Female-bias in systemic lupus erythematosus: How much is the X chromosome to blame?

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Adriana A Vieira, Inês Almada-Correia, Joana Inácio, Patrícia Costa-Reis, S T da Rocha
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Abstract

Systemic lupus erythematosus (SLE or lupus) is an immune-mediated disease associated with substantial medical burden. Notably, lupus exhibits a striking female bias, with women having significantly higher susceptibility compared to men, up to 14-fold higher in some ethnicities. Supernumerary X chromosome syndromes, like Klinefelter (XXY) and Triple X syndrome (XXX), also present higher SLE prevalence, whereas Turner syndrome (XO) displays lower prevalence. Taken together, SLE prevalence in different X chromosome dosage sceneries denotes a relationship between the number of X chromosomes and the risk of developing lupus. The dosage of X-linked genes, many of which play roles in the immune system, is compensated between males and females through the inactivation of one of the two X chromosomes in female cells. X-chromosome inactivation (XCI) initiates early in development with a random selection of which X chromosome to inactivate, a choice that is then epigenetically maintained in the daughter cells. This process is regulated by the X-Inactive-Specific Transcript (XIST), encoding for a long non-coding RNA, exclusively expressed from the inactive X chromosome (Xi). XIST interacts with various RNA binding proteins and chromatin modifiers to form a ribonucleoprotein (RNP) complex responsible for the transcriptional silencing and heterochromatinization of the Xi. This ensures stable silencing of most genes on the X chromosome, with only a few genes able to escape this process. Recent findings suggest that the molecular components involved in XCI, or their dysregulation, contribute to the pathogenesis of lupus. Indeed, nonrandom XCI, elevated gene escape from XCI, and the autoimmune potential of the XIST RNP complex have been suggested to contribute to auto-immune diseases, such as lupus. This review examines these current hypotheses concerning how this dosage compensation mechanism might impact the development of lupus, shedding light on potential mechanisms underlying the pathogenesis of the disease.

系统性红斑狼疮的女性偏爱:X染色体的责任有多大?
系统性红斑狼疮(SLE 或狼疮)是一种由免疫介导的疾病,给患者带来沉重的医疗负担。值得注意的是,狼疮有明显的女性偏向,女性的易感性明显高于男性,在某些种族中,女性的易感性可高达男性的14倍。X 染色体超常综合征,如 Klinefelter(XXY)和三X 综合征(XXX),其系统性红斑狼疮发病率也较高,而特纳综合征(XO)的发病率则较低。总之,不同 X 染色体剂量情况下系统性红斑狼疮的发病率表明,X 染色体的数量与患狼疮的风险之间存在一定的关系。许多在免疫系统中发挥作用的 X 连锁基因的剂量是通过女性细胞中两条 X 染色体中的一条失活来在男性和女性之间进行补偿的。X 染色体失活(XCI)始于发育早期,随机选择要失活的 X 染色体,然后在子细胞中通过表观遗传学保持这一选择。这一过程受 X 非活性特异性转录本(XIST)的调控,该转录本编码一种非编码长 RNA,仅由非活性 X 染色体(Xi)表达。XIST 与各种 RNA 结合蛋白和染色质修饰因子相互作用,形成一个核糖核蛋白(RNP)复合物,负责 Xi 的转录沉默和异染色质化。这确保了 X 染色体上大多数基因的稳定沉默,只有少数基因能够逃脱这一过程。最近的研究结果表明,参与 XCI 的分子成分或它们的失调有助于红斑狼疮的发病机制。事实上,非随机 XCI、基因从 XCI 中逃逸的程度升高以及 XIST RNP 复合物的自身免疫潜能都被认为是红斑狼疮等自身免疫性疾病的诱因。这篇综述探讨了目前关于剂量补偿机制如何影响红斑狼疮发病的假设,揭示了该病发病机制的潜在机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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