Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study.
Durrenberger PF, Fernando FS, Kashefi SN, Bonnert TP, Seilhean D, Nait-Oumesmar B, Schmitt A, Gebicke-Haerter PJ, Falkai P, Grünblatt E, Palkovits M, Arzberger T, Kretzschmar H, Dexter DT, Reynolds R.
Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations.
Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity, iron accumulation and inflammation are observed in many neurodegenerative disorders, suggesting converging pathways of neurodegeneration.
We have generated comparative genome-wide gene expression data, using the Illumina HumanRef 8 Beadchip, for Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, Parkinson's disease, and schizophrenia using an extensive cohort (n = 113) of well-characterized post-mortem brain tissues.
The analysis of whole-genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease-specific changes, but more importantly to look for potential common molecular pathogenic mechanisms.
Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all six diseases. However, 61 dysregulated genes were shared when comparing five and four diseases.
The few genes highlighted by our direct gene comparison analysis hint toward common neuronal homeostatic, survival and synaptic plasticity pathways. In addition, we report changes to several inflammation-related genes in all diseases.
This work is supportive of a general role of the innate immune system in the pathogenesis and/or response to neurodegeneration.
Source: J Neural Transm. 2014 Aug 13. [Epub ahead of print] & Pubmed PMID: 25119539 (21/08/14)
Evidence found in both human multiple sclerosis patients and experimental mouse models, according to research published in the American Journal of Pathology.
A new study published in The American Journal of Pathology identifies a novel gene that controls nerve conduction velocity. Investigators report that even minor reductions in conduction velocity may aggravate disease in multiple sclerosis (MS) patients and in mice bred for the MS-like condition experimental autoimmune encephalomyelitis (EAE).
A strong tool for investigating the pathophysiology of a complex disease is the identification of underlying genetic controls. Multiple genes have been implicated as contributing to the risk of developing MS. Unlike studies that have focused on genetic regulators of inflammation, autoimmunity, demyelination, and neurodegeneration in MS, this study focused on nerve conduction velocity. Investigators found that polymorphisms of the inositol polyphosphate-4-phosphatase, type II (Inpp4b) gene affect the speed of nerve conduction in both mice with EAE and humans with MS.
"Impairment of nerve conduction is a common feature in neurodegenerative and neuroinflammatory diseases such as MS. Measurement of evoked potentials (whether visual, motor, or sensory) is widely used for diagnosis and recently also as a prognostic marker for MS," says lead investigator Saleh M. Ibrahim, MD, PhD, of the Department of Dermatology, Venereology, and Allergology of the University of Lubeck (Germany).
Using several genomic approaches, the investigators narrowed their search to the genetic region controlling the enzyme inositol-polyphosphate-4-phosphatase II (INPP4B), the product of which helps to regulate the phosphatidyl inositol signaling pathway. Enzymes in this family are involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular communication.
In one series of experiments, the researchers analyzed the genetic locus EAE31, which previously had been shown to control the latency of motor evoked potentials and clinical onset of EAE in mice. Using advanced techniques including congenic mapping, in silico haplotype analyses (computer simulations), and comparative genomics (from rats, mice and humans), they were able to "finemap" the focus to Inpp4b as the quantitative trait gene for EAE31.
When the investigators analyzed this region in eight different strains of mice, they found they could divide the strains into two groups based on differences in amino acid sequences. The strains with the longer-latency SJL/J allele had the two amino acids (arginine and proline), whereas those with the shorter-latency C57BL/10S allele had others (serine and histidine). "These data suggest that Inpp4b structural polymorphism is associated with the speed of neuronal conduction," comments Dr. Ibrahim.
In another experiment, the scientists compared motor conduction velocity in genetically modified mice with a mutant Inpp4b gene to that of control mice. The nerve conduction in this group was slower than in the control group.
