自身免疫淋巴增生综合症（ALPS）是一种淋巴细胞稳态失调引起的疾病，由FAS介导的凋亡途径功能障碍所致，特征为非恶性淋巴增殖，并伴有TCRαβ+CD4-CD8-双阴性T细胞（αβDNTs）数量增加。相反，与KRAS或NRAS中获得性功能突变有关的RAS相关白血病增生疾病（RALD）被认为是一组具有相似过程的疾病。在本文中，我们报道了一名携带NRAS变异体的7岁日本女性患有RALD，并迅速发展为儿童髓单核细胞白血病（JMML），同时αβDNTs数量增多。由于JMML原因导致肺部浸润，患者最终接受了造血干细胞移植手术以治疗急性呼吸窘迫。一般来说，ALPS病例中αβDNTs数量显著增加，然而，在本例中未观察到FAS通路基因异常。此RALD病例在病情进展过程中出现了多次休克/休克前期发作。这种休克被认为是由于αβDNTs数量过多。在该病例中观察到的αβDNTs表达高CCR4、CCR6和CD45RO，类似于Th17。这些增多的类似Th17的αβDNTs会触发炎症反应，导致休克的发生，因为Th17会分泌促炎细胞因子，如白细胞介素（IL）-17A和粒细胞-巨噬细胞集落刺激因子。已报道在系统性红斑狼疮（SLE）和干燥综合征中存在分泌IL-17A的αβDNTs。本例并发SLE，暗示了类似Th17的αβDNTs参与了疾病发病机制。研究RALD、JMML和ALPS中αβDNTs的特性可能揭示这些病例的病理过程。© 2023. 作者（持有独家许可）发布给施普林格科学与商业传媒有限责任公司，属于施普林格自然出版集团的一部分。

Autoimmune lymphoproliferative syndrome (ALPS) is a disease of lymphocyte homeostasis caused by FAS-mediated apoptotic pathway dysfunction and is characterized by non-malignant lymphoproliferation with an increased number of TCRαβ+CD4-CD8- double-negative T cells (αβDNTs). Conversely, RAS-associated leukoproliferative disease (RALD), which is caused by gain-of-functional somatic variants in KRAS or NRAS, is considered a group of diseases with a similar course. Herein, we present a 7-year-old Japanese female of RALD harboring NRAS variant that aggressively progressed to juvenile myelomonocytic leukemia (JMML) with increased αβDNTs. She eventually underwent hematopoietic cell transplantation due to acute respiratory distress which was caused by pulmonary infiltration of JMML blasts. In general, αβDNTs have been remarkably increased in ALPS; however, FAS pathway gene abnormalities were not observed in this case. This case with RALD had repeated shock/pre-shock episodes as the condition progressed. This shock was thought to be caused by the presence of a high number of αβDNTs. The αβDNTs observed in this case revealed high CCR4, CCR6, and CD45RO expressions, which were similar to Th17. These increased Th17-like αβDNTs have triggered the inflammation, resulting in the pathogenesis of shock, because Th17 secretes pro-inflammatory cytokines such as interleukin (IL)-17A and granulocyte-macrophage colony-stimulating factor. The presence of IL-17A-secreting αβDNTs has been reported in systemic lupus erythematosus (SLE) and Sjögren's syndrome. The present case is complicated with SLE, suggesting the involvement of Th17-like αβDNTs in the disease pathogenesis. Examining the characteristics of αβDNTs in RALD, JMML, and ALPS may reveal the pathologies in these cases.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.