How Retroviruses and Retrotransposons in Our Genome May Contribute to Autoimmunity in Rheumatological Conditions

Mustelin, Tomas; Ukadike, Kennedy C.

doi:10.3389/fimmu.2020.593891

Cited by 20 publications

(21 citation statements)

References 211 publications

(259 reference statements)

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“…Up to 200 families of HERVs have been described and some of them (HRES-1, ERV-3, HERV-E 4-1, HERV-K10 and HERV-K18) have been especially implicated in SLE [ 54 , 127 , 128 , 129 , 130 ].…”

Section: Role Of Specific Viral Infections In Slementioning

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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“…Up to 200 families of HERVs have been described and some of them (HRES-1, ERV-3, HERV-E 4-1, HERV-K10 and HERV-K18) have been especially implicated in SLE [ 54 , 127 , 128 , 129 , 130 ].…”

Section: Role Of Specific Viral Infections In Slementioning

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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“…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: How L1 Retrotransposons May Trigger Ifn-positive Slementioning

confidence: 99%

“…In accordance with the genetics of SLE summarized above, we focus in this review on an emerging concept that is well compatible with the genetic associations, namely the notion that endogenous virus-like sequences may play a part in the pathogenesis of SLE and other related diseases [ 37 , 38 , 39 , 40 ]. These genomic sequences are either remnants of exogenous retroviruses that infected our ancestors millions of years ago [ 40 , 41 , 42 ], or ancient descendants of retroviruses that retained the ability to embed and replicate within the germline genome to become extremely abundant throughout the human genome [ 40 , 43 ]. Although the vast majority of all these sequences are now inactive due to mutations and truncations, a number of them are still more or less intact and able to create extra-chromosomal DNA, trigger type I IFNs, and provoke an antiviral type of immune response.…”

Section: Introductionmentioning

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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“…Mikko Hurme 1* and Graham Pawelec 2,3 Over evolutionary time, the human genome has incorporated large amounts of genetic material from ancient retroviral infections, comprising ca. 8% of the total DNA.…”

Section: Human Endogenous Retroviruses and Ageingmentioning

confidence: 99%

“…In addition to these complexities in the regulation of the transcription of HERVs, it is now known that the end products, i.e. the env, gag, pol-encoded proteins, are directly involved in the pathogenesis of some diseases, especially those of an autoimmune nature [2]. It seems that these proteins (especially env) can be recognized as foreign and are able to induce the production of autoantibodies (the shared epitope model).…”

Section: Human Endogenous Retroviruses and Ageingmentioning

confidence: 99%