Finally, the investigators studied INPP4B polymorphisms in MS patients. They looked at two cohorts: one from Spain (349 cases and 362 controls) and a second from Germany (562 cases and 3,314 controls). The association between the INPP4B polymorphisms and susceptibility to MS was statistically significant when the cohorts were pooled. However, although the Spanish cohort showed a strong association between INPP4B and MS, the association was weaker in the German cohort. "The exact reason for the diverging effect across these populations remains unresolved," states Dr. Ibrahim.
In an accompanying commentary, Hans Lassmann, MD, of the Center for Brain Research of the Medical University of Vienna (Austria) notes, "This study represents an interesting example of how minor changes in conduction velocity, which do not result in a clinical phenotype in control populations, may aggravate disease in conditions such as EAE or MS." In other words, impaired nerve conduction may have a greater impact on those with MS compared to healthy individuals. Noting that the study reported no major loss of myelin in animals carrying the mutant allele, Dr. Lassmann comments that it is still unclear which neurobiological mechanisms underlie the INPP4B-associated impaired conduction. One suggestion is that INPP4B may be involved in calcium ion signaling within synapses, affecting neurotransmitter release.
Source: EurekaAlert! Copyright ©2014 by AAAS (13/08/14)
A key difference in the brains of male and female MS patients may explain why more women than men get the disease, a study suggests.
Scientists at Washington University School of Medicine in the US found higher levels of protein S1PR2 in tests on the brains of female mice and dead women with MS than in male equivalents.
Four times more women than men are currently diagnosed with MS.
Experts said the finding was "really interesting".
MS affects the nerves in the brain and spinal cord, which causes problems with muscle movement, balance and vision. It is a major cause of disability, and affects about 100,000 people in the UK.
Abnormal immune cells attack nerve cells in the central nervous system in MS patients.
There is currently no cure, although there are treatments that can help in the early stages of the disease.
Researchers in Missouri looked at relapsing remitting MS, where people have distinct attacks of symptoms that then fade away either partially or completely. About 85% of people with MS are diagnosed with this type.
Scientists studied the blood vessels and brains of healthy mice, mice with MS, and mice without the gene for S1PR2, a blood vessel receptor protein, to see how it affected MS severity.
They also looked at the brain tissue samples of 20 people after they had died.
They found high levels of S1PR2 in the areas of the brain typically damaged by MS in both mice and people.
The activity of the gene coding for S1PR2 was positively correlated with the severity of the disease in mice, the study said.
Scientists said S1PR2 could work by helping to make the blood-brain barrier, in charge of stopping potentially harmful substances from entering the brain and spinal fluid, more permeable.
A more permeable barrier could let attacking cells, which cause MS, into the central nervous system, the study said.
Prof Robyn Klein, of the Washington University School of Medicine, said: "We were very excited to find the molecule, as we wanted to find a target for treatment that didn't involve targeting the immune cells.
"This link [between MS and S1PR2] is completely new - it has never been found before."
Prof Klein said she did not know why the levels of S1PR2 were higher in women with MS, adding she had found oestrogen had "no acute role".
She would be looking at taking her findings to clinical trials in the "next few years", she added.
Dr Emma Gray, of the MS Society, said: "We don't yet fully understand why MS affects more women than men, and it's an area that's intrigued scientists, and people with MS, for many years.
"A number of theories have been suggested in the past, including the influence of hormones or possible genetic factors - and this study explores one such genetic factor in further detail, which is really interesting."
She said understanding the causes of MS was a "priority" for the MS Society in the UK, and could be "crucial" in finding new treatments.
The research was published in the Journal of Clinical Investigation.
Source: BBC News © British Broadcasting Corporation 2014 (09/05/14)
The diagnosis and treatment of Multiple Sclerosis (MS) have dramatically improved over recent decades due to scientific advancements, yet MS persists as one of the most disabling neurological disorders, having a significant impact on young adults - the age group most affected by the disease.
Continuing medical education provider, EXCEMED - Excellence in Medical Education, will draw leading international experts in MS to explore the roles of genetics and environment in MS pathology. The conference, "Multiple sclerosis: Improving patient outcomes through scientific and clinical advances" takes place in Dubai, United Arab Emirates, from 9 to 10 May 2014.
