University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA, United States.
Division of Hematology/Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States.
Front Immunol. 2024 Oct 21;15:1466276. doi: 10.3389/fimmu.2024.1466276. eCollection 2024.
Large granular lymphocyte (LGL) leukemia is a rare hematologic malignancy characterized by clonal expansion of cytotoxic T-cells frequent somatic activating mutations. Based on the disease overlap between LGL leukemia rheumatoid arthritis (RA)a putative role for CD8+ T-cells in RA we hypothesized that mutations may be detected in RA patient CD8+ T-cells correlate with clinical characteristics.
Blood samples, clinical parameters, and demographics were collected from 98 RA patients and 9 healthy controls (HCs). CD8+ cell DNA was isolated and analyzed via droplet digital (dd)PCR to detect mutations common in LGL leukemia: Y640F, D661Y, and the S614 to G618 region. data from 99 HCs from a public dataset supplemented our 9 HCs.
RA patients had significantly increased presence of mutations compared to controls (Y640F p=0.0005, D661Y p=0.0005). The majority of these were low variant allele frequency (VAF) (0.008-0.05%) mutations detected in a higher proportion of the RA population (31/98 Y640F, 17/98 D661Y) vs. HCs (0/108 Y640F, 0/108 D661Y). In addition, 3/98 RA patients had a mutation at a VAF >5% compared to 0/108 controls. Serological markers, RF and anti-CCP positivity, were more frequently positive in RA patients with mutation relative to those without (88% vs 59% RF, p=0.047; 92% vs 58% anti-CCP, p=0.031, respectively).
activating mutations were detected in RA patient CD8+ cells and associated with seropositivity. Thus, activating mutations may play a role in disease pathogenesis in a subset of RA patients.
大颗粒淋巴细胞（LGL）白血病是一种罕见的血液系统恶性肿瘤，其特征是细胞毒性 T 细胞的克隆性扩张，常伴有体细胞激活突变。基于 LGL 白血病与类风湿关节炎（RA）之间的疾病重叠，以及 CD8+T 细胞在 RA 中的潜在作用，我们假设在 RA 患者的 CD8+T 细胞中可能检测到突变，并且这些突变与临床特征相关。
收集了 98 例 RA 患者和 9 例健康对照者（HCs）的血液样本、临床参数和人口统计学资料。分离 CD8+细胞 DNA，通过液滴数字（dd）PCR 进行分析，以检测 LGL 白血病中常见的突变：Y640F、D661Y 和 S614 到 G618 区域。补充了来自公共数据集的 99 例 HCs 的数据。
与对照组相比，RA 患者中 突变的存在显著增加（Y640F，p=0.0005；D661Y，p=0.0005）。这些突变主要是低变异等位基因频率（VAF）（0.008-0.05%）突变，在 RA 人群中的比例较高（31/98 Y640F，17/98 D661Y），而在 HCs 中则较低（0/108 Y640F，0/108 D661Y）。此外，与对照组相比，3 例 RA 患者的 突变 VAF>5%。与无突变的患者相比，有 突变的 RA 患者的血清学标志物 RF 和抗 CCP 阳性率更高（88% vs 59% RF，p=0.047；92% vs 58% 抗 CCP，p=0.031）。
在 RA 患者的 CD8+细胞中检测到激活突变，且与血清阳性相关。因此，在一部分 RA 患者中，激活突变可能在疾病发病机制中起作用。
