Molecular Pathobiology of Langerhans Cell Histiocytosis

描述(申请人提供)：朗格汉斯细胞组织细胞增生症(LCH)是一种组织破坏疾病，由朗格汉斯细胞(LC)衍生的组织细胞聚集引起，朗格汉斯细胞(LC)是皮肤树突状细胞的抗原呈递。虽然这些病理性LC(PLC)是克隆性的并过度表达P53，但LCH对局部治疗的高缓解率使人们一致认为它不是一种恶性肿瘤。然而，尽管一些LCH病变可以定位并易于治疗，但在相当大比例的病例中，病变是播散性的，并导致多器官衰竭和死亡。活体内的LC贩运受到严格管制。正常的静息LC表达趋化因子受体CCR6，CCR6将它们引导到分泌其配体的皮肤黏膜炎症部位。一旦LC摄取抗原并被激活，它们就会下调CCR6，上调CCR7。这将LC吸引到淋巴结，这是CCR7的S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PLC具有激活LC的特征，但PLC持续表达CCR6，这可能部分解释了它们在不适当的组织部位堆积。本方案中的实验旨在通过检验以下假设来阐明LCH的病理生物学和发病机制：(1)趋化因子及其受体的异常表达可能是PLC在靶器官中持续存在的原因；(2)克隆性PLC是由于特定基因的表达而产生的。为了验证这些假设，我提出了以下特定目标：特定目标1.检测原代LCH和其他组织细胞趋化因子和趋化因子受体表达的异常。LCS共表达CCR6/CCR7与组织渗透模式的相关性将使用转基因小鼠进行测试。特定目的2.鉴定具有LCH特征表达的基因。差异显示技术将用于克隆PLC和LC之间差异表达的基因。具体目标3.利用来自饲养员组织的血液和系谱，定位并识别伯恩斯山地犬的组织细胞增多症易感基因，伯恩斯山地犬患有类似于人类LCH的组织细胞疾病。具体目的4.建立病理性喉癌的体外分析系统。将尝试通过基因操作使LC和PLC永生化，以便在特定目标1、2和3中发现的基因可以测试它们与疾病的相关性。

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.