"This meeting will present the latest epidemiological and genetic knowledge about MS and link it to pathology and the practical management of therapy for people with MS" says Professor David Bates, Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK, and - scientific organizer of the event.
"We are proud to gather, year after year, an outstanding international panel of experts in neurology and MS research in order to contribute to the debate from the perspective of clinical practices. The goal is to identify the most appropriate treatments for this disease," says Professor Giancarlo Comi, President of the EXCEMED Scientific Committee and Professor in Neurology at University Vita-Salute San Raffaele, Milan, Italy.
The scientific programme of the event offers three sessions and six workshops: Session one will address basic research in MS pathogenesis including epidemiology, risk factors, genetics of MS and mechanism and prevention of neurodegeneration. Session two will address clinical approaches to MS and session three will deal with therapeutic management. The six workshops will be attended in rotation by each participant to allow for optimal exchange of opinions and a deeper understanding of the different MS related topics.
Source: Digital Journal copyright © 2014 digitaljournal.com (09/05/14)
New pharmaceuticals to fight autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and psoriasis, may be identified more effectively by adding genome analysis to standard drug screening, according to a new study by a research team led by UC San Francisco and Harvard researchers, in collaboration with Tempero and GlaxoSmithKlein.
In a study reported online April 17, 2014 in the journal Immunity, the scientists combined drug screening with state-of-the-art techniques for analyzing the genome, leading to three small molecules that improved symptoms in a mouse form of multiple sclerosis.
The three potential drug candidates, selected from a large library of screened chemicals, each knocked down the response of Th17 cells, a type of immune cell that drives many autoimmune diseases by attacking normal cells in the body. More specifically, the drugs homed in on an essential molecule within the Th17 cells.
"We examined what makes Th17 cells – which play a crucial role in multiple autoimmune diseases – distinct from other closely related T cells within the immune system," said Alexander Marson, MD, PhD, a leading T cell expert and member of the UCSF Diabetes Center. "Then we investigated several small molecules that inhibit the development and function of these cells. When the Th17 cells were hit by these molecules we saw less severe multiple-sclerosis-like symptoms in the mice."
The research team, led by Marson and Vijay K. Kuchroo, PhD, an immunologist at Brigham and Women's Hospital in Boston and Harvard Medical School, combined powerful techniques to shed light on a class of protein molecules within cells known as transcription factors.
Drug designers have rarely targeted transcription factors. Each transcription factor binds to DNA at a unique set of locations along the 23 pairs of chromosomes, and thereby influences which genes are turned on and off to trigger the protein production that drives cell development and function.
Different transcription factors shape the development of different types of T cells within the immune system, Marson and others are discovering. In their new study, Marson found that the transcription factor called ROR gamma t has a unique role in guiding development of Th17 cells, while inhibiting the development of other immune cells.
Preventing Th17 cells from developing by inhibiting the function of ROR gamma t appears to be an effective strategy for fighting autoimmune diseases, Marson said. "There already are drugs in clinical trials for autoimmune diseases – including psoriasis and rheumatoid arthritis – that are antibodies for IL-17 or IL-17 receptors," Marson said, referring to signaling molecules secreted by Th17 cells that can help trigger an attack our own healthy tissue, and the receptors that receive those signals. "This is an entirely different and promising approach to fight autoimmune disease," he said.
"Our studies map a path to targeting transcription factors and provide both insight into how transcriptional regulators shape the identity and affect the development of Th17 cells, and also into how different drug molecules might affect these regulatory circuits in the cells," he said.
To reveal the distinct and sometimes subtle effects of the drug candidates, the researchers studied the entire genome to see where ROR gamma t attached to DNA, which genes were activated or turned off as a result, and how these effects were altered by the drug candidates.
"Not only did we look at which genes are turned on and off, but we also systematically looked at DNA-binding sites across this genome," Marson said. "This pushes the boundary of what's typically done."
