Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus.

IF 4.7 2区 生物学 Q1 GENETICS & HEREDITY
Kennedy C Ukadike, Rayan Najjar, Kathryn Ni, Amanda Laine, Xiaoxing Wang, Alison Bays, Martin S Taylor, John LaCava, Tomas Mustelin
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Abstract

Background: Patients with systemic lupus erythematosus (SLE) have autoantibodies against the L1-encoded open-reading frame 1 protein (ORF1p). Here, we report (i) which immune cells ORF1p emanates from, (ii) which L1 loci are transcriptionally active, (iii) whether the cells express L1-dependent interferon and interferon-stimulated genes, and (iv) the effect of inhibition of L1 ORF2p by reverse transcriptase inhibitors.

Results: L1 ORF1p was detected by flow cytometry primarily in SLE CD66b+CD15+ regular and low-density granulocytes, but much less in other immune cell lineages. The amount of ORF1p was higher in neutrophils from patients with SLE disease activity index (SLEDAI) > 6 (p = 0.011) compared to patients with inactive disease, SLEDAI < 4. Patient neutrophils transcribed seven to twelve human-specific L1 loci (L1Hs), but only 3 that are full-length and with an intact ORF1. Besides serving as a source of detectable ORF1p, the most abundant transcript encoded a truncated ORF2p reverse transcriptase predicted to remain cytosolic, while the two other encoded an intact full-length ORF2p. A number of genes encoding proteins that influence L1 transcription positively or negatively were altered in patients, particularly those with active disease, compared to healthy controls. Components of nucleic acid sensing and interferon induction were also altered. SLE neutrophils also expressed type I interferon-inducible genes and interferon β, which were substantially reduced after treatment of the cells with drugs known to inhibit ORF2p reverse transcriptase activity.

Conclusions: We identified L1Hs loci that are transcriptionally active in SLE neutrophils, and a reduction in the epigenetic silencing mechanisms that normally counteract L1 transcription. SLE neutrophils contained L1-encoded ORF1p protein, as well as activation of the type I interferon system, which was inhibited by treatment with reverse transcriptase inhibitors. Our findings will enable a deeper analysis of L1 dysregulation and its potential role in SLE pathogenesis.

Abstract Image

Abstract Image

Abstract Image

活动性系统性红斑狼疮患者粒细胞中L1反转录转座子的表达。
背景:系统性红斑狼疮(SLE)患者具有抗L1编码的开放阅读框1蛋白(ORF1p)的自身抗体。在此,我们报道了(i)ORF1p来自哪些免疫细胞,(ii)哪些L1基因座具有转录活性,(iii)细胞是否表达L1依赖性干扰素和干扰素刺激的基因,以及(iv)逆转录酶抑制剂对L1 ORF2p的抑制作用。结果:流式细胞仪检测到L1 ORF1p主要在SLE CD66b+CD15+规则粒细胞和低密度粒细胞中,但在其他免疫细胞系中检测到的要少得多。SLE疾病活动指数(SLEDAI)患者中性粒细胞中ORF1p的含量较高 > 6(p = 0.011)与无活动性疾病患者相比,SLEDAI 结论:我们确定了在SLE中性粒细胞中具有转录活性的L1Hs基因座,以及通常抵消L1转录的表观遗传学沉默机制的减少。SLE中性粒细胞含有L1编码的ORF1p蛋白,以及I型干扰素系统的激活,该系统被逆转录酶抑制剂抑制。我们的发现将使我们能够更深入地分析L1失调及其在SLE发病机制中的潜在作用。
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来源期刊
Mobile DNA
Mobile DNA GENETICS & HEREDITY-
CiteScore
8.20
自引率
6.10%
发文量
26
审稿时长
11 weeks
期刊介绍: Mobile DNA is an online, peer-reviewed, open access journal that publishes articles providing novel insights into DNA rearrangements in all organisms, ranging from transposition and other types of recombination mechanisms to patterns and processes of mobile element and host genome evolution. In addition, the journal will consider articles on the utility of mobile genetic elements in biotechnological methods and protocols.
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