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Polman C.H.,University of Amsterdam | Bertolotto A.,Multiple Sclerosis Regional Referral Center | Deisenhammer F.,Innsbruck Medical University | Giovannoni G.,Neuroimmunology Unit | And 10 more authors.
The Lancet Neurology | Year: 2010

The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available interferon-beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts in MS and NAbs to interferon-beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual treatment decisions. In cases of sustained high-titre NAb positivity and/or lack of MxA bioactivity, a switch to a non-interferon-beta therapy should be considered. In patients who are doing poorly clinically, therapy should be switched irrespective of NAb or MxA bioactivity. © 2010 Elsevier Ltd. All rights reserved.


Marta M.,Neuroimmunology Unit | Stridh P.,Neuroimmunology Unit | Becanovic K.,Neuroimmunology Unit | Gillett A.,Neuroimmunology Unit | And 4 more authors.
Genes and Immunity | Year: 2010

A 58 Mb region on rat chromosome 4 known to regulate experimental autoimmune encephalomyelitis (EAE) was genetically dissected. High-resolution linkage analysis in an advanced intercross line (AIL) revealed four quantitative trait loci (QTLs), Eae24-Eae27. Both Eae24 and Eae25 regulated susceptibility and severity phenotypes, whereas Eae26 regulated severity and Eae27 regulated susceptibility. Analyses of the humoral immune response revealed that the levels of serum anti-myelin oligodendrocyte glycoprotein (MOG) immunoglobin G1 (IgG1) antibodies are linked to Eae24 and anti-MOG IgG2b antibodies are linked to both Eae24 and Eae26. We tested the parental DA strain and six recombinant congenic strains that include overlapping fragments of this region in MOG-EAE. Eae24 and Eae25 showed significant protection during the acute phase of EAE, whereas Eae25 and Eae26 significantly modified severity but not susceptibility. The smallest congenic fragment, which carries Eae25 alone, influenced both susceptibility and severity, and protected from the chronic phase of disease. These results support the multiple QTLs identified in the AIL. By demonstrating several QTLs comprising immune-related genes, which potentially interact, we provide a significant step toward elucidation of the polygenically regulated pathogenesis of MOG-EAE and possibly multiple sclerosis (MS), and opportunities for comparative genetics and testing in MS case-control cohorts. © 2010 Macmillan Publishers Limited. All rights reserved.


Lo Sardo F.,Dulbecco Telethon Institute | Lanzuolo C.,Dulbecco Telethon Institute | Lanzuolo C.,CNR Institute of Neuroscience | Comoglio F.,ETH Zurich | And 5 more authors.
PLoS Genetics | Year: 2013

Polycomb group proteins (PcG) exert conserved epigenetic functions that convey maintenance of repressed transcriptional states, via post-translational histone modifications and high order structure formation. During S-phase, in order to preserve cell identity, in addition to DNA information, PcG-chromatin-mediated epigenetic signatures need to be duplicated requiring a tight coordination between PcG proteins and replication programs. However, the interconnection between replication timing control and PcG functions remains unknown. Using Drosophila embryonic cell lines, we find that, while presence of specific PcG complexes and underlying transcription state are not the sole determinants of cellular replication timing, PcG-mediated higher-order structures appear to dictate the timing of replication and maintenance of the silenced state. Using published datasets we show that PRC1, PRC2, and PhoRC complexes differently correlate with replication timing of their targets. In the fully repressed BX-C, loss of function experiments revealed a synergistic role for PcG proteins in the maintenance of replication programs through the mediation of higher-order structures. Accordingly, replication timing analysis performed on two Drosophila cell lines differing for BX-C gene expression states, PcG distribution, and chromatin domain conformation revealed a cell-type-specific replication program that mirrors lineage-specific BX-C higher-order structures. Our work suggests that PcG complexes, by regulating higher-order chromatin structure at their target sites, contribute to the definition and the maintenance of genomic structural domains where genes showing the same epigenetic state replicate at the same time. © 2013 Lo Sardo et al.