In addition to attaching to DNA, ROR gamma t has a pocket that looks like it should bind a hormone, Marson said. But what this hormone might be, and its effects, are unknown. The different drug candidates that inhibited Th17 development had different effects on ROR gamma t and resultant DNA binding and gene activation, possibly because of distinct interactions with the hormone-binding pocket, Marson said.
Analyzing the large data sets generated through such experiments could help pharmaceutical companies wading into development of drugs that target transcription factors to test the waters, Marson said, enabling drug developers to better understand mechanisms of drug action and to more easily see gene activity that could trigger side effects. According to Marson, "This is a new, broadly applicable approach for systematically evaluating leading drug candidates for autoimmune diseases."
Source: MedicalXpress © Medical Xpress 2011-2014 (02/05/14)
In patients with multiple sclerosis, the body turns on itself, launching an immune system attack that destroys the coating around nerve fibers in the central nervous system, leaving them exposed like bare wires. Similar to exposed electrical lines, the unprotected fibers touch and short out, leading to the neurodegenerative effects that are a hallmark of multiple sclerosis.
But what if doctors could stop the immune response that destroys the protective coating before the disease becomes debilitating? University of Florida researchers have received a $40,000 grant from the National Multiple Sclerosis Society to test a gene therapy technique in mice that aims to help the body not treat itself like a foreign invader — a process referred to as immune tolerance — in the earliest stages of multiple sclerosis. If the researchers can re-establish this tolerance, they could thwart the immune system attack, all with a technique that could be used on a wide number of patients.
"In previous years, we have learned a lot about how to manipulate tolerance using gene therapy," said Brad E. Hoffman, Ph.D., an assistant professor of pediatrics in the UF College of Medicine. "Tolerance is your body's way of not responding to substances that would otherwise induce an immune response so you don't have an immune response to everything. In multiple sclerosis, the body loses that ability to distinguish between self and not-self so it starts to attack its own nervous system cells."
About 2.5 million people worldwide suffer from multiple sclerosis, according to the National Multiple Sclerosis Society. The disease typically causes problems with vision, fatigue, speech, sensation and mobility. In advanced cases, multiple sclerosis can lead to blindness and paralysis.
Typically, gene therapy is used to correct a faulty gene in the body. In this case, researchers will deliver a gene responsible for a brain protein into the liver, via the harmless virus AAV, in hopes that it will spark production of regulatory T cells. These T cells, which suppress the immune system, are crucial because they could effectively shut down the immune attack in the brain, Hoffman said. The researchers are injecting the gene specifically into the liver because the organ filters out unwanted immune responses.
"Everything filters through the liver for detoxification," Hoffman said. "Because of this, the liver has an innate capacity to induce immune tolerance. We have learned in other gene therapy studies that it is possible for the liver to make cells tolerant to the gene you are putting in."
Other research teams across the country are trying to spark immune tolerance to combat multiple sclerosis, too. However those studies involve developing treatments personalized for specific patients. The UF researchers' work is novel because they hope to develop a technique that could be used on a wide number of patients.
"Everyone has different types of T regulatory cells and receptors," Hoffman said. "By injecting a gene responsible for a brain protein, we are allowing an individual's body to make the specific T regulatory cells it needs.
"If it works, this is potentially more clinically feasible, cost-effective and translatable for a large scale."
Although gene therapy has yet to be used to correct autoimmune disorders such as multiple sclerosis, the foundations for the study are rooted in research Hoffman's team has performed while studying gene therapy for hemophilia. During these studies, the team was able to induce immune tolerance in mice, and Hoffman hopes the techniques will one day be able to help people with multiple sclerosis, too.
"Will we be able to cure MS? That would be ideal, but our strategy is more likely to result in suppressing the immune response to the nervous system," he said. "If you suppress the immune response, you will suppress the neurodegenerative effects and hopefully maintain a higher quality of life."
