Characterizing a New Human Dendritic Cell Lineage and Its Role in LCH

描述(申请人提供)：朗格汉斯细胞组织细胞增生症(LCH)是最常见的组织细胞增生症，是一组罕见的疾病，涉及组织驻留的巨噬细胞和树突状细胞。患有单一系统疾病的患者需要最低限度的治疗，但即使在这些患者中，也可能会有永久性的后果，主要是骨科后果。在另一种极端情况下，最常见的是幼儿，表现为多系统并伴有器官衰竭，在25%的病例中可能是致命的。LCH是郎格汉斯细胞样细胞积聚的结果，也称为LCH细胞。LCH细胞总是伴随着局部的细胞因子风暴和大量的T细胞渗透，导致肺、肝、中枢神经系统和皮肤等几个器官的不可逆转的损害。LCH研究一直受到与儿童罕见疾病有关的问题的阻碍。个别医生看到的病例很少，很难收集到新的材料。仍未解决并阻碍适当治疗的两个中心问题是：1)LCH细胞的起源是什么；2)LCH是真正的肿瘤性疾病还是反应性疾病。回答这些问题将改变我们诊断和治疗这种疾病的方式。目前的研究范式认为，LCH是表皮树突状细胞(DC)聚集的结果，也称为朗格汉斯细胞(LCS)。这一概念是基于观察到LCH病变被Langerin+细胞及其相关Birbeck颗粒(被认为仅限于表皮LCS)渗透的观察结果。然而，人们很难理解LCS(通常仅限于复层上皮细胞)是如何导致这种多灶性疾病的。我们最近发现，在小鼠的大多数非淋巴组织以及人的肺和真皮中，存在独立于LCS的间质Langerin+DC(图5)。与来源于循环单核细胞的langerin-DC不同，我们发现langerin+DC以Flt3配体依赖的方式来源于循环DC限制性祖细胞。此外，我们还发现，抑制受体Flt3会导致langerin+DC的特异性耗竭，而langerin-DC和LCS则不受影响。我们的初步数据还表明，LCH细胞具有类似于间质Langerin+DC的表型，并表达高水平的Flt3。基于这些发现，我们假设LCH是由于间质Langerin+DC的积聚，而不是LCS，并且LCH的分子通路在前者中可能是失调的。我们还假设受体Flt3可能代表了治疗LCH患者的新的治疗靶点。为了解决这一假设，我们在目标1中提出了描述人类健康组织中存在的langerin+DC的特征。在目标2中，我们建议确定控制人类langerin+发展的前体和机制，而在目标3中，我们建议表征聚集在LCH皮损中的循环前体和langerin+DC。

DESCRIPTION (provided by applicant): Langerhans Cell Histiocytosis (LCH) is the most common of histiocytosis, a group of rare diseases that involve tissue-resident macrophages and dendritic cells. Patients with single system disease require minimal treatment, but even in these patients there may be permanent, mainly orthopaedic consequences. At the other extreme and most often in young infants, the presentation is multisystemic with organ failure and can be fatal in 25% of the cases. LCH results from the accumulation of Langerhans cell-like cells also called the LCH cells. LCH cells are always associated with a local cytokine storm and a large T cell infiltrate leading to irreversible damage to several organs that include the lungs, liver, central nervous system and the skin. LCH research has been hampered by problems related to rare diseases of childhood. Individual physicians see few cases and fresh material are hard to collect. The two central questions that remain unresolved and prevent adequate therapy are: 1) what is the origin of the LCH cell and 2) is LCH a true neoplastic or a reactive disorder. Answering these questions would change the way we diagnose and treat the disease. The current paradigm suggests that LCH results from an accumulation of epidermal dendritic cells (DCs) also called "Langerhans cells" (LCs).This concept is based on observations showing that LCH lesions are infiltrated by langerin+ cells and it associated Birbeck granules, features thought to be restricted to epidermal LCs. However, it has been difficult to understand how LCs, which is normally restricted to stratified epithelia, could give rise to such a multi-focal disorder. We recently identified the presence of interstitial langerin+ DCs, independent of LCs, in most non-lymphoid tissue in mice and in human lung and dermis (Fig. 5). In contrast to langerin- DCs that derive from circulating monocytes, we found that langerin+ DCs derive from a circulating DC restricted progenitor in a Flt3 ligand dependent manner. In addition, we found that inhibition of the receptor Flt3 leads to the specific depletion of langerin+ DCs whereas langerin- DCs and LCs remain unaffected. Our preliminary data also suggest that LCH cells have a phenotype that resemble interstitial langerin+ DCs, and express high levels of Flt3. Based on these findings, we hypothesize that LCH is due to an accumulation of interstitial langerin+ DCs, and not LCs, and can be characterized by dysregulated molecular pathways in the former. We also hypothesize that the receptor Flt3 may represent a novel therapeutic target for the treatment of LCH patients. To address this hypothesis we propose in aim 1 to characterize langerin+ DCs that populate in healthy tissues in humans. In aim 2, we propose to identify the precursors and the mechanisms that control the development of human langerin+, while in Aim 3 we propose to characterize the circulating precursors and langerin+ DCs that accumulate in LCH lesions.