Epigenetic Modifications and Therapy in Multiple Sclerosis

Breakthroughs in genetic studies, like whole human genome sequencing and genome-wide association studies (GWAS), have richened our knowledge of etiopathology of autoimmune diseases (AID) through discovery of genetic patterns. Nonetheless, the precise etiology of autoimmune diseases remains largely unknown. The lack of complete concordance of autoimmune disease in identical twins suggests that non-genetic factors also play a major role in determining disease susceptibility. Although there is no certain definition, epigenetics has been known as heritable alterations in gene function without changes in the nucleotide sequence. DNA methylation, histone modifications, and microRNA-associated gene expression suppression are the central mechanisms for epigenetic regulations. Multiple sclerosis (MS) is a disorder of the central nervous system (CNS), characterized by both inflammatory and neurodegenerative features. Although studies on epigenetic alterations in MS only began in the past decade, a mounting number of surveys suggest that epigenetic changes may be involved in the initiation and development of MS, probably through bridging the effects of environmental risk factors to genetics. Arming with clear understanding of epigenetic dysregulations underpins development of epigenetic therapies. Identifying agents inhibiting the enzymes controlling epigenetic modifications, particularly DNA methyltransferases and histone deacetylases, will be promising therapeutic tool toward MS. In the article underway, it is aimed to go through the recent progresses, attempting to disclose how epigenetics associates with the pathogenesis of MS and how can be used as therapeutic approach.     

MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis

Observational cohort studies are a powerful tool to assess the long-term outcome in chronic diseases. This study design has been utilized in local and regional outcome studies in multiple sclerosis (MS) and has yielded invaluable epidemiological information. The World Wide Web now provides an excellent opportunity for an international, collaborative cohort study of MS outcomes. A web platform--MSBase--has been designed to collect prospective data on patients with MS. It is purely observational, enabling participating neurologists to contribute data on diagnosis, treatment and progress, to review anonymous aggregate data and to benchmark their patient population against other patient subsets or the entire dataset. MSBase facilitates collaborative research by allowing the online creation of investigator-initiated regional, national and international substudies. The registry aims to answer epidemiological questions that can only be addressed by prospective assessments of large patient cohorts. The registry is funded through the independent MSBase Foundation, and governed by an International Scientific Advisory Board. The MSBase Foundation commenced operations in July 2004 and since then, 22 neurologists from 11 countries have joined MSBase and are contributing 2400 patients to the total data pool.     

Environmental risk factors in multiple sclerosis

Objectives –  Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation.
Results –  Findings from studies on seasonality in MS patients' birth, disease onset and exacerbations, as well as apparent temporal trends in incidence and gender ratio support an influential effect of viruses, metabolic and lifestyle factors on MS risk. Epstein–Barr virus, vitamin D status, and smoking are factors that may explain such epidemiological patterns.
Conclusions –  Further epidemiological investigations are encouraged and opportunities to use data from existing cohort studies as well as the design of new studies should be pursued. In particular, the development of new large multicentre population-based case-control studies which incorporate the study of the role of environment and genetics, including epigenetic mechanisms, in determining MS risk is proposed.     

Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon β-1a: a Phase II, multicenter, double-blind, randomized, placebo-controlled trial

Recent studies have demonstrated the immunomodulatory properties of vitamin D, and vitamin D deficiency may be a risk factor for the development of MS. The risk of developing MS has, in fact, been associated with rising latitudes, past exposure to sun and serum vitamin D status. Serum 25-hydroxyvitamin D [25(OH)D] levels have also been associated with relapses and disability progression. The identification of risk factors, such as vitamin D deficiency, in MS may provide an opportunity to improve current treatment strategies, through combination therapy with established MS treatments. Accordingly, vitamin D may play a role in MS therapy. Small clinical studies of vitamin D supplementation in patients with MS have reported positive immunomodulatory effects, reduced relapse rates and a reduction in the number of gadolinium-enhancing lesions. However, large randomized clinical trials of vitamin D supplementation in patients with MS are lacking. SOLAR (Supplementation of VigantOL(?) oil versus placebo as Add-on in patients with relapsing-remitting multiple sclerosis receiving Rebif(?) treatment) is a 96-week, three-arm, multicenter, double-blind, randomized, placebo-controlled, Phase II trial (NCT01285401). SOLAR will evaluate the efficacy of vitamin D(3) as add-on therapy to subcutaneous interferon beta-1a in patients with RRMS. Recruitment began in February 2011 and is aimed to take place over 1 calendar year due to the potential influence of seasonal differences in 25(OH)D levels.     

Infectious agents and multiple sclerosis--are Chlamydia pneumoniae and human herpes virus 6 involved?