Source: South Florida Sun-Sentinel Copyright © 2014, South Florida Sun-Sentinel (09/04/14)
DioGenix, Inc. announced today new data supporting the clinical validation of MSPrecise®, its proprietary next-generation sequencing (NGS) assay for the identification of patients with multiple sclerosis (MS) at first clinical presentation. The prospective study met its primary endpoint by demonstrating the ability of MSPrecise to diagnose patients with MS. The test performed consistently with previous clinical studies, having a specificity of 82% while maintaining sensitivity comparable to what has been published for the current standard of care (p= .0027).
Over 200 subjects being evaluated for non-specific neurological symptoms that could be MS, were enrolled in the prospective, blinded clinical trial that validated the performance of MSPrecise. Each subject was undergoing a comprehensive evaluation using the current standard of care for imaging of the central nervous system (CNS) and analysis of their cerebral spinal fluid and blood. This study compared the results of MSPrecise DNA mutational analysis with a consensus diagnosis made by a panel of independent neurologists chosen for their significant clinical experience in diagnosing and treating MS. The MSPrecise interpretive scoring system provides a simple scaled score to the neurologist who differentiates patients with MS from those with other similarly presenting neurological diseases. Thirteen MS clinical centers of excellence participated in the trial – believed to be the largest prospective diagnostic study of its kind in MS – with over 20 thought-leading clinicians consenting subjects. Results from this study will be submitted for peer review.
"MSPrecise interrogates key genes involved in the immune system of patients being evaluated for MS. The growing body of evidence indicates this next-generation sequencing assay may advance our efforts to more accurately diagnose patients with MS or other immune-mediated neurological disease," said Elliot M. Frohman, M.D., Ph.D., FAAN, Professor of Neurology & Ophthalmology and Director, MS Program and Clinical Center for MS at The University of Texas Southwestern Medical Center.
These results are consistent with two prior DioGenix studies that compared MSPrecise to published performance data for the oligoclonal banding (OCB) test and experimental controls. In a previous, mainly retrospective verification study, MSPrecise demonstrated a clear improvement in the ability to classify early-stage MS patients from those with other similarly presenting neurological diseases in comparison to OCB analysis.
"DioGenix continues to clearly demonstrate the power of MSPrecise to accurately identify patients with neurodegenerative diseases like MS. MSPrecise should offer neurologists greater insight into early disease events by exploiting the incredible biological resolution provided by next-generation sequencing. As we are able to now more accurately measure these key early biological changes we believe we can help inform more appropriate courses of treatment for individuals who suffer from these types of immune-mediated diseases," said Larry Tiffany, President and CEO of DioGenix. "The positive results of our validation study give us a green light to initiate our pre-commercial strategy."
Individuals who present with clinical symptoms and evidence of non-specific neurological disease undergo a battery of tests in a diagnostic process that can take months or even years to complete. The diagnostic standard of care for MS includes CSF analysis using the OCB test alongside a comprehensive set of clinical tests to rule-out other neurological diseases. Unfortunately, the OCB test yields a high rate of false positive results, which can unnecessarily expose patients who do not have MS to chronic and expensive therapy that, in some cases, actually exacerbates their underlying disease. Alternatively, false negatives can delay the proper treatment of those patients who do have MS, possibly accelerating the development of permanent physical disability.
MSPrecise utilizes next-generation sequencing to measure DNA mutations found in rearranged immunoglobulin genes in immune cells initially isolated from cerebrospinal fluid. MSPrecise would augment the current standard of care for the diagnosis of MS by providing a more accurate measurement of a patient's immune response to a challenge within the CNS. This novel method of measuring changes in adaptive human immunity may also be able to discern individuals whose disease is more progressive and requires more aggressive treatment.
Source: The Sacramento Bee Copyright © The Sacramento Bee 2014 (27/01/13)
Researchers assess familial risks for MS using population registers, health care registries(22/01/14)
Even though multiple sclerosis is largely caused by genetic factors, the risk of patients' relatives developing the disease is lower than previously assumed. This is the conclusion of a new population registry-based study, published in the scientific journal Brain.
