{"title":"Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond.","authors":"Simone Caielli, Zurong Wan, Virginia Pascual","doi":"10.1146/annurev-immunol-101921-042422","DOIUrl":null,"url":null,"abstract":"<p><p>Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.</p>","PeriodicalId":8271,"journal":{"name":"Annual review of immunology","volume":"41 ","pages":"533-560"},"PeriodicalIF":26.9000,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annual review of immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1146/annurev-immunol-101921-042422","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/2/28 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.
自反应性 B 细胞和干扰素是系统性红斑狼疮(SLE)发病机制的核心因素。然而,针对这些通路的药物取得了部分成功,这证明了导致疾病发病的上游机制存在异质性。在这篇综述中,我们将重点介绍最近对患者进行的遗传和免疫监测研究的最新发现,这些发现正在完善我们对这些基本机制的认识。其中,影响固有 B 细胞活化或干扰核酸清除的基因发生了新的突变。线粒体已成为系统性红斑狼疮发病机制的相关诱因和/或放大器,其机制多种多样,包括细胞器完整性或区隔的破坏、新陈代谢的缺陷以及质量控制措施的失效。这些机制导致细胞外或细胞内干扰核酸的释放,以及先天性和/或适应性免疫细胞的激活。研究发现,多种经典和新型系统性红斑狼疮自身抗体特异性可再现与单基因狼疮相关的基因改变,或触发干扰素扩增环路。最后,非典型 B 细胞和新型叶外 T 辅助细胞亚群被认为有助于系统性红斑狼疮自身抗体的产生。总之,这些新见解为深化对患者的免疫表型监测提供了机会,并为患者分层和个性化、合理的治疗方法打开了大门。
期刊介绍:
The Annual Review of Immunology, in publication since 1983, focuses on basic immune mechanisms and molecular basis of immune diseases in humans. Topics include innate and adaptive immunity; immune cell development and differentiation; immune control of pathogens (viruses, bacteria, parasites) and cancer; and human immunodeficiency and autoimmune diseases. The current volume of this journal has been converted from gated to open access through Annual Reviews' Subscribe to Open program, with all articles published under a CC BY license.