Molecular Pathobiology of Langerhans Cell Histiocytosis

描述（由申请方提供）：朗格汉斯细胞组织细胞增多症（LCH）是一种由朗格汉斯细胞（LC）（皮肤的抗原呈递树突细胞）衍生的组织细胞蓄积引起的组织破坏疾病。虽然这些病理性LC（PLC）是克隆性的，并且过表达p53，但LCH对局部治疗的高缓解率导致了它不是恶性肿瘤的共识。然而，即使一些LCH病变可以定位和容易治疗，在一个显着的百分比的情况下，病变扩散，并导致多器官功能衰竭和死亡。LC在体内的运输受到严格调控。正常静息LC表达趋化因子受体CCR 6，CCR 6将其引导至分泌其配体的粘膜皮肤炎症部位。一旦LC摄取抗原并被激活，它们下调CCR 6并上调CCR 7。这将LC吸引到淋巴结（CCR 7配体的来源），在那里它们将抗原呈递给T细胞。我们的初步数据表明，尽管具有活化LC的特征，PLC显示CCR 6的持续表达，这可能部分解释了它们在不适当的组织部位的积累。在这个建议中的实验被设计来阐明LCH的病理生物学和发病机制，通过测试以下假设：（1）趋化因子及其受体的表达失调可能是导致PLC在靶器官中持续存在的原因;和（2）由于特定基因的表达，LC产生克隆PLC。为了验证这些假设，我提出了以下具体目标：具体目标1。检测原发性LCH和其他组织细胞病的趋化因子和趋化因子受体表达异常。将使用转基因小鼠测试LC的CCR 6/CCR 7共表达与组织浸润模式的相关性。具体目标2。鉴定其表达是LCH特征的基因。差异显示将用于克隆在PLC和LC之间显示差异表达的基因。具体目标3。使用来自育种者组织的血液和谱系，定位并鉴定伯尔尼山地犬的组织细胞病易感基因，伯尔尼山地犬是一种患有类似于人类LCH的组织细胞病的品种。具体目标4。建立一个用于病理性LC分析的体外系统。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的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.