In the present study from Karolinska Institutet, researchers have assessed the familial risks for multiple sclerosis (MS) by using population registers and health care registries. This way, the researchers were able to include in their study almost everyone diagnosed with the disease in Sweden. Slightly over 28,000 individuals diagnosed with MS from 1968 onwards were identified. By using the Swedish Multi-generation registry, both biological and adopted relatives were identified and the researchers could assess the risks for the different groups.
This is the first study for MS in which the familial risks have been analysed using matched controls. By including randomly selected controls and their relatives, the researchers could also assess the risk for relatives of MS patients developing the disease compared to the risk for the population in general.
The estimated risks in this study turned out lower than the previously reported high risks. The risk for a sibling to a person with multiple sclerosis for developing disease was seven times higher compared to the general population, while the risk for a child of an MS patient was five times higher. The study found no increase in risk for grandchildren and nieces/nephews.
"The population registers in Sweden are reliable tools for finding relatives to MS patients and their possible MS diagnosis, instead of relying on the patients' memories. Our study is a good example of how one can quickly achieve more reliable results than the previous studies that were based on patient groups collected in hospitals throughout decades," says Helga Westerlind, a doctoral student at the Department of Clinical Neuroscience and first author of the article.
The researchers have also used the Swedish twin register to identify twins with multiple sclerosis and investigate how genes, shared environment and individual risk factors contribute to the disease. The analysis confirmed previous results: MS seems to be primarily caused by genetic factors, and secondarily by individual risk factors. A shared environment does not appear to be of any significance.
The study was funded by the Swedish Research Council, Karolinska Institutet, Stockholm County Council, the Bibbi and Nils Jensen Foundation and the Swedish Research Council for Health, Working Life and Welfare.
Source: News-Medical.Net (22/01/14)
MS research appeal(22/01/14)
An Orcadian geneticist who is researching the causes of MS in the Northern Isles, is asking people in Orkney to help create a list of all the people with Orkney and Shetland ancestors who have had Multiple Sclerosis.
Dr Jim Wilson who works for the Centre for Population Health Services at the University of Edinburgh said it is important to work out the degree to which MS is genetic in Orkney and Shetland, through building family trees of as many people as possible who have or had MS and asks for people to get in touch with information about “friends, neighbours, relatives or ancestors who had, or have MS.”
Orkney and Shetland have the highest prevalence of MS in the world, and this research has been undertaken as part of the Shetland and Orkney Multiple Sclerosis Research Project, which was set up to support research to try to understand why Orkney and Shetland have such high MS figures.
He said: “Medical studies now routinely use tens of thousands of subjects, but when trying to understand MS in Orkney we are always limited by the comparatively small total number of individuals with the disease. Building family trees back into the past and including everyone who had MS in the last 40 years is one way to increase our power to understand the disease.”
Anyone wishing further information on this research or to contribute, can contact Emily Weiss by email at email@example.com or by writing to her at Emily Weiss, Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EB8 9AG.
Source: The Orcadian © The Orcadian 2014 (22/01/14)
Norwegian researchers have mapped genetic variations associated with an increased risk of multiple sclerosis (MS) and myasthenia gravis (MG), bringing science one step closer to understanding these serious autoimmune disorders.
The Norwegian researchers have taken part in an international cooperative effort to map 110 genetic variations that increase the risk of MS and MG. Most of these genetic variations have been mapped in recent years.
"Rapid advances have been made in this area of research," explains Hanne F. Harbo, professor at the University of Oslo and head of the clinical science group at Oslo University Hospital.
She has received funding under the Research Council of Norway's national initiative on neuroscientific research (NEVRONOR) to head Norwegian research projects on MS and MG. The projects have been carried out in close cooperation with an international network of researchers.
Serious neurological and muscular disorders
Autoimmune disorders result from reactions by the body's immune system which in turn attack and destroy healthy cells.