A good deal of evidence suggests an infectious component in the development of multiple sclerosis (MS) and, to date, some 20 bacteria and viruses have been associated with the disease. Recent independent sets of studies have implicated the respiratory bacterium Chlamydia pneumoniae and human herpes virus 6 (HHV-6) in the pathogenesis of MS. However, as is the case for essentially all earlier microbial associations, experimental evidence linking either this bacterium or this virus to MS is equivocal. We review the published reports concerning involvement of C. pneumoniae and HHV-6 in MS, and data relating to possession of the APOE epsilon 4 allele, which some studies indicate might influence how these or other pathogens affect disease genesis. Based on the large set of inconsistent observations available and given important new information regarding the neuropathology of MS, we contend that no conclusion is possible at this point regarding the potential role of either C. pneumoniae or HHV-6 in MS. We therefore propose future studies that should clarify whether, and if so how, these and other organisms function in the pathogenesis of this disease.     

Cognitive impairment in multiple sclerosis

BACKGROUNd: Cognitive impairment is increasingly being recognized as a common and disabling symptom of multiple sclerosis (MS) that contributes to poor quality of life in affected patients. Despite the high prevalence of cognitive impairment in MS, cognitive function is not assessed routinely in clinical practice or in clinical trials. The perception that cognitive assessments are costly, time-consuming, complicated, and difficult to administer and interpret has contributed, at least in part, to the failure to incorporate cognitive testing into standard clinical evaluation of patients with MS. Detailed studies of cognitive impairment in MS are rare and guidelines for the assessment of cognitive function in MS are lacking.TREATMENT: How to manage cognitive decline in MS also requires further study. Licensed disease-modifying drug (DMD) treatments for MS reduce brain lesion development, and associations between brain lesions and cognitive performance have been reported, providing a rationale for DMD treatment of MS-associated cognitive impairment. There is some evidence for cognitive benefits of DMDs, but as few pivotal DMD trials included cognitive assessments, the effects of these agents on cognition are not fully understood and more studies are needed.CONCLUSIONS: It is only through further studies that it will be possible to identify patients with, or at risk of, cognitive impairment and to provide appropriate therapy to limit the effects of this potentially devastating symptom.     

Multiple sclerosis: risk factors and their interactions

Multiple sclerosis (MS) is a highly debilitating immune mediated disorder of the central nervous system and represents a substantial burden to the developed world. Despite the recent advances in MS research, which risk factors are implicated and how they contribute to MS pathogenesis is largely unknown. However, in line with older studies investigating the genetic and geographical epidemiology of this complex disease, more recent studies have highlighted how MS arises from a combination of genetic susceptibility and environmental exposures acting from gestation to early adulthood. Vitamin D deficiency, season of birth, Epstein Barr virus infection, and smoking behaviour are strongly implicated and able to influence genetic predisposition to MS. Furthermore, these factors appear to act synergistically and the risk of MS in individuals exposed to more than one factor combines multiplicatively. Current evidence suggests that a large part of MS could be prevented and understanding how and when during life risk factors act will ultimately aid the development of prevention strategies.     

Oligodendrocyte development and the natural history of multiple sclerosis. A new hypothesis for the pathogenesis of the disease

The cause of multiple sclerosis (MS) is not known. This article presents a review of recent studies concerned with the development of oligodendrocytes and suggests that the primary lesion in MS could be related to damage to oligodendroglial progenitor cells. Loss of the capacity to generate oligodendrocytes could alter the course of normal development such that insufficient cells are produced to support growth and replace cells lost through attrition, and as a result, regions of demyelination appear. The site and extent of the primary loss of oligodendroglial precursors would then predetermine the time of onset, site, and severity of the neurologic manifestations of MS. It is suggested that MS is a single, continuous process and that clinical, pathologic, and immunologic findings may be understood as the consequences of the acquired inability to generate sufficient oligodendrocytes to maintain myelin.     

Genomics in multiple sclerosis--current state and future directions

Microarray-based gene expression profiling of large numbers of genes or even the whole genome has only recently become possible. Several studies have employed this technology in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), and although results are promising, microarray-based genomics research is still viewed with skepticism. It is often negatively perceived as a fishing expedition rather than a discovery-oriented effort that takes into account the immense complexity of diseases such as MS. Besides these conceptual concerns, technical reproducibility and the strategies to analyze and interpret the massive amounts of data present problems that can cause considerable variability between studies. In this review, we summarize existing data from different gene expression profiling studies that have been conducted in MS and EAE, discuss potential problems and propose future directions for the use of microarrays in MS.     

