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Epstein–Barr virus and multiple sclerosis. From evidence to therapeutic strategies

Journal of the Neurological Sciences, Volume 361, 15 February 2016, Pages 213-219

Abstract

Multiple sclerosis is caused by a complex interaction between genetic predisposition and environmental factors. Epstein–Barr virus (EBV) is an environmental risk factor that is strongly related to multiple sclerosis (MS), since EBV seropositivity is linked to a significant risk of developing MS. EBV may be involved in the pathogenesis of the disease and it is possibly a prerequisite for the development of MS. EBV infection persists in B-cells during the lifetime of the host and can modulate their function. In addition, MS patients might have a deficient capacity to eliminate latent EBV infection in the central nervous system and this would promote the accumulation of infected B cells. Several mechanisms of pathogenesis, including a direct and indirect function of infected B cells, have been postulated in inflammation and neurodegeneration. A relationship between EBV and human endogenous retroviruses in the pathogenesis of MS has also been reported. If EBV is important in the pathogenesis of MS, different therapeutic strategies seem possible for MS treatment.

Highlights

  • We made a review of the bibliography for EBV and MS.
  • The association between MS and EBV infection may be a causal relationship.
  • The role of EBV infected B-cells in the pathogenesis of MS seems to be essential.
  • EBV infected B-cells might have a direct or indirect role in the pathogenic mechanisms.
  • Anti-B cell treatments appear to be a good strategy for anti-EBV therapy.

Abbreviations: BBB - blood–brain barrier, CIS - clinically isolated syndrome, CNS - central nervous system, CSF - Cerebrospinal Fluid, EBV - Epstein–Barr virus, HERVs - Human endogenous retroviruses, HERV-W - W family of human endogenous retroviruses, MRI - magnetic resonance imaging, MS - multiple sclerosis, MSRV - multiple sclerosis associated retrovirus, NK - natural killer, OCB - oligoclonal bands, OR - odds ratio, RRMS - Relapsing remitting multiple sclerosis.

Keywords: Multiple sclerosis, Epstein–Barr virus, Human endogenous retroviruses, B-cell, CD20.

1. Introduction

Multiple sclerosis (MS) is considered an inflammatory demyelinating disease affecting the central nervous system (CNS), leading to myelin and axonal loss and progressively increasing disability in the patient. MS is not a very common disease but it seems that there is a universal increase in prevalence and incidence of MS [36].

It is believed that MS might be caused by a complex interaction between genetic predisposition and environmental factors [27], [38], and [57]. Thus, several environmental risk factors have been proposed as triggers of MS, including Epstein–Barr virus (EBV). The present contribution is a narrative review of the literature on EBV and MS, including their relationship in MS pathogenesis and potential treatment strategies. In order to write this narrative review, a thorough search of medical literature (MEDLINE) to retrieve relevant studies have been done.

2. The biology of Epstein–Barr virus infection

At least 90% of the population worldwide is infected by EBV. EBV infection usually occurs in early childhood and most cases are asymptomatic, but it can cause the clinical syndrome of infectious mononucleosis [7], mostly when the infection occurs in adolescence or later. What makes EBV so interesting is the fact that its infection is linked not only to autoimmune diseases such as MS but also with the aetiology of a variety of human tumours [59] and [96]. This association might be explained by the capacity of EBV to cause a lifelong infection, hiding in a latent form in memory B cells whilst reducing its level of pathogenicity [54].

According to the Germinal centre model of EBV infection [85], the cycle of EBV infection (Fig. Fig. 1) starts with its transmission from an EBV-seropositive host to an EBV-naive person via saliva [95]. The replication of the virus is followed by the infection of naive B cells located in Waldeyer's ring. The virus activates its growth programme in the germinal centre, which leads the newly infected B cells to become activated B blasts and finally resting memory B cells that enter the peripheral circulation. The genome of the virus remains latent as an episome in the nucleus of infected memory B-cells, as part of the latent phase of the infection [56]. Sporadically, latently infected memory B cells return to the germinal centre in the tonsils where they reactivate into the lytic cycle.

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Fig. 1 Cycle of persistent infection of EBV according to the proposed Germinal Centre Model. During primary infection, EBV enters through the saliva and infects naïve B cells located in the tonsil. The cycle goes on with a first transformation to activated B blasts and then in the germinal centres a posterior proliferation and differentiation in latently infected memory B cells. These cells circulate in the blood without any expression of viral proteins except EBNA 1 during cell division due to cell homeostasis. The cycle finally ends in the tonsils again, where latently infected memory B cells return and differentiate into plasma cells. This transformation initiates the lytic phase of infection with production of new virions. A new cycle in the same or a different host starts again. The immune system, mainly the CD8 + cytotoxic cells and EBV antibodies, respond to and control EBV proliferation except in the latent phase of the infection.

