Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Centre, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.
Department of Clinical Chemistry and Hematology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.
Nat Commun. 2017 Jun 21;8:15869. doi: 10.1038/ncomms15869.
Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.
体细胞突变有助于肿瘤的发生。尽管这些突变发生在所有增殖细胞中，但它们在非恶性情况下（如自身免疫性疾病）的积累尚未被研究。在这里，我们表明，新诊断为类风湿关节炎的患者存在扩增的 CD8+T 细胞克隆；在 20%（25 例患者中的 5 例）患者的 CD8+T 细胞中，但不是 CD4+T 细胞，存在体细胞突变。在健康对照组（n=20）中，仅在 CD8+T 细胞池中鉴定出一个突变。突变仅存在于扩增的 CD8+效应记忆亚群中，在随访期间持续存在，并预测会改变蛋白质功能。一些突变基因（SLAMF6、IRF1）先前与自身免疫有关。携带突变的细胞的 RNA 测序显示与细胞增殖相对应的特征。我们的数据提供了证据表明，体细胞突变在扩增的 CD8+T 细胞中积累，这可能对 RA 和其他自身免疫性疾病具有致病性意义。