The natural history of multiple sclerosis

Studies which have attempted to define the outcome of multiple sclerosis (MS) have methodologic difficulties arising from patient referral biases and the length of follow-up required, which make prospective studies of an inception cohort unrealistic. Means to improve the validity of retrospective natural history studies are suggested. Results of existing series are summarized and compared. Survival is only rarely shortened by MS, but disability to the point of requiring aids for ambulation occurs in 30-70% of patients by 15 years from onset of symptoms. Disagreement as to the percentage of patients who are ultimately bedridden by MS likely arises in large part due to differences in patient ascertainment and follow-up. The need to develop early clinical markers for the patient at high risk for rapid development of major disability is stressed.     

Challenges in randomized controlled trials and emerging multiple sclerosis therapeutics

The remarkable global development of disease-modifying therapies(DMTs) specific for multiple sclerosis(MS) has signifi cantly reduced the frequency of relapse,slowed the progression of disability,and improved the quality of life in patients with MS. With increasing numbers of approved DMTs,neurologists in North America and Europe are able to present multiple treatment options to their patients to achieve a better therapeutic outcome,and in many cases,no evidence of disease activity. MS patients have improved accessibility to various DMTs at no or minimal out-of-pocket cost. The ethical guidelines defi ned by the Edinburgh revision of the Declaration of Helsinki strongly discourage the use of placebo control groups in modern MS clinical trials. The use of an active comparator control group increases the number of participants in each group that is essential to achieve statistical signifi cance,thus further increasing the diffi culty of completing randomized controlled trials(RCTs) for the development of new MS therapies. There is evidence of a high prevalence of MS and a large number of patients in Asia. The belief of the existence of Asian types of MS that are distinct from Western types,and regulatory policies are among the reasons why DMTs are limited in most Asian countries. Lack of access to approved DMTs provides a good opportunity for clinical trials that are designed for the development of new MS therapies. Recently,data from RCTs have demonstrated excellent recruitment of participants and the completion of multi-nation and single-nation MS trials within this region. Recent studies using the Mc Donald MS diagnostic criteria carefully excluded patients with neuromyelitis optica(NMO) and NMO spectrum disorder,and demonstrated that patients with MS in Asia have clinical characteristics and treatment responses similar to those in Western countries.     

The influence of sodium on pathophysiology of multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system, and is an important cause of disability in young adults. In genetically susceptible individuals, several environmental factors may play a partial role in the pathogenesis of MS. Some studies suggests that high-salt diet (>5 g/day) may contribute to the MS and other autoimmune disease development through the induction of pathogenic Th17 cells and pro-inflammatory cytokines in both humans and mice. However, the precise mechanisms of pro-inflammatory effect of sodium chloride intake are not yet explained. The purpose of this review was to discuss the present state of knowledge on the potential role of environmental and dietary factors, particularly sodium chloride on the development and course of MS.     

Multiple Sklerose und Epstein-Barr-Virus

Data from studies of twins and migrants with multiple sclerosis (MS) imply environmental factors in the development of MS. In this respect, increasing evidence indicates that Epstein-Barr virus (EBV) plays a unique role as an infectious risk factor for MS. A nearly 100% seroprevalence of antibodies to EBV in patients with MS, elevated EBV antibody titers years before clinical onset of the disease, and an increased risk for MS after symptomatic primary EBV infection (infectious mononucleosis) suggest an association of MS with a previous infection with EBV. However, the precise mechanisms through which EBV may contribute to MS are still unclear. Currently discussed potential mechanisms are outlined. The notion of a persisting (possibly immunological) change caused during the acute phase of primary EBV infection and subsequently leading to permanently elevated MS risk appears compatible with several aspects of the association found between MS and EBV.     

Transcranial brain sonography findings related to neuropsychological impairment in multiple sclerosis

Cognitive dysfunction, fatigue and mood disorder contribute to the neuropsychological impairment that is common in multiple sclerosis (MS). The present paper reviews application of transcranial brain sonography (TCS) in MS patients and TCS findings related to neuropsychological dysfunction. TCS is a new neuroimaging method displaying tissue echogenicity of the brain through the intact skull. Whereas the cortex can not be discriminated from the subcortical white matter with TCS, subcortical brain structures such as ventricles and basal ganglia can be adequately displayed. Even though TCS proved sensitive and reliable in measuring widths of third and lateral ventricles in a number of neurodegenerative diseases, relatively few TCS studies on MS patients have been reported. Data of these studies suggest a good correlation of cognitive dysfunction and width of third ventricle which can be measured reliably with TCS. Moreover, abnormal TCS findings of basal ganglia were associated with cognitive impairment. However, TCS findings of midbrain structures, basal ganglia and ventricles did not correlate with fatigue or depression in MS patients. TCS has the advantages of low costs, short investigation times and unlimited repeatability. The use of third-ventricle and basalganglia TCS for predicting and monitoring neuropsychological impairment in MS patients, however, needs to be elucidated in further studies.     

