Abstract

Purpose: Langerhans Cell Histiocytosis (LCH) is characterized by granulomatous lesions that include pathologic CD1a+/CD207+dendritic cells (DC). Activating somatic MAPK pathway gene mutations have been identified in hematopoietic stem cells and lesion DCs in patients with high-risk LCH, though the differentiation pathway remains uncertain. The purpose of this study was to define the origin of LCH lesion CD1a+/CD207+ cells.

Methods: We compared transcriptomes of LCH lesion CD1a+/CD207+ cells to established gene signatures from human peripheral blood and tissue myeloid populations including CD14+ monocytes, CD16+ monocytes, CD14+ DCs, macrophages, epidermal Langerhans cells, CD1c+ myeloid dendritic cells (mDCs) and CD141+mDCs. Additionally, quantitative PCR of BRAF-V600E and HLA-DQB2, and HLA-DQB2 surface expression were used to identify clonal lesion and peripheral blood monocyte and dendritic cell populations.

Results: When comparing lesion CD1a+/CD207+ cells to blood and tissue DC/monocyte populations, the CD1c+ mDC gene signature was most similar to gene expression profile of lesion CD1a+/CD207+ cells. In order to further test the hypothesis that LCH CD1a+/CD207+ cells arise from CD1c+mDCs, we investigated subpopulations within the LCH lesions for the BRAF-V600E allele and found that, in addition to LCH CD1a+ and CD1a+/CD207+ DCs, BRAF-V600E was also identified in LCH lesional CD1c+ mDCs. Furthermore, HLA-DQB2, highly expressed in LCH CD1a+/CD207+ cells, was also expressed in LCH lesion CD1c+ cells, but not in any other lesion myeloid subpopulations. Furthermore, HLA-DQB2 was expressed only in peripheral blood of patients with active high-risk LCH, and HLA-DQB2+ CD1c+ blood cells were highly enriched for the BRAF-V600E allele.

Conclusion: These data support a model where blood CD1c+ mDCs with hyperactive ERK migrate to lesion sites and differentiate into LCH CD1a+/CD207+ cells. If differentiation from CD1c+ DCs to CD1a+/CD207+ cells is critical to LCH pathogenesis, blocking this process may represent a novel therapeutic opportunity.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.