In immunocompetent hosts, the immune system can detect, attack and control infections. In the latency phase, infected memory B cells do not express viral proteins since the growth-promoting genes of the virus are no longer expressed, and thus the immune system cannot detect them. However, EBV-infected memory B cells express EBNA-1 protein when they divide as part of their cell homeostasis and it occurs because the latent virus is reactivated in order to keep the viral genome in the new memory B cells. This way the infection can continue for a long time [84].

There are particular conditions that change the usual cycle of infection and lead to uncontrolled EBV replication as it occurs specifically in immunosuppressed or immunodeficient hosts, or in patients with a functional defect in their EBV-specific T cells or NK cells. So, the impairment seems to be a risk factor for malignant transformation and the development of autoimmune diseases [54] and [83].

3. 3. The relationship between EBV infection and multiple sclerosis

3.1. EBV serology in MS patients

Recently, an umbrella review of meta-analyses showed that smoking and previous infection with EBV, demonstrated by anti-EBNA IgG seropositivity or previous infectious mononucleosis, were the most strongly linked environmental risk factors for developing MS [9].

An association between EBV infection and MS has been hypothesised for 30 years, since a higher frequency of EBV seropositivity in MS patients in comparison with control patients had been reported [11], [23], and [82].

Successive studies and systematic reviews showed that a history of infectious mononucleosis significantly increases the risk of multiple sclerosis [29], and that EBV seropositive subjects have an increased MS risk, especially in individuals with anti-EBNA-1 igG and anti-VCA IgG antibodies [1] and [72]. Interestingly, an odds ratio (OR) of 0,06 was found in a review that investigated EBV seronegativity and MS [6]. Paediatric onset MS patients do not seem to have the same high EBV infection rates seen in adult onset patients, and it has been calculated that 14% of the children diagnosed with MS were EBV seronegative [8], although another meta-analysis showed the same rate of seropositivity for both, child and adult onset MS patients [58].

The divergences found between studies carried out with adult and paediatric patients might be explained by the fact that it is more difficult to make a correct diagnosis of MS in children than in adults [17] and that there is no 100% sensitive and specific test for EBV antibodies [18].

Although most of the general adult population is infected by EBV, the vast majority do not develop MS. So, it seems that EBV infection is a prerequisite for the development of MS, but it is not sufficient to explain the cause of the disease. This leads to think that EBV infection must be part of the causal pathways leading to MS [26] and its interaction with other factors predispose each individual to developing MS, such as EBV genetic variants [52] or the controversial role of vitamin D deficiency [24], [32], [53], and [69] and genetic predisposition involving immune system function with MHC genes [68] and non-MHC genes ([13], Hadjixenofontos et al. [97]). In the same way there is a strong association between smoking and MS [9]. It has been reported a gene–environment interaction of smoking with genetic polymorphisms [12] and [30] and an interaction between smoking and EBV infection as a risk factor of MS [71].

3.2. EBV and MS pathology

MS pathology is characterized by the presence of tissue injury in the white and grey matter of the brain and spinal cord [41]. While focal demyelinating plaques associated with inflammation and blood–brain barrier (BBB) injury are predominantly seen in patients with Relapsing Remitting Multiple Sclerosis (RRMS), these findings are less frequently seen in patients with progressive MS where the main feature is the degeneration of chronically demyelinated axons, cortical demyelination and diffuse pathology that finally results in brain atrophy [46].

T lymphocytes, mostly CD8 T cells, B lymphocytes, activated microglia and macrophages are implicated in MS inflammation, but the nature of the inflammation varies with the stage of the disease [40]. In RRMS, inflammation is associated with BBB dysfunction and T cell and B cell infiltration in active lesions, white matter and meninges. On the other hand, in progressive MS, inflammation is more associated with microglia activation and the presence of meningeal inflammatory aggregates that resemble follicle structures [46]. These follicle-like structures, that are described in around half of the cases of progressive MS [45], are similar to secondary B-cell follicles with germinal centres [77] and contain the elements needed to stimulate B-cell proliferation and survival. In addition, it was suggested they might be related to intrathecal antibody production in MS patients.

