized to CD1a⁺CD207- DCs and CD1a⁺CD207⁺ DCs, but it was also identified in CD1c⁺ mDCs in LCH lesions. Transcriptomes of CD1a⁺CD207- DCs were nearly indistinguishable from CD1a⁺CD207⁺ DCs (both CD1a⁺CD207low and CD1a⁺CD207high subpopulations). Transcription profiles of LCH lesion CD1a⁺CD207⁺ DCs and peripheral blood CD1c⁺ mDCs from healthy donors were compared to identify potential LCH DC-specific biomarkers: HLADQB2 expression was significantly increased in LCH lesion CD1a⁺CD207⁺ DCs compared with circulating CD1c⁺mDCs from healthy donors. HLA-DQB2 antigenwas identified on LCHlesion CD1a⁺CD2072 DCs and CD1a⁺CD207⁺ DCs as well as on CD1c⁺(CD1a⁺CD2072) mDCs, but it was not identified in any other lesion myeloid subpopulations. HLA-DQB2 expression was specific to peripheral blood of patients with BRAFV600E1 peripheral bloodmononuclear cells, and HLA-DQB21CD1c⁺ blood cells were highly enriched for the BRAFV600E in these patients. These data support a model in which blood CD1c⁺HLA-DQB21 mDCs with activated ERK migrate to lesion sites where they differentiate into pathogenic CD1a⁺CD207⁺ DCs.