Viruses and multiple sclerosis

Multiple sclerosis (MS) is a heterogeneous disease that develops as an interplay between the immune system and environmental stimuli in genetically susceptible individuals. There is increasing evidence that viruses may play a role in MS pathogenesis acting as these environmental triggers. However, it is not known if any single virus is causal, or rather several viruses can act as triggers in disease development. Here, we review the association of different viruses to MS with an emphasis on two herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). These two agents have generated the most impact during recent years as possible co-factors in MS disease development. The strongest argument for association of EBV with MS comes from the link between symptomatic infectious mononucleosis and MS and from seroepidemiological studies. In contrast to EBV, HHV-6 has been found significantly more often in MS plaques than in MS normal appearing white matter or non-MS brains and HHV-6 re-activation has been reported during MS clinical relapses. In this review we also suggest new strategies, including the development of new infectious animal models of MS and antiviral MS clinical trials, to elucidate roles of different viruses in the pathogenesis of this disease. Furthermore, we introduce the idea of using unbiased sequence-independent pathogen discovery methodologies, such as next generation sequencing, to study MS brain tissue or body fluids for detection of known viral sequences or potential novel viral agents.     

The role of intravenous immunoglobulin in the treatment of multiple sclerosis

Intravenous immunoglobulin (IVIG) has several effects on the immune system that could have a beneficial influence on disease processes in multiple sclerosis (MS). Owing to its anti-inflammatory properties, IVIG may be beneficial in the treatment of acute relapses and in prevention of new relapses. By promoting remyelination, IVIG could have a beneficial effect on disability and disease progression. Four double-blind trials in relapsing-remitting MS have demonstrated that IVIG reduces the relapse rate and the number of gadolinium enhancing lesions, and in this respect seems comparable to established therapies in relapsing-remitting MS, i.e. interferon-beta and glatiramer acetate. The doses of IVIG that have been used for treatment in relapsing-remitting have varied 10-fold, and the ideal dosage of IVIG for treating MS still needs to be determined. Three studies have been performed to assess the effect of IVIG on chronic visual impairment or established motor symptoms in MS. None of these trials could confirm that established symptoms in MS can be reversed by IVIG. In secondary progressive MS, a large randomized placebo-controlled trial has recently shown that IVIG is without beneficial effects in this phase of the disease. In conclusion, IVIG is a valuable alternative for treatment of relapsing-remitting MS in patients who do not tolerate or are unwilling to take the approved injectable medications, but additional studies are needed to establish the role of IVIG in the management of multiple sclerosis.     

Natural history of primary progressive multiple sclerosis

The relationship of primary progressive multiple sclerosis (PPMS) to relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) remains unclear. Natural history data from a population-based cohort of patients with PPMS followed for approximately 25 years demonstrate remarkable similarities in the progressive phases of PPMS and SPMS. Immunogenetic and magnetic resonance imaging studies in large numbers of patients also fail to differentiate between the two MS categories. PPMS thus resembles SPMS without the relapses, although the two forms do differ with respect to sex ratio. An unfavourable outcome in PPMS in predicted by rapid early progression of disability and involvement of three or more systems. Natural history studies provide information on likely long-term outcomes and can be used in the design and interpretation of clinical trials in PPMS. The evidence that PPMS is distinct remains weak.     

How factors secreted from astrocytes impact myelin repair

Over a century ago, hypertrophy of astrocytes was noted as a pathology of multiple sclerosis (MS) and was hypothesized to play an important role in this disease, yet the contribution of astrocytes has been largely underemphasized in the pathophysiology of CNS demyelination. Astrocytes perform many homeostatic functions within the developing and adult CNS, including enhancing formation and maintenance of the blood–brain barrier, moderating neuronal connections through the tripartite synapse, and perhaps evenoffering intercellular communication independently of neurons. Although there is a significant body of literature characterizing different types of MS lesions, the inflammatory demyelination in an active MS lesion is accompanied by the presence of macrophages, lymphocytes, and large reactive astrocytes. The astrocyte has long been viewed as a cell that promotes inflammation and demyelination, while also forming the glial scar, thus hindering remyelination and axon growth. Renewed interest in the astrocyte has been brought about by recent studies demonstrating that astrocytes can also function as cellular mediators of CNS myelination by promoting oligodendrocyte progenitor migration, proliferation, and differentiation. Thus, refining our knowledge of astrocytic functions in the regulation of CNS myelination may help us to better understand why remyelination fails in MS. © 2010 Wiley‐Liss, Inc.