Circulating plasmablasts contribute to antiphospholipid antibody production, associated with type I interferon upregulation
Circulating plasmablasts contribute to antiphospholipid antibody production, associated with type I interferon upregulation
复制标题
DOI：
10.1111/jth.14427
复制
发表时间：
2019-07-01
影响因子：
10.4
通讯作者：
Atsumi, Tatsuya
中科院分区：
文献类型：
--
作者：
Hisada, Ryo;Kato, Masaru;Atsumi, Tatsuya
抗磷脂抗体(APL)产生的机制尚不清楚。我们研究了淋巴细胞亚群、单核苷酸多态(SNP)和APL产生细胞。循环浆母细胞增多与I型干扰素上调有关。我们新的体外实验显示，循环中的浆母细胞是APL的主要来源。背景/目的抗磷脂抗体(APL)是抗磷脂综合征(APS)的病原性自身抗体。本研究旨在阐明APL的产生机制。方法检测26例原发APS(PAPS)、19例系统性红斑狼疮相关APS(SLE/APS)患者和10例健康人外周血单个核细胞(PBMC)中T细胞和B细胞亚群的变化。对这些患者进行SLE相关或APS相关的单核苷酸多态性(SNP)分析。根据PBMCs中Ly6e、Mx1、IFIT1和IFIT3mRNA的表达情况计算干扰素评分。去除CD20阳性或阴性B细胞后，对APS患者的PBMC进行体外培养，培养上清液用于APL检测。结果与正常对照组比较，PAPS、SLE/APS患者外周血中Th2、Th17、浆母细胞增多，调节性T细胞、记忆性B细胞、调节性B细胞减少。遗传分析显示，在携带Toll样受体(TLR)7SNP rs3853839风险等位基因的患者中，浆母细胞的增加更为明显。高危等位基因携带者的干扰素评分显著高于非易感性携带者。体外实验表明，在缺乏CD20+CD19+亚群的PBMC培养上清液中存在APL，而在缺乏CD20-CD19+亚群的PBMC培养上清液中不存在APL。结论浆母细胞在急性早幼粒细胞白血病的发生中起重要作用。此外，浆母细胞的增多与TLR7和I型干扰素有关，提示SLE和APS存在共同的病理生理机制。靶向浆母细胞可能是治疗APS的一种新的免疫治疗方法。
EssentialsThe mechanism of antiphospholipid antibodies (aPL) production remains unclear. We investigated lymphocyte subset, single nucleotide polymorphisms (SNP), and aPL-producing cells. The increase of circulating plasmablasts was associated with type I interferon upregulation. Our novel ex vivo assay revealed circulating plasmablasts as a major source of aPL. Background/objective Antiphospholipid antibodies (aPL) are pathogenic autoantibodies in antiphospholipid syndrome (APS). This study aimed to clarify the mechanism of aPL production. Methods T cell and B cell subsets were evaluated in peripheral blood mononuclear cells (PBMCs) of 26 primary APS (PAPS), 19 systemic lupus erythematosus-associated APS (SLE/APS) patients and 10 healthy controls. The SLE-related or APS-related single nucleotide polymorphisms (SNP) were analyzed in those patients. Interferon (IFN) score was calculated based on the mRNA expression of Ly6e, Mx1, IFIT1, and IFIT3 in PBMCs. The PBMCs obtained from APS patients were cultured ex vivo following depletion of CD20 positive or negative B cells and the culture supernatants were applied to aPL measurements. Results In PAPS and SLE/APS patients, Th2, Th17, and plasmablasts were increased while regulatory T, memory B, and regulatory B cells were decreased compared to healthy controls. Genetic analysis revealed that the increase of plasmablasts was more pronounced in patients carrying a risk allele of toll like receptor (TLR) 7 SNP rs3853839. The IFN score was significantly higher in the risk allele carriers. Ex vivo experiments showed that aPL were present in the culture supernatant of PBMCs lacking CD20+CD19+ subset, but not in that of cells lacking CD20-CD19+ subset. Conclusions Our data indicate an important role of plasmablasts in the production of aPL. Furthermore, the increase of plasmablasts was associated with TLR 7 and type I IFN, suggesting a common pathophysiology in SLE and APS. Targeting plasmablasts might be a novel immunological therapeutic approach in the treatment of APS.