Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. However, the potential interaction between EBV and vitamin D, if any, still remains a matter of debate. Despite lack of association between seasonal variation of infectious mononucleosis and risk for MS, the mean serum OH D level was significantly lower in infectious mononucleosis patients than healthy controls, suggesting a potential interplay between infectious mononucleosis and vitamin D Maghzi et al.
This finding corroborated previous identical reports of a positive effect of vitamin D 3 supplementation in the ability to reduce anit-EBNA-1 levels, but no effect on other EBV markers VCA or other common viruses like cytomegalovirus or varicella zoster virus Najafipoor et al. Altogether, these findings suggest a complex interaction between EBV, vitamin D, and genetic factors that should be considered in future epidemiological studies.
Smoking is becoming a well-established risk factor for MS development and it is further associated with disease progression measured as increased disability and worse MRI outcomes Zivadinov et al. In MS patients, current smoking status and cumulative tobacco consumption are associated with high levels of EBV-specific antibodies Nielsen et al. Smoking induces epigenetic changes such as citrullination, which has been implicated in the conversion of destructive MOG processing to the productive processing by EBV-infected B-cells Morandi et al.
The interaction between smoking and EBV may differ based on the heterogeneity of the study population Salzer et al. For instance, a positive interaction between smoking and anti-EBNA-1 antibody titer was only observed in MS subjects older than 26 years old Salzer et al.
For clinically isolated syndrome CIS patients, anti-EBNA-1 antibody and cotinine level indicator of tobacco use were not associated with conversion to clinically definite MS or further disease progression Munger et al. Other studies suggest that infectious mononucleosis and smoking seem to have independent effects on MS disease outcome Bjornevik et al.
These findings point towards a complex interaction between smoking and EBV that is indirect and possibly mediated by other variables. Therefore, the development of MS should not be attributed to any single factor, but to the combined effects of genetic and environmental factors. The joint impact of all 5 key risk factors, measured as the summary population attributable fraction, accounted for The paper also suggested that adding anti-EBNA-1 titer into this multifactorial model would further increase the summary population attributable fraction beyond The contribution of EBV infection to MS disease progression in early phases of MS is subject to contradictory findings, with some studies suggesting contribution to conversion to clinically definite MS and some not.
A country-wide study of the enrolled military personnel demonstrated that among the 10 initially EBV-negative soldiers who later developed MS during their time in the service, they did seroconvert before their disease onset Levin et al.
A large, multicenter study followed CIS patients for 4. Among the many factors that were investigated, they found that only increasing T2 lesion number, earlier age of onset, and oligoclonal bands positivity were strong prognostic markers for conversion to clinically definite MS. A follow-up study from the same CIS sample using a more detailed testing revealed that only 1 out of the 49 originally determined EBV-negative patients was truly seronegative Dobson et al.
They argued that it was extremely rare for an EBV seronegative individual to develop MS, and suggested that future serological studies should consider testing antibodies across multiple antigens, or using more than one independent antibody screening assays Dobson et al.
After the MS onset, antibody responses toward EBV antigens correlate with disease activity and disease progression Christensen, Recent serological investigations have shown that intermittent EBV reactivation during the active disease course may occur in parallel with exacerbations in RRMS patients. For the RRMS subgroup, the increased serum level of anti-EBNA-1 antibody corresponded with significantly higher number of contrast enhancing lesions and disability accumulation over a five-year period Farrell et al.
Another study presented with opposite findings: it was shown that anti-EA IgG level remained stable within each of the 73 RRMS patient who were followed for an average of 1. They attributed the discrepancy between the two studies to technical differences and the lack of IgA serology Buljevac et al. However, there were no association between changes in EBV antibody titer and disability progression during the 5-year follow-up Farrell et al.
On the other hand, numbers of MRI studies presented evidences that supported the association between EBV antibody and MS progression, which will be discussed in details later in this review. Therefore, EBV reactivation can be a useful marker for predicting clinical disease activity in RRMS patients, but its significance in monitoring disease progression in progressive MS patients requires future investigation.