Hedstrom A.K.,Karolinska Institutet | Hillert J.,Neuroimmunology Unit | Olsson T.,Neuroimmunology Unit | Alfredsson L.,Karolinska Institutet
JAMA Neurology | Year: 2014

IMPORTANCE: Alcohol consumption may be a modifiable lifestyle factor that affects the risk of developing multiple sclerosis (MS). Results of previous studies have been inconsistent. OBJECTIVE: To investigate the possible association of alcohol consumption with the risk of developing MS and to relate the influence of alcohol to the effect of smoking. DESIGN, SETTING, AND PARTICIPANTS: This report is based on 2 case-control studies: Epidemiological Investigation of Multiple Sclerosis (EIMS) included 745 cases and 1761 controls recruited from April 2005 to June 2011, and Genes and Environment in Multiple Sclerosis (GEMS) recruited 5874 cases and 5246 controls between November 2009 and November 2011. All cases fulfilled the McDonald criteria. Both EIMS and GEMS are population-based studies of the Swedish population aged 16 to 70 years. In EIMS, incident cases of MS were recruited via 40 study centers, including all university hospitals in Sweden. In GEMS, prevalent cases were identified from the Swedish national MS registry. In both studies, controls were randomly selected from the national population register, matched by age, sex, and residential area at the time of disease onset. MAIN OUTCOME AND MEASURE: Multiple sclerosis status. RESULTS: There was a dose-dependent inverse association between alcohol consumption and risk of developing MS that was statistically significant in both sexes. In EIMS, women who reported high alcohol consumption had an odds ratio (OR) of 0.6 (95% CI, 0.4-1.0) of developing MS compared with nondrinking women, whereas men with high alcohol consumption had an OR of 0.5 (95% CI, 0.2-1.0) compared with nondrinking men. The OR for the comparison in GEMS was 0.7 (95% CI, 0.6-0.9) for women and 0.7 (95% CI, 0.2-0.9) for men. In both studies, the detrimental effect of smoking was more pronounced among nondrinkers. CONCLUSIONS AND RELEVANCE: Alcohol consumption exhibits a dose-dependent inverse association with MS. Furthermore, alcohol consumption is associated with attenuation of the effect of smoking. Our findings may have relevance for clinical practice because they give no support for advising patients with MS to completely refrain from alcohol. Copyright 2014 American Medical Association. All rights reserved.


Ben-Ami E.,Technion - Israel Institute of Technology | Berrih-Aknin S.,Institute of Myology | Miller A.,Technion - Israel Institute of Technology | Miller A.,Neuroimmunology Unit
Autoimmunity Reviews | Year: 2011

Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent progenitor cells which can be isolated from various human adult tissues. In recent years, MSCs have been shown to possess broad immunoregulatory capabilities, modulating both adaptive and innate immunity. This review discusses the documented immunomodulatory capabilities of the MSCs, the possible mechanisms underlying these functions and presents the potential of using this stem cell-based approach as an immunomodulatory tool for the treatment of autoimmune diseases. © 2011 Elsevier B.V.


Annibali V.,University of Rome La Sapienza | Mechelli R.,University of Rome La Sapienza | Romano S.,University of Rome La Sapienza | Buscarinu M.C.,University of Rome La Sapienza | And 8 more authors.
Cytokine and Growth Factor Reviews | Year: 2015

Several immunomodulatory treatments are currently available for relapsing-remitting forms of multiple sclerosis (RRMS). Interferon beta (IFN) was the first therapeutic intervention able to modify the course of the disease and it is still the most used first-line treatment in RRMS.Though two decades have passed since IFN-β was introduced in the management of MS, it remains a valid approach because of its good benefit/risk profile. This is witnessed by new efforts of pharmaceutical industry to improve this line: a PEGylated form of subcutaneous IFN-β 1a, (Plegridy®) with a longer half-life, has been recently approved in RRMS.This review will survey the various stages of the use of type I IFN in MS, with special attention to the effect of the treatment on the supposed viral etiologic factors associated to the disease. The antiviral activities of IFN (that initially prompted its use as immunomodulatory agent in MS), and the mounting evidences in favor of a viral etiology in MS, allowed us to outline a re-appraisal from etiology to therapy and back. © 2014 Elsevier Ltd.