The presence of EBV in the MS brain is controversial [42]. Some reports described signs of latent EBV infection in MS brains, or even that the majority of B cells in MS brains or meningeal follicle-like structures were EBV-positive cells [75], [78], and [88], while others found none, or only a small proportion of EBV-positive cells in the brain of MS patients [60], [74], and [94].

These discrepancies might be due to the sensitivity and specificity of the detection methods employed as well as to differences in the experimental design, interpretation, tissue selection and processing [42] and [61]. Finally, if the presence of EBV-infected B cells in the MS brain were confirmed, the role of the meningeal follicle-like structures in promoting the intracerebral expansion and maturation of B cells would be similar to that of the germinal centres located in the tonsils [85].

3.3. Cellular immune response to EBV in MS patients

MS may be the result of EBV capacity to establish a persistent infection in the brain, and this capacity would be a consequence of a deficient control of EBV infection in persons predisposed to developing the disease, allowing EBV infected B cells to accumulate in the CNS [61].

Deficiency of CD8 + effector memory T cells has been reported in MS patients [63] and it might denote a potential impairment of the control of EBV infection. In this line, several studies have investigated T-cell immune response to EBV in MS patients, but the results are conflicting. On the one hand, normal reactivity or increased reactivity has been reported in both clinically isolated syndrome (CIS) and established MS [15], [28], [31], [33], [34], and [44], but on the other hand, a reduced frequency of EBV-specific CD8 + T cells in MS patients has been reported too[62]. The diverse T cell immunity analysis techniques or the heterogeneous groups of MS patients used in these studies are the probable causes of the different results obtained.

Interestingly, a recent work has investigated CD8 + T cell response to EBV latent and lytic antigens in relapsing–remitting MS patients [2]. The results were consistent with an alteration in the immune control of EBV replication depending on the activity of MS. A higher CD8 + T cell specific response to lytic EBV antigens was found in active MS patients while in inactive MS patients, the response was higher to latent EBV antigens. These observations were also found in two untreated MS patients on whom a longitudinal study was performed [2]. These results indicate that active MS in terms of clinical relapses or MRI T2 brain lesions can be explained as the result of an immune attack attempting to control EBV reactivation [2] and [61]. Interestingly, the presence of signs of EBV reactivation in perivascular areas of acute lesions had been previously reported [76].

3.4. EBV and pathogenesis

The role of EBV in the pathogenesis of MS in not clearly understood but several hypotheses have been proposed in an attempt to explain how EBV infection can lead to the development of MS. These hypotheses can fit both the outside-inside and inside-outside models of the disease [81] (Fig 2 and Fig 3).

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Fig. 2 The outside-in model. Autoimmunity provokes MS pathology with inflammation and posterior neurodegeneration and, finally, if the damage has been large enough, neurodegeneration goes on independently of the external autoimmunity.

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Fig. 3 The inside-out model. A primary cause of neurodegeneration leads to a secondary “External” immune reaction that aggravates the neurodegenerative process. Using this model, the EBV participates directly in neurodegeneration and stimulates an autoimmune attack on the CNS.

The least complex hypothesis is the EBV crossreactivity hypothesis [39], which suggests that T cells attack CNS antigens by a cross-reactivity mechanism to previous exposure to EBV antigens, but this seems unlikely. Other hypotheses such as a ‘mistaken self’ centring on alpha B-crystallin [89] might explain some aspects of the pathogenesis [61]. Another possibility, as it has been mentioned before, is that the immune system attack on the CNS may be driven by brain EBV replication [2] and [76] and this attack results in bystander damage to the CNS and posterior degeneration.

Another hypothesis involving EBV postulate that the primary cause of neurodegeneration is influenced by the presence of EBV infected B cells in CNS and the external immune reaction is driven by EBV replication or by EBV-infected B cells presenting CNS antigens [61].

Interestingly, it appears that there is a decrease in the CD8 + T cell response with ageing [2], [61], and [93], which may be associated with the fact that in older patients external inflammatory activity is usually lower and progressive disease seems to be age-dependent [87]. In other words, when the patient becomes older, the inflammatory CD8 + T cell response to EBV reactivation in the CNS is inferior, resulting in lower external inflammatory activity in terms of clinical relapses and MRI T2 lesions, although neurodegeneration goes on. Finally, the patient enters a clinical progressive phase of the disease.

