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Abstract：
Neurologic Rosai-Dorfman disease (RDD) is a rare type of non-Langerhans cell histiocytosis that affects the central nervous system. Most neurologic RDDs grow like meningiomas, have clear boundaries, and can be completely resected. However, a few RDDs are invasive and aggressive, and no effective treatment options are available because the molecular mechanisms involved remain unknown. Here, we report a case of deadly and glucocorticoid-resistant neurologic RDD and explore its possible pathogenic mechanisms via single-cell RNA sequencing. First, we identified two distinct but evolutionarily related histiocyte subpopulations (the C1Q+ and SPP1+ histiocytes) that accumulated in the biopsy sample. The expression of genes in the KRAS signaling pathway was upregulated, indicating gain-of-function of KRAS mutations. The C1Q+ and SPP1+ histiocytes were highly differentiated and arrested in the G1 phase, excluding the idea that RDD is a lympho-histio-proliferative disorder. Second, although C1Q+ histiocytes were the primary RDD cell type, SPP1+ histiocytes highly expressed several severe inflammation-related and invasive factors, such as WNT5A, IL-6, and MMP12, suggesting that SPP1+ histiocytes plays a central role in driving the progression of this disease. Third, oligodendrocytes were found to be the prominent cell type that initiates RDD via MIF and may resist glucocorticoid treatment via the MDK and PTN signaling pathways. In summary, in this case, we report a rare presentation of neurologic RDD and provided new insight into the pathogenic mechanisms of progressive neurologic RDD. This study will also offer evidence for developing precision therapies targeting this complex disease.
摘要：
神经Rosai-Dorfman病（RDD）是一种罕见的非朗格汉斯细胞组织细胞增生症，影响中枢神经系统。大多数神经RDD像脑膜瘤一样生长，有明确的界限，并且可以完全切除。然而,一些雷达具有侵入性和攻击性，并且没有有效的治疗选择，因为涉及的分子机制仍然未知。这里,我们报道一例致命性和糖皮质激素耐药的神经系统RDD,并通过单细胞RNA测序探讨其可能的致病机制.首先,我们确定了活检样本中积累的两个不同但进化相关的组织细胞亚群(C1Q+和SPP1+组织细胞).KRAS信号通路中的基因表达上调,表明KRAS突变的功能获得。C1Q+和SPP1+组织细胞高度分化,阻滞在G1期,排除RDD是一种淋巴组织增生性疾病的观点。第二,虽然C1Q+组织细胞是原代RDD细胞类型，SPP1+组织细胞高表达几种严重的炎症相关和侵袭因子，如WNT5A，IL-6和MMP12，表明SPP1+组织细胞在驱动这种疾病的进展中起着核心作用。第三，发现少突胶质细胞是通过MIF启动RDD的主要细胞类型，并可能通过MDK和PTN信号通路抵抗糖皮质激素治疗。总之,在这种情况下,我们报道了神经系统RDD的罕见表现，并为进行性神经系统RDD的致病机制提供了新的见解。这项研究还将为开发针对这种复杂疾病的精确疗法提供证据。
