Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis.
Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis.
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DOI：
10.1038/ncomms15869
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发表时间：
2017-06-21
影响因子：
16.6
通讯作者：
Mustjoki S
中科院分区：
文献类型：
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作者：
Savola P;Kelkka T;Rajala HL;Kuuliala A;Kuuliala K;Eldfors S;Ellonen P;Lagström S;Lepistö M;Hannunen T;Andersson EI;Khajuria RK;Jaatinen T;Koivuniemi R;Repo H;Saarela J;Porkka K;Leirisalo-Repo M;Mustjoki S
体细胞突变有助于肿瘤发生。虽然这些突变发生在所有增殖细胞中，但它们在非恶性条件下的积累，例如在自身免疫性疾病中，尚未研究。在这里，我们发现新诊断的类风湿性关节炎患者的CD 8 + T细胞克隆扩增;在20%（5/25）的患者中，CD 8 + T细胞，而不是CD 4 + T细胞，具有体细胞突变。在健康对照组（n=20）中，CD 8 + T细胞库中仅发现一种突变。突变仅存在于扩展的CD 8+效应记忆亚群中，在随访期间持续存在，并且预计会改变蛋白质功能。一些突变基因（SLAMF 6，IRF 1）以前与自身免疫相关。携带突变的细胞的RNA测序显示对应于细胞增殖的特征。我们的数据提供了在扩增的CD 8 + T细胞中积累体细胞突变的证据，这可能对RA和其他自身免疫性疾病具有致病意义。体细胞突变在淋巴细胞中的积累是某些癌症的特征。在这里，作者表明，近期发作的类风湿性关节炎患者也在其扩增的CD 8+效应记忆T细胞库中积累突变，而与癌症无关。
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. Accumulation of somatic mutations in lymphocytes is a feature of some cancers. Here the authors show that patients with recent onset of rheumatoid arthritis also accumulate mutations in their expanded CD8+ effector memory T cell pool independent of cancer association.