The association of EBV and MS has been additionally documented and corroborated with MRI, the most sensitive diagnostic tool for detecting MS development and for monitoring disease progression Zivadinov et al. After the first demyelinating event, CIS patients with higher anti-VCA IgG antibody titer demonstrated a greater number of contrast enhancing and T2 lesions, and increased brain atrophy at 2-year follow-up Horakova et al.
Patients with enhanced anti-EBV antibody response also developed more contrast enhancing lesions, greater T2 lesion volume on MRI, and higher disability score Farrell et al. Therefore, EBV infection may have triggered innate immune responses, such as cytokine production which further increased the inflammation within the MS lesions. In addition to the possible relationship with neuroinflammatory responses discussed above, recent studies have demonstrated that EBV antibody activity could be linked to neurodegeneration in MS patients.
The MS patients within the highest anti-VCA quartile displayed significantly increased T2 lesion volume, T1 lesion number and volume, and greater white matter loss than patients in the lower quartile Zivadinov et al. The positive correlation between anti-VCA antibody and cortical atrophy was most prominently observed among RRMS subjects, but not in progressive MS subtypes, possibly due to the small sample size Zivadinov et al.
Moreover, the significant difference in MRI outcomes between anti-VCA quartile groups was MS-specific, as it was not observed in the healthy controls or patients with other neurologic diseases Zivadinov et al. Findings from the CIS population were rather controversial. The correlation between humoral response to EBV and MRI disease activity supported the involvement of EBV-infected B-cells in grey matter and cortical pathology that can be seen early in the disease. Altogether, these findings reinforced the association between EBV and MS disease progression, and suggests that brain atrophy measurement can be a useful MRI metric in clinical routines Zivadinov et al.
The discovery of tertiary lymphoid follicles within the meninges of progressive MS patients have elicited new research interests, and several studies reported that these structures might be associated with greater extent of cortical atrophy and higher clinical disability Magliozzi et al.
Since memory B-cells act as life-long repertoire for latent EBV infection, the aggregation of B-cells and T-cells within tertiary lymphoid follicles may indicate possible site of interaction following virus infection Jakimovski et al.
Interestingly, only one healthy control from this study presented with a focal leptomeningeal contrast enhancement loci Absinta et al. They additionally found that the presence of leptomeningeal contrast enhancement was associated with nearby cortical demyelination, and was accompanied by significantly smaller brain volume and white matter volume in MS patients Absinta et al.
Similarly, leptomeningeal contrast enhancement detected in RRMS patients was associated with reduced thickness of surrounding cortical tissues Bergsland et al. A longitudinal study of 50 MS patients 27 RRMS and 23 SPMS also demonstrated that leptomeningeal contrast enhancement positive patients had significantly greater percentage of total grey matter and cortical volume loss, as well as greater increase in ventricular CSF volume at the 5-year time point than patients without leptomeningeal contrast enhancement Zivadinov et al.
The association between leptomeningeal contrast enhancement and grey matter atrophy was supported by a similar study, which additionally found that leptomeningeal contrast enhancement correlated with longer disease duration and higher disability Makshakov et al. Observation from 7T MRI study revealed that leptomeningeal contrast enhancement occurred in higher frequency in MS patients than prior studies with 3T MRI, which was more closely resembling histological findings Harrison et al.
Brain tissue from a mice EAE model showed a higher density of immune cells localized in the meninges, corresponding to the areas of leptomeningeal contrast enhancement Pol et al. A consensus MRI guideline for measuring leptomeningeal contrast enhancement has yet to be established, but recent studies have attempted to improve this imaging technique for translation into clinical routine Zivadinov et al. The study of leptomeningeal contrast enhancement is especially important for understanding the mechanism underlying the observed positive correlation between EBV antibody titer and cortical atrophy in longitudinal studies.
With further development of a standardized protocol, leptomeningeal contrast enhancement can potentially be useful for detecting EBV-related brain pathology in clinical routine examination and contribute to identification of new therapeutic targets. The discovery of tertiary lymphoid follicles within meninges of MS brain containing large proportion of EBV-activated B-cells and T-cells might suggest an alternative route of entry for lymphocytes into the CNS region.