The most characteristic finding in patients with MS is the presence of oligoclonal bands (OCB) in Cerebrospinal fluid (CSF), found in more than 95% of the patients with MS [16]. OCB in CSF are a consequence of clonally expanded B-cells in the CNS [55], and although the pathogenicity of OCB is controversial [21], their presence indicates that the role played by B cells in MS pathogenesis must be important. How primary neurodegeneration can be influenced by the accumulation of EBV infected B-cells in the CNS is far from being elucidated (Fig. Fig. 4).

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Fig. 4 Conceptual Schema showing different proposed roles of EBV infection in the development of MS. The different mechanisms do not have to be necessarily independent of each other. By a deficient control of EBV infection that leads EBV infected B cells to accumulate in the CNS, several possibilities have been proposed. 1: Autoreactive memory B cells produce oligoclonal IgG and pathogenic autoantibodies; myelin and other components are attacked leading to neurodegeneration. 2: Autoreactive T cells cross the BBB, where they are reactivated by EBV-infected B cells presenting CNS antigens, leading to a cytotoxic effect against the CNS. 3: An anti EBV CD8 response against lytic EBV proteins causes bystander CNS damage. In this case the antibody production of the plasma cells does not necessarily have to be pathogenic. 4: EBV-infected B-Cells trigger the direct role of HERV-W in inflammation and neurodegeneration.

Another interesting point that needs to be resolved is the relationship between EBV and human endogenous retroviruses (HERVs) [3] and [80]. HERVs are thought to be vestiges of past germ-cell infections in human ancestors [43]. Most HERVs entered in the human genome between 10 and 50 million years ago during primate evolution and around 8% of the human genome has a retroviral origin.

The most consistent association of HERVs with MS is the implication of two members of the W family of human endogenous retroviruses (HERV-W), multiple sclerosis associated retrovirus (MSRV) and an element located on chromosome 7q21–22 that is not able to form virus-like particles, named syncytin-1 [3]. Expression of HERV-W in microglial and endothelial cells of MS brain lesions have already been reported [4], [47], and [67] and the association of MS with the presence of HERV-W particles in both blood and spinal fluid have been confirmed as well [5]. Therefore, their presence and transcription load have been correlated with MS clinical evolution and prognosis [25] and [66].

These particles have shown potential pathogenicity towards immune and glial cells, with proinflammatory properties, provoking neurotoxic effects and neuroinflammation, causing cytotoxicity to oligodendrocytes and impairing remyelination in both in vitro and animal models [4], [22], [37], [65], [70], and [73].

The potential relation between EBV and HERVs in MS pathogenesis is an interesting issue that is being studied. Different in vitro [49] and in vivo [48] (in blood) studies indicated the possibility of HERV-W activation by EBV infection.

4. Therapeutic strategies

There are several biases in the study design of MS treatments using animal models, mainly experimental autoimmune encephalomyelitis, probably because the pathological alterations seen in the progressive phases of the disease are not well represented in these animal models, in this case the potential role of EBV infection. So it's hard to translate the potential therapeutic strategies to a prior animal model studies [86].

As it has been said before, EBV persists for the lifetime of the host in infected B-cell and these cells are directly or indirectly involved in the development of the disease.

Current treatments approved for RRMS seem to have no effect or limited effects on B-cells located in the CNS, since they have no impact on OCB and Intrathecal IgG synthesis [10]. However, natalizumab might be the exception, as this treatment can reduce intrathecal secretion in MS patients [50]. The exact mechanism underlying this effect is not clearly understood but natalizumab impacts on B-cell function with an inhibitory effect [91].

New treatment strategies are needed to directly affect EBV infection. Nucleoside analogues are particularly effective against Herpes simplex virus 1 and 2 [92]. Antiviral therapy directed against EBV has been principally studied in EBV-related lymphoproliferative disorders but it was found to be generally ineffective [20], probably because the virus was in a latent phase of its cycle.

As B-cells are the viral reservoir of EBV in the host, it seems reasonable that anti-B cell strategies would serve as a good anti-EBV therapy in the absence of anything else. The CD20 antigen is expressed in different stages of B-cell differentiation but is absent in the earlier stages and plasma cells [21]. CD20 is a reasonably good target if the objective of B-cell depletion is being sought. CD19 would be another possible target to act against during the earlier stages of B-cell differentiation, as would be BAFF-R [90]. Several anti-CD20 monoclonal antibodies are being studied in MS: Rituximab (chimeric), Ocrelizumab (humanized) and Ofatumumab (completely humanized). The efficacy of these treatments in terms of relapses and MRI inflammatory activity is quite promising, and recently, it has been announced the efficacy of ocrelizumab in primary progresive MS [14], [35], and [79]. Independently of the safety issues, there is an important concern about these treatments and their potential efficacy in progressive phases of the disease and also their effect on CNS B-cell and OCB depletion [10]. Monoclonal antibodies are heavy molecules that can barely pass the BBB, which limits their action in B-cells of the CNS. For this reason, monoclonal antibodies must be delivered intrathecally if an effect on B-cells located in the CNS is intended.

