The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants. RNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines. Transcriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement. Overproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS. Abnormal NOD2-RIP2-MAPK pathways were activated in YAOS with NOD2 variant Q902K.

中文翻译：

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识别 Yao 综合征患者 NOD2 变异 Q902K 的功能失调

该研究调查了 Yao 综合征 (YAOS) 的发病机制，Yao 综合征是一种罕见的系统性自身炎症性疾病，与含有 2 (NOD2) 基因变异的核苷酸结合寡聚结构域相关。RNA测序分析用于检测转录组谱的变化。采用免疫印迹和免疫组织化学检测NOD2介导的炎症信号通路，并采用ELISA检测细胞因子。YAOS 的转录组分析揭示了 NOD 样受体信号通路的富集。与HC相比，YAOS患者的PBMC中P-RIP2、p-p65、p-p38、p-ERK和p-JNK显着增加。小肠粘膜组织中 P-RIP2、p-p65 和 p-p38 升高。YAOS 滑膜组织中的 P-p65 和 p-p38 高于类风湿关节炎 (RA) 和骨关节炎 (OA) 患者。与健康对照 (HC) 相比，YAOS 患者的血清白细胞介素 (IL)-6 水平以及 PBMC 分泌的肿瘤坏死因子 (TNF)-α 和 IL-6 显着较高。YAOS 患者滑膜细胞上清液中的 IL-1β 和 IL-6 水平明显高于 RA 和 OA 患者。卡那奴单抗治疗 Q902K 杂合子 YAOS 患者取得了显着的临床改善。在患有 YAOS 的 NOD2 变异 Q902K 患者中发现促炎细胞因子过量产生和 NOD2 介导的信号通路过度激活。NOD2-RIP2-MAPK通路可能在YAOS的发病机制中发挥关键作用。这些结果为 YAOS 的靶向治疗提供了新的视角。NOD2 变体 Q902K 在 YAOS 中激活异常的 NOD2-RIP2-MAPK 通路。