Molecular Pathobiology of Langerhans Cell Histiocytosis

朗格汉斯细胞组织细胞增多症（LCH）是一种由与朗格汉斯细胞（LC）相关的组织细胞积累引起的组织破坏疾病，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LC （PLC）是克隆性和过表达p53，但局部治疗后的高缓解率导致了LCH不是恶性肿瘤的共识。LCH病变可以是局部的，容易治疗，也可以是弥散性的，导致多器官衰竭和死亡。LC是可运动的细胞，它们在体内的活动受到严格控制。正常的静息LC表达趋化因子受体CCR6，该受体引导它们到达其配体分泌的皮肤粘膜炎症部位。一旦LC摄取抗原并被激活，它们下调CCR6并上调CCR7。这将LC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’s的特征，PLC’s显示CCR6的持续表达，部分解释了它们在不适当的组织部位的积累。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组织中趋化因子和趋化因子受体表达的异常。这将使用定制芯片为基础的杂交技术和免疫组织化学证实。相关数据将被录入临床数据库。

Langerhans Cell Histiocytosis (LCH) is a disease in which tissue destruction is caused by accumulation of histiocytes related to Langerhans cells (LC), the antigen presenting dendritic cells of skin. Although these pathologic LC's (PLC's) are clonal and overexpress p53, the high rate of remission in response to local treatment has led to the consensus that LCH is not a malignancy. LCH lesions can be localized and easily treated, or disseminated and lead to multiorgan failure and death. LC's are motile cells and their trafficking in vivo is tightly regulated. Normal resting LC's express the chemokine receptor CCR6 which directs them to mucocutaneous inflammatory sites where its ligand is secreted. Once LC's ingest antigen and become activated, they down- regulate CCR6 and up-regulate CCR7. This attracts LC's 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 LC's, PLC's show persistent expression of CCR6 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 tissues for abnormalities in chemokine and chemokine receptor expression. This will be done using custom chip-based hybridization techniques and confirmed by immuno- histochemistry. Correlates will be made to a clinical database.