Self-antigen presentation by EBV-immortalized B-cells may be important for the reactivation of T-cells occurring in the subarachnoid space Louveau et al. Evidence from EAE studies suggested that T-cells caused the development of meningeal infiltrates and local invasion of the parenchyma, events that were tightly associated with disease onset Kivisakk et al.
This is supported by evidence from another EAE study which showed that at 10 days-post induction, higher gadolinium signal intensity was detected in superior sagittal sinus major draining vein for the anterior cerebral cortex of EAE mice brain than in healthy mice brain Pol et al.
The enhanced signal intensity was also associated with higher density of immune cells Pol et al. It was proposed that under pathological conditions, antigen-specific T-cells leave the peripheral blood stream and enter into the CSF at choroid plexus sites, a place ideal for their re-stimulation by local myeloid antigen presenting cells Ransohoff and Engelhardt, These T-cells then release cytokines that increase the permeability of blood-brain barrier to other peripheral lymphocytes, thus enabling them to enter the brain parenchyma and cause further damage Ransohoff and Engelhardt, Increasing evidence now suggests that bidirectional trafficking of B-cells can occur between the CNS and cervical lymph nodes via the meningeal lymphatic vessels.
The meninges and tertiary lymphoid follicles are important sites for lymphocyte affinity maturation, and their functions as entry points for autoreactive T-cells to the CNS. The described rudimentary lymphatic vessel have been additionally shown in vivo in higher level primates and in humans Absinta et al.
In addition to EBV, other viral agents such as human endogenous retroviruses are thought to be involved in MS onset Tao et al. An initial large-scale, comparative cohort study suggested that HIV was associated with a lower risk for MS, possibly either due to the immune-suppressive state induced by the virus itself, or by the effects of HIV-associated antiretroviral therapies Gold et al.
This study followed up 21, HIV-positive patients and 5 million controls between the years of to , and showed that the rate of developing MS in people with HIV was relative lower than people without Gold et al. A potential pathological cascade triggered by syncytin-1 induction is the release of soluble factors by astrocytes, such as inducible nitric oxide synthase and other redox reactants, which might lead to oligodendrocyte damage and cell death Antony et al.
In vivo mice model also supported the role of syncytin-1 in demyelination and impaired neurological functions, both which can be rescued by antioxidant ferulic acid Antony et al.
This was achieved by the env protein activating TLR4 on OPCs, which induced nitric oxide synthase levels and increased production of pro-inflammatory cytokines Kremer et al. All 75 MS brain samples acquired from two separate studies were positive for MSRV-env protein, with specifically high expression of MSRV in macrophages and microglia near active lesion sites, and lower expression in normal-appearing white matter, while no MSRV expression was detected in healthy controls van Horssen et al.
The clinical effect of disease-modifying therapies may interfere with the rate and extent of the persistent EBV infection. The therapeutic effects of natalizumab may also involve the regulation of humoral responses against EBV. The expression of miR, a microRNA involved in pro-inflammatory cytokine expression, was induced in un-treated MS patients compared to healthy controls Mameli et al. This higher miR expression was positively correlated with anti-EBNA-1 antibody level in MS samples, and it was down-regulated by 6 months of natalizumab treatment Mameli et al.
Another study presented negative findings, by showing that a group of 20 MS patients who were followed for 21 months during natalizumab treatment experienced no significant differences in serum anti-EBNA-1 IgG levels Castellazzi et al. Other disease-modifying therapies have also been shown to exert therapeutic effects on B-cell subpopulations Baker et al.
Rituximab, ocrelizumab, and ofatumumab are anti-CD20 mAbs that induce marked depletion of CDexpressing lymphocytes Greenfield and Hauser, This finding supported the potential of B-cell depleting therapy and the utility of leptomeningeal contrast enhancement in the drug efficacy monitoring. When compared to the complete and long-lasting peripheral B-cell depletion, the depletion of CSF B-cells by intrathecal rituximab treatment was incomplete and only transient Bhargava et al.
