Elucidated pathogenesis and therapeutic prospects in Langerhans cell histiocytosis
Elucidated pathogenesis and therapeutic prospects in Langerhans cell histiocytosis
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阐明朗格汉斯细胞组织细胞增多症的发病机制和治疗前景
DOI：
10.11406/rinketsu.63.373
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Kudo K.
中科院分区：
文献类型：
--
作者：
Morimoto A;Shioda Y;Sakamoto K;Kudo K;Imamura T;Kudo K.
朗格汉斯细胞组织细胞增生症（LCH）的特征是未成熟的树突状细胞增殖，目前被归类为炎性髓系肿瘤。临床特征和结局各不相同，从自发消退的孤立性骨病到致死性肝、脾或造血系统（危险器官）受累阳性的多系统疾病。LCH细胞在促分裂原活化蛋白激酶（MAPK）信号传导途径基因中具有唯一突变，以BRAF V600E突变为代表，其为驱动突变。疾病的类型取决于发生突变的造血细胞分化阶段。LCH细胞通过癌基因诱导的衰老获得抗凋亡和衰老相关的分泌表型，但不能迁移到淋巴结。这些导致LCH细胞积聚和病变中的各种炎性细胞募集，导致严重炎症。LCH中的组织损伤是由于这种炎症，而不是LCH细胞增殖。有器官受累风险但无初始治疗应答的患者，在使用MAPK抑制剂降低疾病活动性后，可通过异基因造血干细胞移植进行挽救。静脉注射唑来膦酸和鞘内注射阿糖胞苷已被引入日本正在进行的临床试验，以减少骨复发和预防神经退行性变后遗症。
Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, which is currently classified as an inflammatory myeloid neoplasm. Clinical features and outcomes vary from spontaneously regressing isolated bone disease to fatal liver, spleen, or hematopoietic system (risk organ) involvement-positive multisystem disease. LCH cells have the only mutation in the mitogen-activated protein kinase (MAPK) signaling pathway gene, represented by the BRAF V600E mutation, which is the driver mutation. The type of disease depends on the stage of hematopoietic cell differentiation at which the mutation occurs. LCH cells acquire anti-apoptosis and senescence-associated secretory phenotype by oncogene-induced senescence, with migration failure to lymph nodes. These cause LCH cell accumulation and various inflammatory cell recruitment in the lesion, resulting in severe inflammation. Tissue damage in LCH is due to this inflammation, not the LCH cell proliferation. Patients with a risk of organ involvement without the initial treatment response may be rescued by allogeneic hematopoietic stem cell transplantation after reducing the disease activity with MAPK inhibitors. Intravenous zoledronic acid and intrathecal cytarabine injections have been introduced into the ongoing clinical trial in Japan to reduce bone recurrence and prevent neurodegeneration as sequelae.