Abstract：
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.
摘要：
自身免疫性淋巴细胞增生综合征(ALPS)是由FAS介导的凋亡途径功能障碍引起的淋巴细胞稳态性疾病,其特征是非恶性淋巴细胞增生,伴随着TCRαβ+CD4-CD8-双阴性T细胞(αβDNTs)数量增加。相反，RAS相关的白细胞增生性疾病（RALD），这是由KRAS或NRAS中的功能获得体细胞变异引起的，被认为是一组具有相似病程的疾病。在这里，我们介绍了一名7岁的RALD日本女性，其携带NRAS变异体，该变异体积极发展为αβDNTs增加的幼年型粒单核细胞白血病（JMML）。由于JMML母细胞的肺部浸润引起的急性呼吸窘迫，她最终接受了造血细胞移植。总的来说,αβDNTs在ALPS中显著增加；然而，在这种情况下未观察到FAS途径基因异常。随着病情的发展，这种RALD患者反复出现休克/休克前发作。这种休克被认为是由大量αβDNTs的存在引起的。在这种情况下观察到的αβDNTs显示高CCR4，CCR6和CD45RO表达，与Th17相似。这些增加的Th17样αβDNTs引发了炎症，导致休克的发病机制，因为Th17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。目前的病例与SLE很复杂,提示Th17样αβDNTs参与疾病的发病机制。检查RALD中αβDNTs的特性，JMML,ALPS可能揭示这些病例的病理。
