First Department of Propaedeutic Internal Medicine, Joint Rheumatology Program, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
First Department of Propaedeutic Internal Medicine, Joint Rheumatology Program, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
J Autoimmun. 2019 Nov;104:102311. doi: 10.1016/j.jaut.2019.102311. Epub 2019 Aug 1.
Type I Interferon gene expression has been shown to play an important role in the pathogenesis of several systemic autoimmune disorders, paving the way for its potential use as a surrogate marker or a therapeutic tool. While the concept of type I interferon signature and its correlation with clinical phenotypes and disease activity, along with anti-interferon targeted therapy have been vastly investigated in patients with systemic lupus erythematosus, there is a paucity of data concerning antiphospholipid syndrome patients. In this review, we summarize the current knowledge on the pathogenetic and clinical implications of type I interferon expression in antiphospholipid syndrome and discuss the therapeutic possibility of targeting molecules along the interferon signaling pathway. A number of recent studies have shown a type I interferon gene expression induction in patients with primary antiphospholipid syndrome via the plasmacytoid dendritic cell pathway, toll like receptors (TLRs) such as TLR7 and TLR9, anti-beta2glycoprotein I antibody-mediated neutrophil activation and neutrophil extracellular traps (NETs) release in a TLR4-dependent fashion, and a subsequent B cell and plasmablast activation. An association between type I interferon expression and several demographic, clinical and laboratory characteristics including age, gender, pregnancy complications such as eclampsia, anti-beta2glycoprotein I antibodies, and a negative correlation with hydroxychloroquine and/or statin use, has been shown. Correlation of high interferon scores to worse outcomes in prospective studies could direct the initiation for a prompt treatment in high-risk populations. Potential therapeutic approaches targeting type I interferon production and signaling pathway components might include anti-interferon or interferon receptor monoclonal antibodies, or an interferon based therapeutic vaccine as was indicated from previous systemic lupus erythematosus studies, TLR inhibitors including hydroxychloroquine and anti-TLR antibodies, plasmacytoid dendritic cell inhibition, adenosine-receptor agonists, and plasmablast targeting treatments. Well-designed studies are needed to further assess the immunomodulatory potential of the above targets for therapeutic intervention in patients with primary antiphospholipid syndrome.
I 型干扰素基因表达已被证明在几种系统性自身免疫性疾病的发病机制中发挥重要作用，为其作为替代标志物或治疗工具的潜在用途铺平了道路。虽然 I 型干扰素特征及其与临床表型和疾病活动的相关性，以及针对干扰素的靶向治疗在系统性红斑狼疮患者中已得到广泛研究，但关于抗磷脂综合征患者的数据却很少。在这篇综述中，我们总结了 I 型干扰素在抗磷脂综合征中的发病机制和临床意义的最新知识，并讨论了针对干扰素信号通路中分子的治疗可能性。许多最近的研究表明，原发性抗磷脂综合征患者通过浆细胞样树突状细胞途径、Toll 样受体（TLR）如 TLR7 和 TLR9、抗β2糖蛋白 I 抗体介导的中性粒细胞激活和中性粒细胞细胞外陷阱（NETs）释放，以 TLR4 依赖性方式诱导 I 型干扰素基因表达，并随后激活 B 细胞和浆母细胞。I 型干扰素表达与几种人口统计学、临床和实验室特征相关，包括年龄、性别、妊娠并发症如子痫前期、抗β2糖蛋白 I 抗体，以及与羟氯喹和/或他汀类药物使用呈负相关。前瞻性研究中高干扰素评分与较差结局的相关性可能指导高危人群及时开始治疗。针对 I 型干扰素产生和信号通路成分的潜在治疗方法可能包括抗干扰素或干扰素受体单克隆抗体，或基于干扰素的治疗性疫苗，正如之前系统性红斑狼疮研究所示，TLR 抑制剂包括羟氯喹和抗 TLR 抗体、浆细胞样树突状细胞抑制、腺苷受体激动剂和浆母细胞靶向治疗。需要进行精心设计的研究来进一步评估上述靶点在原发性抗磷脂综合征患者中的免疫调节潜力，以进行治疗干预。
