Potential molecular mimicry between the human endogenous retrovirus W family envelope proteins and myelin proteins in multiple sclerosis

Ramasamy, Ranjan; Joseph, Blessy; Whittall, Trevor

doi:10.1016/j.imlet.2017.02.003

Cited by 32 publications

(54 citation statements)

References 32 publications

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“…In the case of HERV molecules, however, their stable presence and expression in the organism could provide continuous triggers to the host immune sensors. In fact, the main findings linking HERVs to autoimmune and inflammatory disorders rely on the chronic stimulus exerted by endogenous retroviral molecules, which could sustain molecular mimicry events based on the sequence identity between HERV products and either exogenous viruses or body components ( 16 , 28 , 30 , 131 , 132 ). Worth to note, after the initial immune activation, the production of IFN establishes a positive-feedback that further upregulates IFN-stimulated genes by both a paracrine and an autocrine loop, fostering chronic inflammation and autoimmunity.…”

Section: Hervs As Activators Of Antiviral Innate Immunitymentioning

confidence: 99%

“…It has been shown that HERV expression products can act as pathogen-associated molecular patterns (PAMPs), triggering the cellular receptors responsible for the first line of defenses ( 25 – 27 ). They can moreover provide antigenic epitopes recognized by lymphocytes (especially through molecular mimicry with exogenous viral molecules) and stimulating the onset of specific T- and B- cells ( 28 – 30 ). These mechanisms might be particularly relevant for the tentative involvement of HERVs in autoimmunity and inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Hervs As Activators Of Antiviral Innate Immunitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2018

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“…Expression of HERV-W Env protein has been repeatedly detected on the surface of microglia and macrophages in the brains of MS patients near or in actively demyelinating lesions [ 45 , 172 , 176 ]. Moreover, several regions of the Env protein show sequence homology with MOG and at least some of these sequences function as epitopes capable of provoking T and B cell activation [ 177 , 178 ]. This is of importance as interactions between macrophages and microglia acting as APCs and autoreactive Th1 and Th17 T cells entering the CNS from the periphery are now considered to lie at the core of neuroinflammatory processes and myelin destruction in MS [ 179 ] (reviewed [ 113 ]).…”

Section: Potential Contribution Of Herv-w Herv-h and Herv-fc1 To Ms mentioning

confidence: 99%

Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How?

et al. 2018

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The gammaretroviral human endogenous retrovirus (HERV) families MRSV/HERV-W and HERV-H (including the closely related HERV-Fc1) are associated with an increased risk of multiple sclerosis (MS). Complete HERV sequences betray their endogenous retroviral origin, with open reading frames in gag, pro, pol and env being flanked by two long terminal repeats containing promoter and enhancer sequences with the capacity to regulate HERV transactivation and the activity of host genes in spite of endogenous epigenetic repression mechanisms. HERV virions, RNA, cDNA, Gag and Env, and antibodies to HERV transcriptional products, have variously been found in the blood and/or brain and/or cerebrospinal fluid of MS patients, with the HERV expression level being associated with disease status. Furthermore, some HERV-associated single nucleotide polymorphisms (SNPs), such as rs662139 T/C in a 3-kb region of Xq22.3 containing a HERV-W env locus, and rs391745, upstream of the HERV-Fc1 locus on the X chromosome, are associated with MS susceptibility, while a negative association has been reported with SNPs in the tripartite motif-containing (TRIM) protein-encoding genes TRIM5 and TRIM22. Factors affecting HERV transcription include immune activation and inflammation, since HERV promoter regions possess binding sites for related transcription factors; oxidative stress, with oxidation of guanine to 8-oxoguanine and conversion of cytosine to 5-hydroxymethylcytosine preventing binding of methyl groups transferred by DNA methyltransferases; oxidative stress also inhibits the activity of deacetylases, thereby favouring the acetylation of histone lysine residues favouring gene expression; interferon beta; natalizumab treatment; impaired epigenetic regulation; and the sex of patients.

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“…Why the expression of a known risk factor for MS is higher in a population with a lower risk of the disease is puzzling, though it seems likely that other genetic or epigenetic factors must be in play here. There has been some work indicating that epitopes of the HERV-W envelope protein could be recognised by the HLA alleles DRB1*1501 and DRB5*0101 (Ramasamy et al, 2017). Therefore, it could be suggested that the failure of HLA allele recognition of the higher levels of HERV-W expression in the RUS MS cohort may account for some of the difference in MS risk.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of HERV-W in Peripheral Blood in Multiple Sclerosis and Healthy Patients in Two Different Ethnic Groups

et al. 2020

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Overexpression of the Human endogenous retrovirus W (HERV-W) group of inherited retroviruses has been consistently linked with Multiple Sclerosis (MS). However most of the studies on this link have focused on European genetic groups with a very high risk of MS and it is not clear that this relationship holds for all ethnic groups. This study examined via qPCR the RNA expression in peripheral blood of HERV-W (the multiple sclerosis associated retrovirus variant MSRV) of MS patients and healthy controls from two ethnic groups with very different risk rates of MS. Population one was derived from the UK with a Northern European genetic background and an MS risk rate of 108/100,000, population two was derived from the republic of Tatarstan, Russian Federation, with a mixed Russian (Eastern European) and Tartar (Turkic or Volga/Urals) population with an MS risk rate of 21-31/100,000. The Russian population displayed a significantly higher basal level of expression of MSRV in both healthy and MS individuals when compared to the British control population with a trend in the Russian population towards higher expression levels in MS patients than healthy patients.

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Potential molecular mimicry between the human endogenous retrovirus W family envelope proteins and myelin proteins in multiple sclerosis

Cited by 32 publications

References 32 publications

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

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

Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How?

Differential Expression of HERV-W in Peripheral Blood in Multiple Sclerosis and Healthy Patients in Two Different Ethnic Groups

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