Epstein-Barr virus and disease activity in multiple sclerosis

OBJECTIVES: To study in relapsing-remitting (RR) multiple sclerosis (MS) whether exacerbations and brain activity as measured by magnetic resonance imaging (MRI) are associated with plasma levels of anti-Epstein Barr (EBV) antibodies and EBV DNA. METHODS: This was a prospective study with 73 RR MS patients followed for an average of 1.7 years with frequent neurological examination and blood sampling. Antibodies to various EBV proteins were measured by ELISA and plasma EBV DNA was measured by PCR. RESULTS: All MS patients had IgG antibodies to EBV (viral capsid antigen (VCA) and/or EBV nuclear antigen (EBNA)), irrespective whether samples were taken at stable disease or exacerbation. A significantly elevated percentage of the patients (48%) had antibodies against EBV antigens (early antigen, EA) that indicate active viral replication, compared with the age matched healthy controls (25%). Antibodies against a control herpesvirus, cytomegalovirus, were similar between the two groups. The percentage of EA positive individuals and EA titres did not differ between stable disease or exacerbation. Anti-VCA IgM was positive in three cases, unrelated to disease activity. Using a highly sensitive PCR on 51 samples taken at exacerbation visits, only three patients were found to have one timepoint with viraemia, and this viraemia was unrelated to disease activity. Of special note was the fact that anti-EA seropositive patients remained seropositive during follow up, with stable titres over time. We hypothesised that these patients may constitute a subgroup with higher disease activity, due to the triggering effect of a chronic attempt of the virus to reactivate. The EA positive group did not differ from the EA negative with respect to clinical disease activity or other characteristics. However, in the EA positive group, analysis with gadolinium enhanced MRI indicated more MRI disease activity. CONCLUSIONS: There was no evidence for increased clinical disease activity in the subgroup of MS patients with serological signs of EBV reactivation. However, the observation that chronic EBV reactivation may be associated with increased inflammatory activity as assessed by gadolinium enhanced MRI lesions should be reproduced in a larger and independent dataset.     

Quantitative PCR for Epstein-Barr virus DNA and RNA in multiple sclerosis

BACKGROUND: Epstein-Barr virus (EBV) is associated with MS, but it is not clear whether EBV plays a role in the pathogenesis of MS. HYPOTHESIS: We hypothesized that the immune control of EBV might be defective in MS, and that reactivation of EBV might drive the immune response in MS. METHODS: We collected blood from controls and patients with MS, and measured the amounts of EBV DNA and RNA using quantitative PCR. RESULTS: We found that EBV DNA and RNA were frequently detectable in peripheral blood leukocytes from both patients with MS and normal controls. There was no significant difference between patients with MS or controls. Paired samples from a small number of subjects suggest that EBV DNA may increase before and during clinical relapse. CONCLUSIONS: We conclude that the immune control of EBV infection is similar in MS and controls, and that reactivation of EBV may correlate with MS disease activity.     

Borna disease virus and psychiatry.

Borna disease virus (BDV), a noncytolytic neurotropic nonsegmented negative-stranded RNA virus with a wide geographic distribution, infects several vertebrate animal species and causes an immune-mediated central nervous system (CNS) disease with various manifestations, depending on both host and viral factors. In animal infections, BDV can persist in the CNS and induce alterations in brain cell functions, neurodevelopmental abnormalities and behavioral disturbances. An association between BDV and psychiatric disorders (essentially schizophrenia and affective disorders) has been suggested by some serologic and molecular studies but further investigations are required to substantiate the possible contribution of this virus to the pathogenesis of these disorders.     

Epstein-barr virus in multiple sclerosis

Recent seroepidemiologic and pathologic evidence suggests that prior infection with Epstein-Barr virus (EBV) may be necessary for the development of multiple sclerosis (MS). EBV infects more than 90% of all humans, most of whom remain healthy. In contrast, 99% of MS patients have evidence of prior infection with EBV. EBV infects resting B lymphocytes, immortalizing them into long-lived memory B cells that survive largely undetected by the immune system in the peripheral circulation. MS patients show elevated titers to EBV years before developing any neurologic symptoms. Postmortem pathologic analysis of brains of patients with MS has revealed diffuse EBV-associated B-cell dysregulation in all forms of MS. Theories of pathogenesis of EBV in MS include antigenic mimicry, immortalization of B-cell clones, and cytotoxic T-cell dysfunction against virally infected B cells. This article reviews the existing evidence of the relationship between EBV and MS and considers the therapeutic implication of this evidence.     

