Cell-Specific Gene Expression in Langerhans Cell Histiocytosis Lesions Reveals a Distinct Profile Compared with Epidermal Langerhans Cells

Abstract

Langerhans-cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions containing CD207+ Langerhans cells and lymphocytes that can arise in almost any tissue and cause significant morbidity and mortality. After decades of research, the cause of LCH remains speculative. A prevailing model suggests that LCH arises from malignant transformation and metastasis of epidermal Langerhans cells. In this study, CD207+ cells and CD3+ T cells were isolated from LCH lesions to determine cell-specific gene expression. Compared to control epidermal CD207+ cells, the LCH CD207+ cells yielded 2113 differentially-expressed genes (FDR<0.01). Surprisingly, expression of many genes previously associated with LCH, including cell-cycle regulators, pro-inflammatory cytokines and chemokines were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly over-expressed in LCH CD207+ cells. Furthermore, several genes associated with immature myeloid dendritic cells were over-expressed in LCH CD207+ cells. Compared to the peripheral CD3+ cells from LCH patients, the LCH lesion CD3+ cells yielded only 162 differentially-regulated genes (FDR<0.01), and the expression profile of the LCH lesion CD3+ cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4 as well as SPP1. Results from this study support a model of LCH pathogenesis in which lesions do not arise from epidermal Langerhans cells, but from accumulation of bone-marrow derived immature myeloid dendritic cells that recruit activated lymphocytes.

Frequent BRAFV600E mutation has no effect on tumor invasiveness in patients with Langerhans cell histiocytosis

“…Recent studies have shown that LCH might be malignant in certain cases. Firstly, it was observed that the original cells affected by LCH might arise from early myeloid precursors rather than mature Langerhans cells (9,12). Secondly and of note, our study (China) along with studies by Badalian-Very et al (8) (USA), Satoh et al (10) (France) and Sahm et al (9) (Germany and Austria) identified the BRAF V600E mutation in 31-57% of LCH cases.…”

Thyroid Langerhans cell histiocytosis and papillary thyroid carcinoma

“…It will be interesting to postulate that this induced inflammatory infiltrate may further develop into a neoplastic transformation into LCH (14,15).…”

Histiocitosis De Células De Langerhans: ¿una Entidad Rara De Síntomas Comunes?

“…Sin embargo, la expresión genética del CD207+ (langerina) de los histiocitos en las lesiones óseas en comparación con las cé-lulas de Langerhans de la piel demuestra que son dos tipos celulares diferentes 4 . Las células patoló-gicas en la HCL son más probablemente derivadas de las células mieloides dendríticas circulantes que expresan los mismos marcadores (CD1a y CD207) que las células de Langerhans de la piel, pero que además expresan CD14 a diferencia de esta última.…”