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Langerhans Cells Profile Compared with Epidermal Cell Histiocytosis

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Langerhans Cells Profile Compared with Epidermal Cell Histiocytosis The Journal of Immunology Cell-Specific Gene Expression in Langerhans Cell Histiocytosis Lesions Reveals a Distinct Profile Compared with Epidermal Langerhans Cells Carl E. Allen,*,† Liunan Li,* Tricia L. Peters,‡ Hon-chiu Eastwood Leung,*,†,x Alexander Yu,* Tsz-Kwong Man,*,† Sivashankarappa Gurusiddappa,* Michelle T. Phillips,* M. John Hicks,‡ Amos Gaikwad,* Miriam Merad,{ and Kenneth L. McClain*,† 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 differen- tially 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. The Journal of Immunology, 2010, 184: 4557–4567. angerhans cell histiocytosis (LCH) is a potentially fatal dis- limited organ system involvement have a very good prognosis, and ease characterized by invasive lesions infiltrated with multiple patients with multisystem disease have survival rates ∼80% (5). L cell types, including CD1a+/CD207+ cells presumed to be However, survival is poor in patients with high-risk multisystem disease pathologic Langerhans cells (LCs). The incidence of LCH is approxi- who fail to respond to induction therapy (6). Chemotherapy for LCH is by guest on September 30, 2021. Copyright 2010 Pageant Media Ltd. mately five cases per million children and 1/10,000 live births per year based on a lymphoma model of general immune suppression and cy- (1). Approximately 30% as many adults are afflicted, although this totoxicity to rapidly proliferating cells (reviewed in Ref. 7). incidence is likely underestimated (2). LCH includes a spectrum of The etiology of LCH is not known. Scientific debate has focused clinical presentations from single-system involvement in skin or bone to on LCH resulting from malignant transformation or from functional diffuse multisystem involvement of liver, lungs, bone marrow, CNS, proliferation of epidermal LCs in response to external stimuli (8– and other organ systems (reviewed in Refs. 3 and 4). Patients with 12). Regardless of whether clonal proliferation is the initiating factor in LCH, the CD207+ cells from these lesions require mul- tiple interactions with other cell types, including T cells, eosino- *Department of Pediatrics, Texas Children’s Cancer Center and Hematology Service, †Dan L. Duncan Cancer Center, ‡Department of Pathology, and xDepartment of phils, and macrophages (13). LCs will not grow in isolation in vitro http://classic.jimmunol.org Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; or as xenografts in immune-deficient mice. The mainstay of re- { and Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New search on LCH tissues has been immunohistochemical analysis of York, NY 10029 biopsy samples. Although this approach has been useful, it is also Received for publication July 21, 2009. Accepted for publication February 2, 2010. limited by various difficulties, such as testing multiple Abs si- This work was supported in part by research funding from the Histiocytosis Associ- ation of America (to C.E.A. and K.L.M.), the Histiocytosis Association of Canada (to multaneously, variable sensitivity of Abs, inability to quantita- C.E.A. and K.L.M.), the American Society of Clinical Oncology (to C.E.A.), the tively interpret results, and lack of control tissues. RNA and Thrasher Research Fund (to C.E.A.), the Larry and Helen Hoag Foundation Clinical Downloaded from protein studies from whole-biopsy samples are also difficult to Translational Research Award (to C.E.A.), and the National Institutes of Health Pediatric Oncology Research Training Grant T32 CA115303-03 (to C.E.A.) and interpret because of the heterogeneous composition of LCH le- R21 CA 114981-01A2 (to K.L.M.). M.T.P. received support from the American sions. To overcome some of the experimental challenges in Cancer Society Institutional Research Grant (2007–08) 93-034-23. studying LCH, we devised a robust procedure to study cell-specific The sequences presented in this article have been submitted to the Gene Expression gene-expression profiling in the cells that most likely contribute to Omnibus Web site under accession number GSE16395. pathology in LCH patients: LCs (CD207+) and T cells (CD3+). Address correspondence and reprint requests to Dr. Carl E. Allen, Texas Children’s Hospital, 6621 Fannin