Circulating CD1c+ myeloid dendritic cells are precursors to Langerhans cell histiocytosis (LCH) lesion CD1a+CD207+cells

Expression data from LCH lesion subpopulations and healthy donors' peripheral blood specimens Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder that is characterized by the inflammatory lesions with 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. In order to identify candidate LCH CD1a+CD207+DCs’ precursor populations, gene expression profiles of LCH lesion CD1a+CD207+DCs were first compared to established gene signatures from human myeloid cell subpopulations. Interestingly, the CD1c+ myeloid DC (mDC) gene signature was most 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 CD207low and 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 to circulating CD1c+mDCs from healthy donors, and HLA-DQB2 antigen was identified on LCH lesion CD1a+CD207- and CD1a+CD207+DCs as well as on CD1c+(CD1a+CD207-) mDCs, but not in any other lesion myeloid subpopulations. Interestingly, HLADQB2 expression was specific to peripheral blood of patients with BRAFV600E+ peripheral blood mononuclear cells (PBMC), and HLA-DQB2+CD1c+blood cells were highly enriched for the BRAFV600E in these patients. These data support a model where blood CD1c+mDCs with activated ERK migrate to lesion sites where they differentiate into pathogenic CD1a+CD207+ DCs. 57 samples: 18 healthy donor peripheral blood/skin subpopulations and 39 LCH lesion subpopulation specimens

本数据集包含朗格汉斯细胞组织细胞增生症（Langerhans Cell Histiocytosis, LCH）病变亚群与健康供者外周血标本的基因表达谱数据。朗格汉斯细胞组织细胞增生症（LCH）是一种骨髓增殖性疾病，其特征为存在致病性CD1a+CD207+树突状细胞（Dendritic Cells, DCs）的炎性病变。研究已在分化中的骨髓与血液髓系细胞中检出BRAFV600E及其他体细胞激活型MAPK基因突变，但LCH病变中CD1a+CD207+树突状细胞的起源与病变形成机制仍未完全阐明。为筛选LCH源性CD1a+CD207+树突状细胞的候选前体亚群，研究人员首先将LCH病变中CD1a+CD207+树突状细胞的基因表达谱与已确立的人类髓系细胞亚群基因特征集进行比对。有趣的是，CD1c+髓系树突状细胞（myeloid DC, mDC）的基因特征集在LCH源性CD1a+CD207+树突状细胞的转录组中富集程度最高。此外，BRAFV600E等位基因不仅存在于CD1a+CD207-树突状细胞与CD1a+CD207+树突状细胞中，还可在LCH病变内的CD1c+髓系树突状细胞中被检出。CD1a+CD207-树突状细胞的转录组与CD1a+CD207+树突状细胞（包括CD207低表达与CD207高表达两个亚群）几乎无差异。为筛选潜在的LCH树突状细胞特异性生物标志物，研究人员将LCH病变中CD1a+CD207+树突状细胞与健康供者外周血CD1c+髓系树突状细胞的转录谱进行了比对。相较于健康供者外周血中的循环CD1c+髓系树突状细胞，LCH病变中CD1a+CD207+树突状细胞的HLADQB2表达水平显著升高；且HLA-DQB2抗原可在LCH病变内的CD1a+CD207-、CD1a+CD207+树突状细胞以及CD1c+(CD1a+CD207-)髓系树突状细胞表面检出，但未在其他病变髓系亚群中发现。值得注意的是，HLADQB2的表达仅特异性见于携带BRAFV600E+外周血单个核细胞（Peripheral Blood Mononuclear Cells, PBMC）的患者外周血中，且此类患者体内HLA-DQB2+CD1c+外周血细胞中BRAFV600E的富集程度极高。上述数据支持如下模型：携带激活型ERK的血液CD1c+髓系树突状细胞迁移至病变部位，并在此分化为致病性CD1a+CD207+树突状细胞。本数据集共收录57份标本：其中18份为健康供者外周血/皮肤亚群标本，剩余39份为LCH病变亚群标本。