重庆地区精神疾病患者Borna病病毒感染的初步报道

目的　研究中国人中是否存在Borna病病毒 (BDV)感染 ,以及探讨BDV感染是否与人类精神疾病有关。方法　收集精神疾病患者 80例 (精神分裂症 5 0例 ,情感性精神障碍 30例 )和健康献血者标本 6 0名。每例采血 10ml,分离外周血单个核细胞 ,提取RNA ;用BDV P2 4基因特异性内外引物进行套式逆转录聚合酶链反应 ,扩增产物经琼脂糖凝胶电泳和特异性探针的Southern印迹杂交检测。结果　 5 0例精神分裂症患者中检出BDV P2 4基因片段 5例 ( 10 % ) ,6 0名健康对照者均未检出 ,两者间的差异有显著性 (P <0 0 5 ) ;30例情感性精神障碍患者中检出 1例 ( 3% ) ,与健康对照者的差异无显著性。结论　重庆地区精神疾病患者中存在BDV感染 ;精神分裂症与BDV感染可能有一定关系     

Precision medicine in chronic disease management: The multiple sclerosis BioScreen

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine—that is, the application of information technology to medicine—has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real‐time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence‐based medicine, support shared decision making, and ultimately lead to improved outcomes. Ann Neurol 2014;76:633–642     

博尔纳病毒感染与精神分裂症的相关研究

目的 探讨博尔纳病毒(Borna disease virus,BDV)感染与精神分裂症的相关性,分析感染BDV的精神分裂症患者临床特征.方法 采用荧光定量巢式逆转录聚合酶链式反应方法检测86例精神分裂症患者(患者组)和84名健康体检者(对照组)外周血单个核细胞中BDVp24和BDVp40基因片段,以β-肌动蛋白作为内参照,将BDVp24和BDVp40基因片段均为阳性的标本基因进行测序分析,外周血进行抗BDV抗体滴度测定,对患者的精神症状采用PANSS进行量化评分,并总结阳性患者的临床特征.结果 86例精神分裂症患者中外周血标本BDV p24基因片段阳性检出率11.6％ (10/86),BDVp40基因片段检出率13.4％ (12/86),拷贝数均＞102 kb/μl.对照组检测BDVp24、BDVp40基因片段均为阴性,两组阳性率比较差异有统计学意义(x2=9.26,P＜0.05).对BDV p24和BDVp40基因片段均为阳性的标本测序后,与马源的BDV病毒株亲缘关系最近.阳性标本的精神分裂症患者精神症状主要以幻觉、妄想等阳性症状为主,PANSS量表评分均＞40分.结论 精神分裂症发病与BDV感染有一定的相关性,是否是唯一的相关性还有待进一步研究,BDV感染的精神分裂症患者主要以阳性精神症状为主.     

Epstein-Barr virus genotypes in multiple sclerosis

Background –  Multiple sclerosis (MS) is associated with Epstein–Barr virus (EBV) infection, but the relationship between the virus and the disease is not clear. As many different types of EBV exist, it is possible that MS is caused by one particular type of EBV.
Objectives –  The aim of this study was to determine whether MS is associated with a particular genotype of EBV.
Materials and methods –  We collected blood from MS patients and controls, amplified and sequenced the latent membrane protein-1 (LMP-1) gene, and compared the groups.
Results –  We found a variety of LMP-1 sequences in both MS and controls, with no significant differences between the groups.
Conclusion –  We conclude that MS is not associated with a particular genotype of EBV.     

Epstein-Barr virus antibodies in multiple sclerosis

Serum antibody titers to Epstein-Barr virus (EBV), an agent that persists in a latent form after the initial infection, were determined in 157 patients with multiple sclerosis and in 81 control subjects. Two patients (1.3%) and five control subjects (6.2%) lacked antibodies to EBV. In the subjects with antibodies, the prevalence of high titers (greater than or equal to 1:160) was significantly greater in patients, 69 (44.5%), than in control subjects, 22 (28.9%). The geometric mean titer of antibodies to EBV was significantly higher in patients, 107.0, than in control subjects, 77.1. There was no association between antibody titers and duration or activity of the disease. These findings further support the contention that patients with multiple sclerosis have a general aberration of the immunological system.     

Epstein-Barr virus and multiple sclerosis

This review of the considerable evidence linking Epstein-Barr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a dose-response relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified.     

Epstein-Barr virus and multiple sclerosis

Epstein-Barr virus (EBV) is one of the most common and successful human viruses, infecting more than 90% of the world’s adult population. Despite its strong tumorigenic potential, most virus carriers remain healthy due to maintenance of a delicate balance between the host’s immune system, which limits production of virus particles, and the virus, which persists for the duration of the host’s life. New data show that this balance is altered on a subtle level in patients with multiple sclerosis (MS) and other autoimmune diseases who show enhanced as well as less restricted T-cell and antibody responses to EBV-encoded antigens. Such quantitatively and qualitatively distinct immune responses and the virus’ unique ability to immortalize B cells as well as to continuously stimulate strong T-cell responses during persistent infection suggest a possible role for EBV in the initiation and progression of symptomatic autoimmunity. We hypothesize that EBV promotes both autoimmune B and T-cell responses. EBV gene products might stimulate cross-reactive autoimmune B cells directly or increase their survival after infection. In addition, autoimmune T cells could be maintained via molecular mimicry between autoantigens and EBV antigens, and via the Th1 polarizing cytokine milieu of protective antiviral T-cell immunity. A better understanding of how EBV and EBV-specific immune control mechanisms interfere with the evolution of autoimmunity may generate a rationale for novel EBV-targeting therapeutic strategies aimed at the prevention and more efficient treatment of autoimmune diseases.