Guo Ruru, Zhang Ting, Li Yixuan, Liu Xuesong, Meng Xinyu, Tong Lei, Chen Xiaoxiang, Ding Xianting, Lu Liangjing
Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Middle Shandong Rd, Shanghai, 200001, China.
State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, People's Republic of China.
J Transl Med. 2025 Jun 2;23(1):610. doi: 10.1186/s12967-025-06597-x.
Early administration of IL-6R blockade is effective in adult-onset Still's disease (AOSD), but the underlying immune alterations during combined immunotherapy remain unclear.
We employed high-dimensional single-cell mass cytometry and an unbiased bioinformatics pipeline to characterize the immune landscape in treatment-naïve AOSD patients, stable AOSD patients after 24 weeks of IL-6R blockade plus methotrexate and prednisone, and matched healthy controls. Cytokine profiling was conducted using a high-throughput cytometric bead array, and potential regulatory networks were identified using the PerformanceAnalytics package. Validation was performed via flow cytometry and mRNA sequencing.
We identified 22 peripheral immune cell populations and characterized their composition and phenotypic markers. Treatment-naïve AOSD patients exhibited significant depletion of CD4 T cells and B cells, along with excessive activation of CD8 T cells and a previously unreported CD45CD3CD19CD10CD66a population, findings that were validated in an independent AOSD cohort. mRNA sequencing revealed the proinflammatory role of CD8 T cells. Notably, these dysregulated immune profiles were markedly restored following immunotherapy. IL-18, IL-21, and IFN-γ demonstrated strong associations with adaptive immune cells and AOSD clinical indices.
Combined IL-6R blockade effectively modulates immune dysregulation in refractory AOSD, reversing key pathological immune alterations and highlighting its therapeutic potential.
早期给予白细胞介素-6受体（IL-6R）阻断剂对成人斯蒂尔病（AOSD）有效，但联合免疫治疗期间潜在的免疫改变仍不清楚。
我们采用高维单细胞质谱流式细胞术和无偏倚生物信息学流程，对未经治疗的AOSD患者、接受IL-6R阻断剂联合甲氨蝶呤和泼尼松治疗24周后的病情稳定的AOSD患者以及匹配的健康对照者的免疫格局进行了表征。使用高通量细胞因子微珠阵列进行细胞因子分析，并使用PerformanceAnalytics软件包识别潜在的调控网络。通过流式细胞术和mRNA测序进行验证。
我们鉴定出22种外周免疫细胞群，并对其组成和表型标志物进行了表征。未经治疗的AOSD患者表现出CD4 T细胞和B细胞显著减少，同时CD8 T细胞过度活化以及一个此前未报道的CD45CD3CD19CD10CD66a细胞群，这些发现在一个独立的AOSD队列中得到了验证。mRNA测序揭示了CD8 T细胞的促炎作用。值得注意的是，免疫治疗后这些失调的免疫谱明显恢复。白细胞介素-18、白细胞介素-21和干扰素-γ与适应性免疫细胞和AOSD临床指标显示出强烈关联。
联合IL-6R阻断可有效调节难治性AOSD中的免疫失调，逆转关键的病理性免疫改变，并突出其治疗潜力。