Recently, it has been reported that an EBV-specific adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8 + T cells directed against viral latent proteins was successful in treating a patient with secondary progressive MS in whom clinical improvement with a reduction of intrathecal immunoglobulin production was observed [64]. Nevertheless, more studies with more patients and long-term follow-up are necessary to study this treatment strategy.

Additionally, new treatments related to the potential role of HERVs in MS pathogenesis are being developed. In this context, the use of antiretroviral drugs, particularly Raltegravir [51], and a humanized monoclonal antibody (GNbAC1) targeting MSRV-Env protein [19] are being studied and considered as possible treatments for MS. Both treatments are still in the preliminary phases of development.

5. Conclusions

MS is probably a consequence of an immune mediated process secondary to a complex interaction of environmental factors in genetically predisposed individuals. EBV infection seems to be widely accepted as one of the risk factors.

The association between MS and EBV infection may be a causal relationship (Table 1). In fact, EBV persists for the lifetime of the host in B-cells and can modulate their function; the role of B-cells in the pathogenesis of MS is coming to be considered as essential and it seems to be strongly associated with the progressive and neurodegenerative component of the disease.

Table 1 Table presenting pros and cons list regarding the role of EBV in MS.

Pros
The infection with EBV is linked not only with autoimmune diseases but also with a variety of human tumours ([59]; [96]).
EBV infection persists for the lifetime of the host in B-cells and can modulate their function [85].
The role of B-cells in the pathogenesis of MS is coming to be considered as essential and it seems to be strongly associated with the progressive and neurodegenerative component of MS [21].
Previous infection with EBV, demonstrated by anti-EBNA IgG seropositivity or previous infectious mononucleosis, are one of the most strongly linked environmental risk factors for developing MS [9].
There is some evidence of MS results from a deficient control of EBV infection that leads EBV infected B cells to accumulate in the CNS ([63]).
 
Cons
The divergences between studies [42].
EBV infection is very common, most of the adult population is infected but the vast majority does not develop MS.
The exact mechanism of how EBV might be involved in the pathogenesis of the disease is not completely understood [61].

The exact mechanism of how EBV might be involved in the pathogenesis of the disease is not completely understood, although it seems possible that MS results from a deficient control of EBV infection that leads EBV infected B cells to accumulate in the CNS. EBV infected B cells might have a direct role in inflammation and neurodegeneration and/or they can reactivate autoreactive T cells to contribute to the pathological process, although an indirect mechanism of pathogenesis by activation of HERV-W has also been postulated. Another interesting possibility that has been reported is that activity in terms of clinical relapses and MRI lesions are due to attempts of the immune system to control EBV reactivation.

Anti-B cell treatments appear to be a good strategy for anti-EBV therapy and furthermore, several anti-CD20 monoclonal antibodies are being studied in MS with good preliminary signs of efficacy. Other treatments, such as EBV-specific adoptive immunotherapy or anti HERV-W therapies are still in a very early phase of development to draw conclusions about their effectiveness.

Declaration of conflicting interests

Dr. Fernández Menéndez reports non-financial support from Biogen Idec and Teva, and personal fees from UCB, outside the submitted work. Dr. Fernández-Morán and Dr. Pérez-Álvarez report no disclosures. Dr. Fernández-Vega receives research support from Basque Country Foundation for Health Innovation and Research. Dr. Villafani-Echazú reports receipt of lecture fees from Bayer-Schering, Biogen Idec, Merck Seron, Novartis, UCB, Almirall and Teva.

Acknowledgement

The authors are grateful to Mr. Nicholas Aire BSc and Xabier Lekube for English-language corrections and Beatfilms (Oviedo, Spain) for figures corrections.

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Footnotes

a Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain

b Department of Neuropaediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain

c Pathology department (Neuropathology division), Hospital Universitario Araba, Álava, Spain

Corresponding author at: Servicio de Neurología, Hospital Universitario Central de Asturias, Avenida de Roma S/N, 33011, Spain.


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