The contribution of HERV‐E clone 4‐1 and other HERV‐E members to the pathogenesis of rheumatic autoimmune diseases

Talotta, Rossella; Atzeni, Fabiola; Laska, Magdalena Janina

doi:10.1111/apm.13039

Cited by 12 publications

(14 citation statements)

References 83 publications

(102 reference statements)

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“…Increased HERV-E clone 4-1 mRNA expression was found in SLE CD4+ T-cells and PBMCs, secondary to a variety of factors: activation of Ca ++ /calcineurin (CaN)/Nuclear factor of activated T cells 1 (NFAT1), due to UVB or foreign infections with high IL6 and TNFα levels; Estrogen receptor-α (ERα) signaling pathway; abnormal DNA hypomethylation of HERV-E clone 4-1 5'LTR. Once expressed, this HERV clone 3'LTR restrains miR-302d activity (an inhibitory miRNA, abnormally downregulated in SLE monocytes), activating a cascade which leads to DNA hypomethylation, IL17 release from CD4+ T-cells and type I IFN response [146][147][148]. Increased expression of HERV-E clone 4-1 gag transcripts has been associated with immunological activity and anti-U1RNP and anti-Sm autoantibodies [149].…”

Section: Human Endogenous Rvs (Hervs)mentioning

confidence: 99%

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

Quaglia

Merlotti

Andrea

et al. 2021

Viruses

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A causal link between viral infections and autoimmunity has been studied for a long time and the role of some viruses in the induction or exacerbation of systemic lupus erythematosus (SLE) in genetically predisposed patients has been proved. The strength of the association between different viral agents and SLE is variable. Epstein–Barr virus (EBV), parvovirus B19 (B19V), and human endogenous retroviruses (HERVs) are involved in SLE pathogenesis, whereas other viruses such as Cytomegalovirus (CMV) probably play a less prominent role. However, the mechanisms of viral–host interactions and the impact of viruses on disease course have yet to be elucidated. In addition to classical mechanisms of viral-triggered autoimmunity, such as molecular mimicry and epitope spreading, there has been a growing appreciation of the role of direct activation of innate response by viral nucleic acids and epigenetic modulation of interferon-related immune response. The latter is especially important for HERVs, which may represent the molecular link between environmental triggers and critical immune genes. Virus-specific proteins modulating interaction with the host immune system have been characterized especially for Epstein–Barr virus and explain immune evasion, persistent infection and self-reactive B-cell “immortalization”. Knowledge has also been expanding on key viral proteins of B19-V and CMV and their possible association with specific phenotypes such as antiphospholipid syndrome. This progress may pave the way to new therapeutic perspectives, including the use of known or new antiviral drugs, postviral immune response modulation and innate immunity inhibition. We herein describe the state-of-the-art knowledge on the role of viral infections in SLE, with a focus on their mechanisms of action and potential therapeutic targets.

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Section: Human Endogenous Rvs (Hervs)mentioning

confidence: 99%

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

Quaglia

Merlotti

Andrea

et al. 2021

Viruses

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“…Similar findings in other autoimmune diseases have led to the formulation of a model in which HERV antigens stimulate immunity due to their similarity to exogenous viral proteins, a process termed 'molecular mimicry'. Several reviews have extensively discussed the evidence for HERV in the aetiopathogenesis of autoimmune disorders, including lupus, diabetes mellitus, multiple sclerosis, Sjögren's syndrome, and rheumatoid arthritis, among others (Balada et al 2009(Balada et al , 2010Brodziak et al 2012;Morandi et al 2017;Tramontano 2018a, 2018b;Greenig 2019;Morris et al 2019;Talotta et al 2020).…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

Sensing of transposable elements by the antiviral innate immune system

Gázquez-Gutiérrez

Witteveldt

Heras

et al. 2021

RNA

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Around half of the genome in mammals is composed of transposable elements (TEs) such as DNA transposons and retrotransposons. Several mechanisms have evolved to prevent their activity and the detrimental impact of their insertional mutagenesis. Despite these potentially negative effects, TEs are essential drivers of evolution, and in certain settings, beneficial to their hosts. For instance, TEs have rewired the antiviral gene regulatory network and are required for early embryonic development. However, due to structural similarities between TEderived and viral nucleic acids, cells can misidentify TEs as invading viruses and trigger the major antiviral innate immune pathway, the type I interferon (IFN) response. This review will focus on the different settings in which the role of TE-mediated IFN activation has been documented, including cancer and senescence. Importantly, TEs may also play a causative role in the development of complex autoimmune diseases characterised by constitutive type I IFN activation. All these observations suggest the presence of strong but opposing forces driving the coevolution of TEs and antiviral defence. A better biological understanding of the TE replicative cycle as well as of the antiviral nucleic acid sensing mechanisms will provide insights into how these two biological processes interact and will help to design better strategies to treat human diseases characterised by aberrant TE expression and/or type I IFN activation.

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“…The HERVs in our genome belong to three classes: gammaretroviruses (class I), betaretroviruses (class II), and spumaretroviruses (class III) [69]. The published literature proposes various roles for class I (HERV-E, and to a lesser extent -W, and -H) and class II (HERV-K) HERVs in autoimmune diseases [70][71][72][73]. A common denominator among these papers is the idea that their transcriptional upregulation will trigger various aspects of an antiviral immune response, including autoantibodies against retroviral proteins [74][75][76][77].…”

Section: Hervsmentioning

confidence: 99%

“…Elevated expression [67,126] of many HERVs and autoantibodies against HERV-K and HERV-E Gag and Env proteins [40,72,[74][75][76] have been reported in SLE [127] and other autoimmune diseases [71]. The broader genomic hypomethylation observed in SLE may well explain the upregulation of HERV transcription, but since most HERVs have lost their ability to encode full-length retroviral proteins, only a few of these transcripts are capable of supporting autoantibody production.…”

Section: Hervs and Other Non-l1 Retrotransposons In Slementioning

confidence: 99%

Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

Ukadike

Mustelin

2021

JCM

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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be at least partly explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.

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The contribution of HERV‐E clone 4‐1 and other HERV‐E members to the pathogenesis of rheumatic autoimmune diseases

Cited by 12 publications

References 83 publications

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

Sensing of transposable elements by the antiviral innate immune system

Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

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