Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells.
Langerhans cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions containing CD207(+) Langerhans cells (LCs) 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 LCs. In this study, CD207(+) cells and CD3(+) T cells were isolated from LCH lesions to determine cell-specific gene expression. Compared with control epidermal CD207(+) cells, the LCH CD207(+) cells yielded 2113 differentially expressed genes (false discovery rate < 0.01). Surprisingly, the expression of many genes previously associated with LCH, including cell-cycle regulators, proinflammatory 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 overexpressed in LCH CD207(+) cells. Furthermore, several genes associated with immature myeloid dendritic cells were overexpressed in LCH CD207(+) cells. Compared with the peripheral CD3(+) cells from LCH patients, the LCH lesion CD3(+) cells yielded only 162 differentially regulated genes (false discovery rate < 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, and SPP1. Results from this study support a model of LCH pathogenesis in which lesions do not arise from epidermal LCs but from accumulation of bone marrow-derived immature myeloid dendritic cells that recruit activated lymphocytes.
Allen
Carl E
CE
Department of Pediatrics, Texas Children's Cancer Center and Hematology Service, Baylor College of Medicine, Houston, TX 77030, USA. ceallen@txccc.org
Li
Liunan
L
Peters
Tricia L
TL
Leung
Hon-Chiu Eastwood
HC
Yu
Alexander
A
Man
Tsz-Kwong
TK
Gurusiddappa
Sivashankarappa
S
Phillips
Michelle T
MT
Hicks
M John
MJ
Gaikwad
Amos
A
Merad
Miriam
M
McClain
Kenneth L
KL
D000293:Adolescent; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D017252:CD3 Complex / Q000096:biosynthesis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007223:Infant; D007801:Langerhans Cells / Q000166:cytology* / Q000276:immunology* / Q000473:pathology; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D037241:Mannose-Binding Lectins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis
D015703:Antigens, CD; D015415:Biomarkers; C121916:CD207 protein, human; D017252:CD3 Complex; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins