Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells.
Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells.
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DOI：
10.4049/jimmunol.0902336
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发表时间：
2010-04-15
期刊：
影响因子：
--
通讯作者：
McClain KL
中科院分区：
文献类型：
--
作者：
Allen CE;Li L;Peters TL;Leung HC;Yu A;Man TK;Gurusiddappa S;Phillips MT;Hicks MJ;Gaikwad A;Merad M;McClain KL
朗格汉斯细胞组织细胞增生症（LCH）是一种罕见的疾病，其特征是含有CD207+朗格汉斯细胞和淋巴细胞的异质性病变，几乎可以出现在任何组织中，并导致显著的发病率和死亡率。经过几十年的研究，LCH的原因仍然是推测性的。一个流行的模型表明，LCH源于表皮朗格汉斯细胞的恶性转化和转移。在这项研究中，CD207+细胞和CD3+ T细胞分离LCH病变，以确定细胞特异性基因表达。与对照表皮CD207+细胞相比，LCH CD207+细胞产生2113个差异表达基因（FDR<0.01）。令人惊讶的是，在我们的研究中，许多以前与LCH相关的基因的表达，包括细胞周期调节因子，促炎细胞因子和趋化因子与对照LC没有显著差异。然而，几个新的基因，其产品激活和招募T细胞的炎症部位，包括SPP1（骨桥蛋白），在LCH CD207+细胞中高度过表达。此外，与未成熟髓样树突状细胞相关的几个基因在LCH CD207+细胞中过表达。与来自LCH患者的外周CD3+细胞相比，LCH病变CD3+细胞仅产生162个差异调节基因（FDR<0.01），并且LCH病变CD3+细胞的表达谱与活化的调节性T细胞表型一致，其中FOXP3、CTLA 4以及SPP 1的表达增加。这项研究的结果支持LCH发病机制的模型，其中病变不是由表皮朗格汉斯细胞引起的，而是由骨髓来源的未成熟髓样树突状细胞的积累引起的，所述未成熟髓样树突状细胞募集活化的淋巴细胞。
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.
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