Street, CC1410.00, Houston, TX 77030. E-mail address: [email protected] Materials and Methods The online version of this article contains supplemental material. Subjects Abbreviations used in this paper: DC, dendritic cell; LC, Langerhans cell; LCH, + + Langerhans cell histiocytosis; PI, propidium iodide; Treg, regulatory T cell. LCH diagnosis was established by the presence of CD1a or CD207 histiocytes in clinical biopsy specimens. Samples from the 15 individuals Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 with LCH in this study included patients with relapsed disease and high- www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902336 4558 CELL-SPECIFIC GENE EXPRESSION IN LCH risk multisystem disease (Supplemental Table IA). Control epidermal LCs GAPDH ratios, as well as signal distribution, were assessed to determine were isolated from discarded skin, primarily elective circumcisions, from the outlier cases. Normalization and probe set summarization was done in patients ,18 y of age. Control tonsil CD3 cells were isolated from dis- BRB-Arraytools (available at http://linus.nci.nih.gov/BRB-ArrayTools. carded samples from elective tonsillectomy in patients ,18 y of age. html) using the Robust Multichip Average algorithm. Hierarchical clus- Studies were performed according to protocols approved by the In- tering was performed using centered correlation and average linkage. The stitutional Review Board of Baylor College of Medicine. Significance Analysis of Microarrays algorithm (16) was used for analysis of differential expression, with a false discovery rate , 0.01. Samples were Isolation of LCs and T cells split into three groups for analysis. Group 1 consisted of 13 CD207 tumor LCH samples. Fifteen fresh LCH biopsy samples were collected. They were samples and 12 CD207 controls obtained from normal skin. Group 2 transported in RPMI 1640 media (Invitrogen, Carlsbad, CA) and processed consisted of seven CD3 LCH lesion samples and seven CD3 matched within 24 h. All samples were processed into single-cell suspension over paired samples obtained from patients’ peripheral blood. Group 3 con- a 70-mM-mesh filter. Cells were washed twice with RPMI 1640 supple- sisted of 12 CD3 LCH lesion samples and 4 CD3 pooled controls obtained mented with 10% FBS and then incubated with conjugated Abs, CD207- from tonsil. Heatmaps and other graphics were created using Multi- PE (Beckman Coulter, Fullerton, CA) and CD3-FITC (BD Biosciences, Experiment Viewer, part of the TM4 Microarray Software Suite (17). San Jose, CA) for 30 min on ice. Cells were washed again and resuspended Quantitative real-time PCR in RPMI 1640/FBS with 2 mg/ml propidium iodide (PI; Molecular Probes, Eugene, OR). Cells were then separated by flow cytometry by gating on 2 Real-time PCR reactions were performed with TaqMan Gene Expression the PI population and Ab-specific fluorescence. Cells were sorted with Assays (Applied Biosystems, Foster City, CA), which include a mix of two a MoFlo Sorter (Beckman Coulter) directly into PicoPure RNA Extraction unlabeled PCR primers (900 nM final concentration) and 1 FAM dye-labeled Buffer (Molecular Devices, Sunnyvale, CA) (Supplemental Table IB). TaqMan MGB Probe (250 nM final concentration). Single-stranded cDNA Select samples were reanalyzed by flow cytometry for purity (Fig. 1). was generated by RNA amplification, as described above, in experiments Control skin LC samples. Control LCs were isolated from 12 skin samples independent from the amplifications used to generate cDNA probe for mi- that were transported in RPMI 1640 media and processed within 24 h. croarray studies. For the CD207+ analysis, one cDNA pool was made from Tissue was incubated in RPMI 1640 with 5 U/ml dispase II (Roche, equal contributions from the 13 LCH CD207+ samples and another from equal Indianapolis, IN) at 4˚C for 8 h prior to separation of the epidermal layer. contributions from the 12 control CD207+ samples. For the CD3+ analysis, The epidermal layer was further treated with 0.25% trypsin-EDTA one cDNA pool was made from equal contributions from the seven peripheral (Invitrogen) for 15 min at 37˚C and then LCs were isolated with CD207- LCH CD3+ samples and another from equal contributions from the seven PE–conjugated Ab (Beckman Coulter), as described above. Patient details matched LCH lesion CD3+ samples. Each reaction included 20 ng cDNA.
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