Translational and Clinical Research Institute, Newcastle University, Central Parkway, Newcastle-upon-Tyne NE1 3BZ, United Kingdom.
Endocrine Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-upon-Tyne NE1 4LP, United Kingdom.
Eur J Endocrinol. 2023 Aug 2;189(2):208-216. doi: 10.1093/ejendo/lvad107.
The specific mechanisms driving autoimmunity in Graves' disease (GD) remain largely unknown. Kappa-deleting recombination excision circles (KRECs) are circular DNA molecules generated during B cell maturation in the bone marrow which provide a measure of B cell production and proliferation. We aimed to investigate the association between KRECs and B cell subpopulations, with thyroid status and clinical outcome in GD patients.
Kappa-deleting recombination excision circles were measured by quantitative real-time PCR using a triple-insert plasmid control in 132 GD patients and 140 healthy controls. In addition, KRECs in GD patients on withdrawal of antithyroid drug (ATD) and 6-10 weeks later were analysed according to a clinical outcome at 1 year. Flow cytometry was performed on isolated CD19+ B cells to quantitate 7 B lymphocyte subpopulations in 65 GD patients.
Circulating KRECs were higher in GD vs. controls (P = 1.5 × 10-9) and demonstrated a positive correlation to thyroid hormones and autoantibodies (free thyroxine: P = 2.14 × 10-5, rho = .30; free triiodothyronine: P = 1.99 × 10-7, rho = .37; thyroid stimulating hormone receptor autoantibodies: P = 1.36 × 10-5, rho = .23). Higher KRECs in GD patients 6-10 weeks after ATD withdrawal were associated with relapse of hyperthyroidism at 1 year (P = .04). The KRECs were positively correlated to the total CD19+ B cell count (P = 3.2 × 10-7).
This study reports a robust association between KRECs and GD, highlighting the importance of B cells in the pathogenesis of GD and the influence of thyroid status on B cell activity. The findings indicate a potential role for KRECs as a marker of disease activity and outcome in GD.
导致格雷夫斯病（GD）自身免疫的确切机制在很大程度上仍然未知。κ 缺失重组切除环（KRECs）是在骨髓中 B 细胞成熟过程中产生的环状 DNA 分子，可提供 B 细胞产生和增殖的衡量标准。我们旨在研究 KRECs 与 B 细胞亚群、甲状腺状态和 GD 患者临床结局之间的关系。
使用三插入质粒对照物，通过实时定量 PCR 测量 132 例 GD 患者和 140 例健康对照者的 KRECs。此外，根据 1 年后的临床结局，分析 GD 患者停用抗甲状腺药物（ATD）后 6-10 周的 KRECs。在 65 例 GD 患者中，通过分离 CD19+B 细胞进行流式细胞术，定量 7 种 B 淋巴细胞亚群。
GD 患者的循环 KRECs 高于对照组（P=1.5×10-9），并与甲状腺激素和自身抗体呈正相关（游离甲状腺素：P=2.14×10-5，rho=0.30；游离三碘甲状腺原氨酸：P=1.99×10-7，rho=0.37；促甲状腺激素受体自身抗体：P=1.36×10-5，rho=0.23）。ATD 停药后 6-10 周，GD 患者的 KRECs 较高，与 1 年后发生甲状腺功能亢进复发有关（P=0.04）。KRECs 与总 CD19+B 细胞计数呈正相关（P=3.2×10-7）。
本研究报告了 KRECs 与 GD 之间存在显著关联，突出了 B 细胞在 GD 发病机制中的重要性以及甲状腺状态对 B 细胞活性的影响。研究结果表明，KRECs 可能作为 GD 疾病活动和结局的标志物发挥作用。
