Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Center for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Front Immunol. 2020 Apr 28;11:662. doi: 10.3389/fimmu.2020.00662. eCollection 2020.
Elevated cell-free DNA (cfDNA) levels in the plasma and synovial fluid of rheumatoid arthritis (RA) patients are proposed to be pathologically relevant. However, direct evidence to support this perception is lacking, and molecular feature of the cfDNA molecules with assumed pathological function is not well characterized. Here, we confirm remarkably increased levels of total synovial fluid and plasma cfDNAs in a large cohort of patients with rheumatoid arthritis compared to the counterparts in osteoarthritis, and demonstrate the potent inflammatogenic effects of RA synovial fluid cfDNA on both human monocyte cell line and primary cells related to RA. Massively parallel sequencing identifies distinct molecular pattern of cfDNA in RA, as characterized by enriching CpG-motif containing sequences. Importantly, these identified CpG-motif-rich sequences are hypomethylated in RA patients and induce severe inflammatory responses both and . Our data demonstrate the pathological role of global and specific cfDNA molecules in RA, thereby identifying novel therapeutic target candidate and potential biomarker for RA.
在类风湿关节炎（RA）患者的血浆和滑液中，细胞游离 DNA（cfDNA）水平升高被认为与病理相关。然而，缺乏直接证据来支持这种观点，并且具有假定病理功能的 cfDNA 分子的分子特征尚未得到很好的描述。在这里，我们在大量 RA 患者的滑液和血浆 cfDNA 中证实了明显升高的水平，与骨关节炎患者相比，并且证明了 RA 滑液 cfDNA 对人单核细胞系和与 RA 相关的原代细胞具有强烈的促炎作用。大规模平行测序确定了 RA 中 cfDNA 的独特分子模式，其特征在于富含 CpG 基序的序列。重要的是，这些鉴定出的富含 CpG 基序的序列在 RA 患者中呈低甲基化状态，并且在体外和体内均诱导严重的炎症反应。我们的数据表明，cfDNA 分子在 RA 中的整体和特定作用具有病理性，从而确定了 RA 的新型治疗靶标候选物和潜在生物标志物。