Kassim I.A.,University College London | Ruth L.J.,University College London | Creeke P.I.,Neuroimmunology Unit | Gnat D.,Saint Pierre Hospital | And 2 more authors.
Maternal and Child Nutrition | Year: 2012

Iodine deficiency and excess are both associated with adverse health consequences, with fetuses, children and pregnant women being most vulnerable to the devastating effects of severe deficiency. It is often assumed that the iodine status of a population if displaced or in a remote or emergency situation is low. However, there is little evidence available to support this assumption, especially among long-term food-aid-dependent pregnant women. An effectiveness trial of a prenatal multiple-micronutrient supplement that contained 150μgday-1 iodine was conducted in two refugee camps in the North Eastern Province of Kenya in 2002. Urinary iodine concentration (UIC) was measured in a subsample of pregnant women attending antenatal care in Dagahaley (control camp) (n=74) and Ifo (intervention camp) (n=63). There was no significant difference in median UIC between the two camps (P=0.118). The combined median UIC was 730μgL-1 (interquartile range, 780) (5.77μmolL-1) and exceeded the upper safe limit of 500μgL-1 (3.95μmolL-1) for pregnant women (P<0.001), indicating excessive iodine intake. About 20% of the study subjects had 'more than adequate' urinary iodine, while over 71% had excessive UIC. Salt iodine content varied between 5.1 and 80.1ppm in the five market salt samples analysed. In conclusion, excessive iodine intake was evident in the Dadaab refugee camps. Further research needs to be conducted to investigate the source of excess iodine, to determine the measures needed to address excessive iodine intake and to reconsider the World Health Organization/World Food Programme/United Nations Children's Fund guidance on supplementation of vulnerable groups in emergencies. © 2010 Blackwell Publishing Ltd.


Angelini D.F.,Neuroimmunology Unit | Serafini B.,Instituto Superiore Of Sanita | Piras E.,Neuroimmunology Unit | Severa M.,Instituto Superiore Of Sanita | And 11 more authors.
PLoS Pathogens | Year: 2013

It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse. © 2013 Angelini et al.


Shatil E.,Max Stern Academic College of Emek Yezreel | Metzer A.,Neuroimmunology Unit | Horvitz O.,Haifa University | Miller A.,Neuroimmunology Unit
NeuroRehabilitation | Year: 2010

Objectives: To explore unprompted adherence to a personalized, home-based, computerized cognitive training program in patients with multiple sclerosis (MS), and to examine the impact of training on cognitive performance. Methods: Participants were assigned to a training (n=59) or a control group (n=48). Those in the training group were instructed to train three times a week for 12 weeks. The control group received no training. All participants were evaluated with a Neuropsychological Examination (N-CPC) at baseline and at the end of the study. Results: In the training group, 42 (71.2%) participants adhered to the training schedule and 22 (37.3%) completed the entire training regimen. In the control group, 24 (50.0%) participants agreed to be retested on the N-CPC. The training group showed a significant improvement over that shown by the control group in three memory-based cognitive abilities (general memory, visual working memory and verbal working memory). Post-hoc exploration of data from the N-CPC showed that cognitive training was also associated with increased naming speed, speed of information recall, focused attention and visuo-motor vigilance. Conclusions: The appreciable rates of adherence and cognitive improvements observed indicate that personalized cognitive training is a practical and valuable tool to improve cognitive skills and encourage neuronal plasticity in patients with MS. © 2010-IOS Press and the authors. All rights reserved.


Calabrese R.,University of Rome La Sapienza | Valentini E.,University of Rome La Sapienza | Ciccarone F.,University of Rome La Sapienza | Guastafierro T.,University of Rome La Sapienza | And 9 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Aberrant DNA methylation can lead to genome destabilization and to deregulated gene expression. Recently, 5-hydroxymethylcytosine (5hmC), derived from oxidation of 5-methylcytosine (5mC) by the Ten-Eleven Translocation (TET) enzymes, has been detected. 5hmC is now considered as a new epigenetic DNA modification with relevant roles in cell homeostasis regulating DNA demethylation and transcription. Our aim was to investigate possible changes in the DNA methylation/demethylation machinery in MS. We assessed the expression of enzymes involved in DNA methylation/demethylation in peripheral blood mononuclear cells (PBMCs) from 40 subjects with MS and 40 matched healthy controls. We performed also, DNA methylation analysis of specific promoters and analysis of global levels of 5mC and 5hmC. We show that TET2 and DNMT1 expression is significantly down-regulated in MS PBMCs and it is associated with aberrant methylation of their promoters. Furthermore, 5hmC is decreased in MS PBMCs, probably as a result of the diminished TET2 level. © 2014 Elsevier B.V.

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