Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission.
Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission.
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单细胞洞察类风湿性关节炎发作与无药物缓解中的免疫失调。
DOI：
10.1038/s41467-024-45213-2
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发表时间：
2024
影响因子：
16.6
通讯作者：
Baker KF
中科院分区：
文献类型：
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作者：
Baker KF
免疫介导性炎症性疾病(IMID)的典型特征是炎症复发和缓解。然而，疾病爆发的不可预测性阻碍了他们的研究。为了解决这一关键的知识鸿沟，我们在类风湿性关节炎(RA)缓解期使用免疫调节药物停药的实验医学方法来同步耀斑过程，以便进行详细的特征描述。探索性的质量细胞术分析揭示了三个循环细胞亚群-CD45RO+PD1hiCD4+和CD8+T细胞，以及CD27+CD86+CD21-B细胞-通过单细胞测序进一步表征。不同的淋巴细胞亚群，包括细胞毒性和耗尽的CD4+记忆性T细胞，记忆性CD8+CXCR5+T细胞和IGHA1+浆细胞，在急性发作患者中准备激活。调节性记忆的CD4+T细胞(Treg细胞)在发病时增加，但与非药物缓解期相比，调节性标志物表达障碍。停药后，T细胞有明显的克隆性增殖，但B细胞没有；这在记忆性CD8+T细胞亚群中普遍存在，但仅限于CD4+记忆性T细胞中表达颗粒酶的细胞毒亚群。基于我们的观察，我们提出了一个理解类风湿性关节炎暴发的免疫失调模型，并有可能对其治疗和预防的新途径进行进一步的翻译研究。
Immune-mediated inflammatory diseases (IMIDs) are typically characterised by relapsing and remitting flares of inflammation. However, the unpredictability of disease flares impedes their study. Addressing this critical knowledge gap, we use the experimental medicine approach of immunomodulatory drug withdrawal in rheumatoid arthritis (RA) remission to synchronise flare processes allowing detailed characterisation. Exploratory mass cytometry analyses reveal three circulating cellular subsets heralding the onset of arthritis flare – CD45RO+PD1hiCD4+and CD8+T cells, and CD27+CD86+CD21-B cells – further characterised by single-cell sequencing. Distinct lymphocyte subsets including cytotoxic and exhausted CD4+memory T cells, memory CD8+CXCR5+T cells, andIGHA1+ plasma cells are primed for activation in flare patients. Regulatory memory CD4+T cells (Treg cells) increase at flare onset, but with dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion is observed in T cells, but not B cells, after drug cessation; this is widespread throughout memory CD8+T cell subsets but limited to the granzyme-expressing cytotoxic subset within CD4+memory T cells. Based on our observations, we suggest a model of immune dysregulation for understanding RA flare, with potential for further translational research towards novel avenues for its treatment and prevention.