The differences between ocrelizumab and rituximab in their ability to deplete CDexpressing B-cells might be the result of the variable extents in triggering complement-dependent and antibody-dependent cellular cytotoxicity Jakimovski et al. In contrast to B-cell depletion therapies, the augmentation of memory B-cells worsens symptoms in MS. Atacicept depletes mature B-cells but upregulates interleukin, which in turn can lead to increased production of memory B-cells and induction of relapse rates in MS patients Ma et al.
Although the long-term risks associated with anti-B-cell therapies have not been fully characterized, these evidence underscore the potential of B-cells as a therapeutic target in MS. The effect of disease-modifying therapies on leptomeningeal contrast enhancement still remains poorly understood. The limited data suggest that intrathecal administration of rituximab did not disrupt tertiary lymphoid follicles in progressive MS patients Bhargava et al.
At month post-treatment, there was no change in the number of leptomeningeal contrast enhancement despite the reduction of peripheral blood B-cell Bhargava et al. Teriflunomide stands out as a unique disease-modifying therapies with less destructive effects on the host immune system. This compound inhibits de novo pyrimidine synthesis pathway and suppresses proliferation of EBV-transformed lymphocytes without affecting cell viability Bar-Or et al.
Studies have shown that treating lymphoblastoid cell line with teriflunomide enhanced expression of the LMP1 and p53 genes, suggesting altered gene expression in latent EBV-infected B-cells, as well as reduced viral replication and increased apoptosis in infected B-cells Table 1 Bilger et al. This therapy was also beneficial based on MRI outcomes, demonstrating reduction of total lesion volume and cortical atrophy Wolinsky et al.
The baseline differences in brain volume and diffusion tensor imaging measurements between RRMS and matched-healthy controls diminished at month after patients initiated teriflunomide treatment Zivadinov et al. By comparing anti-EBV antibody titers at baseline and month follow-up, Zivadinov et al. While the majority of disease-modifying therapies that are currently available for MS treatment exert their effects through inducing active depletion of the overall lymphocyte population, teriflunomide may possess a unique mechanism of action which limits the involvement of autoreactive T-cells and EBV-infected B-cells in neuroinflammation.
Interestingly, anti-retroviral therapies have shown considerable benefits for treating MS patients Drosu et al. In the previously discussed comparative cohort HIV study, the lower MS rate among HIV-positive subjects suggested possible protective effects exerted by antiretroviral medications against MS development Gold et al.
This was further supported by a recent case report of a year-old female student who recovered from a MS exacerbation and remained clinically and MRI stable after being treated with Combivir Drosu et al. As mentioned previously, the env protein also interrupts OPC differentiation by inducing inducible nitric oxide synthase and pro-inflammatory cytokine release Kremer et al. OPC cultures that were incubated with anti-MSRV-env antibody GNbAC1 before env stimulation showed significantly reduced inducible nitric oxide synthase transcript level and restored myelin expression compared to OPC cultures that were incubated with buffer Kremer et al.
Despite the favorable safety profile of the drug, the interpretation of the efficacy data from this phase 2a trial was limited and warranted a subsequent phase 2b or phase 3 trial with larger cohort and longer duration period Curtin et al.
Traditional disease-modifying therapies are also associated with changes in MSRV-env expression Mameli et al. These findings suggest that measuring MSRV level in MS patients under therapy can be important for monitoring disease progression and treatment efficacy Arru et al. Create a personalised ads profile. Select personalised ads. Apply market research to generate audience insights.
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Do You Have Mono? How It's Diagnosed. Could It Be Mono? Symptoms to Look For. Vascular, toxic, infectious, genetic and immune hypotheses have been repeatedly invoked over the decades, with the advent of new evidence and at times, even scientific fashion. On the surface, this seems simple, and yet each of these statements raises fresh uncertainties. Firstly, is MS a disease or a symptom complex, caused by multiple aetiologies?
The pathology has suggested to some that there is a heterogeneity in lesion types, sharing some common features, but with some variances possibly pointing to differing aetiopathogenetic mechanisms. Secondly, widely varying environmental factors have been found to be associated with the disease, ranging from infectious agents to Vitamin D deficiency and smoking. In this respect it would seem that the debate revolves more around whether the immune pathogenesis is primary, or acts secondarily to some other trigger.
