Molecular Pathobiology of Langerhans Cell Histiocytosis

描述（由申请人提供）：朗格汉斯细胞组织细胞增多症（LCH）是一种由来自朗格汉斯细胞（LC）的组织细胞积累引起组织破坏的疾病，朗格汉斯细胞是皮肤的抗原呈递树突状细胞。尽管这些病理性LCs （plc）是克隆性和过表达p53，但LCH在局部治疗后的高缓解率使人们一致认为它不是恶性肿瘤。然而，尽管一些LCH病变可以定位并易于治疗，但在很大比例的病例中，病变是弥散性的，并导致多器官衰竭和死亡。活体生物贩运受到严格监管。正常的静息LCs表达趋化因子受体CCR6，该受体引导LCs到达其配体分泌的皮肤粘膜炎症部位。一旦LCs摄取抗原并被激活，它们下调CCR6并上调CCR7。这将LCs吸引到淋巴结（CCR7配体的来源），在那里它们向T细胞呈递抗原。我们的初步数据表明，尽管具有活化的lc的特征，plc显示CCR6的持续表达，这可能部分解释了它们在不适当的组织部位积聚的原因。本实验旨在通过验证以下假设来阐明LCH的病理生物学和发病机制：(1)趋化因子及其受体的表达失调可能是导致PLC在靶器官持续存在的原因；(2)由于特定基因的表达，从LC’s中产生克隆PLC’s。为了验证这些假设，我提出以下具体目标：检测原发性LCH和其他组织细胞的趋化因子和趋化因子受体表达异常。LCs的CCR6/CCR7共表达与组织浸润模式的相关性将通过转基因小鼠进行测试。具体目标2。鉴定具有LCH特异性表达的基因。差分显示将用于克隆plc和lc之间表达差异的基因。具体目标3。伯尔尼山犬是一种患有与人类LCH相似的组织细胞疾病的犬种，使用来自育种机构的血液和血统，对其进行定位和鉴定组织细胞增多症易感基因。具体目标构建病理性lc体外分析系统。将尝试通过遗传操作使lc和plc永生化，以便可以测试在特定目标1、2和3中发现的基因与疾病的相关性。

DESCRIPTION (provided by applicant): Langerhans Cell Histiocytosis (LCH) is a disease in which tissue destruction is caused by accumulation of histiocytes derived from Langerhans cells (LC), the antigen presenting dendritic cells of skin. Although these pathologic LCs (PLCs) are clonal and overexpress p53, LCH's high rate of remission in response to local treatment has led to the consensus that it is not a malignancy. However, even though some LCH lesions can be localized and easily treated, lesions in a significant percentage of cases are disseminated and lead to multiorgan failure and death. LC trafficking in vivo is tightly regulated. Normal resting LCs express the chemokine receptor CCR6 which directs them to mucocutaneous inflammatory sites where its ligand is secreted. Once LCs ingest antigen and are activated, they down-regulate CCR6 and up-regulate CCR7. This attracts LCs to lymph nodes, the source of CCR7's ligands, where they present antigen to T cells. Our preliminary data demonstrate that despite having characteristics of activated LCs, PLCs show persistent expression of CCR6 perhaps explaining, in part, their accumulation at inappropriate tissue sites. The experiments in this proposal are designed to elucidate the pathobiology and pathogenesis of LCH by testing the hypotheses that: (1) Dysregulated expression of chemokines and their receptors may be responsible for the persistence of PLC's in target organs; and (2) Clonal PLC's arise from LC's because of the expression of specific genes. To test these hypotheses, I propose the following specific aims: Specific Aim 1. Test primary LCH and other histiocytoses for abnormalities in chemokine and chemokine receptor expression. The relevance of CCR6/CCR7 co-expression by LCs to tissue infiltration patterns will be tested using transgenic mice. Specific Aim 2. Identify genes whose expression is characteristic of LCH. Differential display will be used to clone genes showing differential expression between PLCs and LCs. Specific Aim 3. Positionally map and identify histiocytosis susceptibility genes in Bernese mountain dogs, a breed which suffers a histiocytic disorder similar to human LCH, using blood and pedigrees from a breeder's organization. Specific Aim 4. Construct an in vitro system for analysis of pathological LCs. Attempts will be made to immortalize LCs and PLCs by genetic manipulation so that the genes discovered in Specific Aims 1, 2, and 3 can be tested for their relevance to disease.