The Retrovirus/Superantigen Hypothesis of Multiple Sclerosis

Emmer, Alexander; Staege, Martin S.; Kornhuber, Malte

doi:10.1007/s10571-014-0100-7

Cited by 31 publications

(20 citation statements)

References 114 publications

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“…Thus, slow disease progression following neurodegeneration might be induced by re-activation of HERV expression directly, while relapses in parallel to inflammation might be secondary to the expression of HERV-encoded superantigens [169]. In Northern and Southern European cohorts, an association with susceptibility to bout-onset MS was established and confirmed for the HERV-Fc1 (ERVFC1) sequence in chromosome X and the enclosing polymorphism rs391745 [170].…”

Section: Neurological Diseasesmentioning

confidence: 97%

Molecular functions of human endogenous retroviruses in health and disease

Suntsova

Garazha

Ivanova

et al. 2015

Cell. Mol. Life Sci.

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Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

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Section: Neurological Diseasesmentioning

confidence: 97%

Molecular functions of human endogenous retroviruses in health and disease

Suntsova

Garazha

Ivanova

et al. 2015

Cell. Mol. Life Sci.

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“…Such a HERV-W Env mediated pro-inflammatory effect was responsible for reduced oligodendrocytes differentiation and affected myelin expression and renewal ( 101 ), as also demonstrated by the fact that treatment with a specific antibody for HERV-W Env (GNbAC1) was able to rescue myelin expression ( 115 ). In addition, HERV-W Env hold a significant superantigen activity ( 116 ), that has also been proposed to play a role in demyelination, by evoking a polyclonal non-specific T-cell activation and the massive release of multiple cytokines ( 98 , 109 ). A similar interaction between HERV-W Env and the TLR4 of pancreatic β cells has been proposed to promote autoimmune reactions and to affect insulin secretion in type I diabetes patients ( 117 ).…”

Section: Hervs As Activators Of Antiviral Innate Immunitymentioning

confidence: 99%

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

2018

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About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert.

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“…Retroviral genes are heavily methylated in normal tissues, whereas tumors show increased levels of HERV transcripts due to hypomethylation (Cegolon et al, 2013 ). In addition to epigenetic regulation, other factors including hormones, microorganisms, and the environment were shown to modulate HERV expression (Balada et al, 2009 ; Emmer et al, 2014 ).…”

Section: Regulation Of Herv Expressionmentioning

confidence: 99%

Human Endogenous Retroviruses and Their Putative Role in the Development of Autoimmune Disorders Such as Multiple Sclerosis

Gröger

Cynis

2018

Front. Microbiol.

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Human endogenous retroviruses (HERVs) are remnants of retroviral germ line infections of human ancestors and make up ~8% of the human genome. Under physiological conditions, these elements are frequently inactive or non-functional due to deactivating mutations and epigenetic control. However, they can be reactivated under certain pathological conditions and produce viral transcripts and proteins. Several disorders, like multiple sclerosis or amyotrophic lateral sclerosis are associated with increased HERV expression. Although their detailed contribution to individual diseases has yet to be elucidated, an increasing number of studies in vitro and in vivo suggest HERVs as potent modulators of the immune system. They are able to affect the transcription of other immune-related genes, interact with pattern recognition receptors, and influence the positive and negative selection of developing thymocytes. Interestingly, HERV envelope proteins can both stimulate and suppress immune responses based on different mechanisms. In the light of HERV proteins becoming an emerging drug target for autoimmune-related disorders and cancer, we will provide an overview on recent findings of the complex interactions between HERVs and the human immune system with a focus on autoimmunity.

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The Retrovirus/Superantigen Hypothesis of Multiple Sclerosis

Cited by 31 publications

References 114 publications

Molecular functions of human endogenous retroviruses in health and disease

Molecular functions of human endogenous retroviruses in health and disease

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

Human Endogenous Retroviruses and Their Putative Role in the Development of Autoimmune Disorders Such as Multiple Sclerosis

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