Finally, there is widespread acceptance of the underlying genetic susceptibility. Convincing studies, based on studies of compatibility associations, complex families, adopted and natural siblings, twins, and maternal and paternal transmission, all point to a familial predisposition. Therefore, by finding no evidence for genetic, epigenetic or transcriptome differences to explain MS disease discordance, this study strongly suggests the role of other environmental?
How to select from, or to tie genetic, environmental and immunological theories together, is the biggest challenge facing MS researchers today. Although much has been written about each of these areas, recent studies have again highlighted the role of infectious agents in causing the disease. In a sense this is ironic, because the infectious theory was first invoked in the late 19th Century, during the dawn of the great discoveries in bacteriology. Later, the striking observations on the incidence of MS in migrating communities led to a revival in the search for an infectious agent.
These studies showed strong evidence for exposure to an environmental agent infectious by the age of about 15 years. Simple clinical studies almost two decades ago have also revealed a strong association between the onset of clinical infectious disease, especially respiratory, and MS attacks.
These have included the measles virus, 15 parainfluenza virus, human herpesvirus type 6 HHV-6 , EBV, canine distemper virus and retroviruses. Indeed, it appears that with every new virus discovery, there are reports that attempt to link this novel agent with chronic neurological diseases in which viruses have been thought to be involved, i. XMRV and chronic fatigue syndrome. Partial list of viruses and the year they were reported to be associated with MS adapted from R Johnson, The advent of sophisticated molecular and immunological diagnostic methods has again revived a serious search for an infectious agent.
Much has been learned from animal models of viral and helminthic neurological disease, especially Theilers murine encephalomyelitis virus, JHM virus and canine distemper virus. In addition, the so-called hygiene theory of susceptibility to immune disease, suggests that a vigorous early immune response to infections is necessary to protect against the development of autoimmune disease. Improved sanitation interfering with this immune development has led to an increase in the incidence of immune-disease in both developed and developing countries.
Specifically, it has been shown that patients with helminthic infections may have immunoregulatory molecules acting on dendritic and B-cells, to lower the incidence and severity of MS attacks. Patients with MS also have higher titres than controls. Other corroborative evidence shows that EBV DNA is higher in patients during relapses, that sera taken from patients prior to the onset of their disease, showed much higher titres than the normal population, 22 and that patients with MS are more likely to have had infectious mononucleosis.
Many years ago, in patients with active MS, it was shown that circulating lymphocytes tended to transform spontaneously under EBV induction, and MS patients have a higher level of circulating EBV-specific cytotoxic T-cells than the general population. In Denmark, a cluster of MS cases following a community outbreak of infectious mononucleosis also supports this association. The serological differences between MS patients and the general population are even more striking in the paediatric population.
There is also evidence that a higher number of antibodies in the cerebrospinal fluid CSF of MS patients recognize EBV antigen, than other viruses, and that there is a high level of intrathecal synthesis of these antibodies.
In this regard, much has been discussed about the finding of extensive infection of MS patient B-cells by EBV, and the finding of lymphoid follicles in the meninges filled with EBV antigen 8 see below. One of the hallmarks of MS, the oligoclonal banding OCB pattern in the CSF, has not been shown to be specific for most of the putative infectious agents, in contrast to their specificity in other known virological diseases.
There is also a suggestion that an increase in anti-EBV antibodies is associated with grey-matter atrophy in MS patients. One may therefore ask, with all this evidence, why there still is hesitancy in labelling EBV as the causative agent of MS? In fact, there are many arguments that show this strong association may be just that, and not a cause. The very high infection rates by EBV in the general population render the very slight increase in incidence in MS less convincing. A very real possibility exists that patients genetically predisposed to MS, may also be similarly more susceptible to EBV infection, or indeed other infections.
The well-described phenomenon of MS attacks following respiratory infections may very well represent two parallel, but separate processes, with MS taking longer to manifest clinically.
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