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(+)CD207(low) and CD1a(+)CD207(high) subpopulations). Transcription profiles of LCH lesion CD1a(+)CD207(+) DCs and peripheral blood CD1c1 mDCs from healthy donors were compared to identify potential LCH DC-specific biomarkers: HLA-DQB2 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(+)CD207(-) DCs and CD1a(+)CD207(+) DCs as well as on CD1c(+)(CD1a(+)CD207(-)) mDCs, but it was not identified in any other lesion myeloid subpopulations. HLA-DQB2 expression was specific to peripheral blood of patients with BRAFV600E(+) peripheral bloodmononuclear cells, and HLA-DQB2(+)CD1c(+) blood cells were highly enriched for the BRAFV600E in these patients. These data support a model in which blood CD1c(+)HLA-DQB2(+) mDCs with activated ERK migrate to lesion sites where they differentiate into pathogenic CD1a(+)CD207(+) DCs.