RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.
RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.
复制标题
DOI：
10.1056/nejmoa2004114
复制
发表时间：
2020-07-16
期刊：
影响因子：
--
通讯作者：
Darnell RB
中科院分区：
文献类型：
--
作者：
Orange DE;Yao V;Sawicka K;Fak J;Frank MO;Parveen S;Blachere NE;Hale C;Zhang F;Raychaudhuri S;Troyanskaya OG;Darnell RB
风湿性关节炎，像许多炎症性疾病，其特征在于间歇性静止和恶化（耀斑）。导致耀斑的分子事件是未知的。我们建立了一个临床和技术方案，用于类风湿性关节炎患者的重复家庭血液采集，以允许纵向RNA测序（RNA-seq）。我们的索引患者在4年内8次发作期间的364个时间点获得标本，另外3例患者在发作期间的235个时间点获得标本。我们确定了耀斑前差异表达的转录本，并将其与滑膜单细胞RNA-seq的数据进行了比较。在其他患者中使用流式细胞术和分选的血细胞RNA-seq来验证这些发现。在类风湿性关节炎发作前1至2周，在血液转录谱中观察到一致的变化。B细胞活化后，类风湿性关节炎患者血液中的循环CD 45 − CD 31 −PDPN+炎症前间充质细胞（PRIME）扩增;这些细胞具有炎症性滑膜成纤维细胞的特征。在所有4名患者中，循环PRIME细胞的水平在发作期间下降，流式细胞术和分选细胞RNA-seq证实了另外19名类风湿性关节炎患者中存在PRIME细胞。类风湿性关节炎发作的纵向基因组分析揭示了发作前血液中的PRIME细胞，并提出了一种模型，其中这些细胞在发作前几周被B细胞激活，随后从血液中迁移到滑膜中。（由美国国立卫生研究院和其他机构资助。
Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown. We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings. Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45−CD31−PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis. Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.)