"Our understanding of the causes of these diseases remains limited, but we do know that the immune system plays a key role in the debilitating processes that occur. MS attacks the central nervous system, causing inflammatory processes that lead to a variety of neurological symptoms including paralysis, loss of sensory function, and problems with vision and bladder function. MG affects the transmission of signals between the peripheral motoric nerve cells and muscles, resulting in muscular fatigue in the patient," Dr Harbo explains.
Genetic and environmental factors linked
Approximately 8 000 Norwegian are afflicted with MS. MG is far less prevalent, with only around 500 Norwegians affected.
One element preventing a better understanding of these disorders is that they are caused by a mix of genetic and environmental factors. They arise due to the unfortunate combination of genes that are associated with the disorders along with common factors occurring in the environment.
Viral infections - especially the Epstein-Barr virus – along with low levels of vitamin D in the blood and smoking are presumed to be moderate risk factors contributing to MS.
Finding new risk genes using genetic testing
Participating in large international research projects, Dr Harbo and colleagues have helped to identify a number of new risk genes for MS and MG. This has contributed significantly to a breakthrough in the genetics of MS.
The most important finding was that over 110 common risk variants show some sort of link to the risk of developing MS.
"We know that most of these risk variants on their own play little role in the development of MS. But mapping the collection of genes associated with MS represents an important advance in efforts to identify the key mechanisms behind its development," Dr Harbo says.
"Once we gain more insight into the mechanisms behind this disorder, it will be easier to shut down the pathways that trigger the disorder in cells," she concludes.
Common among the population
Approximately 150 of 100 000 inhabitants in Norway have MS, with the disorder afflicting more women than men and typically affecting young adults. The risk variant mostly highly associated with MS (HLA-DRB1*1501) triples the risk of developing the disorder.
"We know that the risk variant HLA-DRB1*1501 is common among the population and that its occurrence differs significantly among those who have MS and those who do not," Dr Harbo explains.
The Norwegian study of myasthenia gravis covers 370 MG patients and 650 healthy control subjects. The risk variant HLA-B*08 showed the highest risk for developing MG among young persons while HLA-DRB1*1501 posed the greatest risk among the elderly.
Genetic analyses solely as a research method
Genetic testing is not currently part of the clinical treatment of patients with MS or MG, and is only used as a research method for uncovering causal mechanisms. "Risk gene studies have provided new knowledge that is important to those working in the field. We will now move on to studying molecular mechanisms and how risk genes affect the clinical expression of the disorder," Dr Harbo explains.
The researchers have also examined environmental factors behind the incidence of MS and MG. Certain factors such as smoking appear to increase the risk of developing these disorders.
Targeting better treatment
There is no existing treatment to completely cure MS or MG, but new medications are constantly emerging that reduce inflammation and the role it plays in the disorder. "We hope to use our research findings to improve the knowledge base for developing more effective methods of treatment," Professor Harbo concludes.
Source: Medical Xpress © Medical Xpress 2011-2014 (10/01/14)
HERV-W polymorphism in chromosome X is associated with MS risk and with differential expression of MSRV(10/01/13)
Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis.
MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested.
Results: MSRV transcription levels were higher in MS patients than in controls (U-Mann-Whitney; p = 0.004).
Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A).
After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [chi2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann-Whitney; p = 0.039) or TT patients (U-Mann-Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann-Whitney; p = 0.003).
Conclusions: Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS.
Author: Marta GarcÃa-MontojoBelÃ©n de la HeraJezabel VaradÃ©Ana de la EncarnaciÃ³nIris CamachoMarÃa DomÃnguez-MozoAna Arias-LealÃ?ngel GarcÃa-MartÃnezIgnacio CasanovaGuillermo IzquierdoMiguel LucasMaria FedetzAntonio AlcinaRafael ArroyoFuencisla Mate
Source: 7thSpace Interactive © 2014 7thSpace Interactive (10/01/13)
The diseases have more than the immune system in common, sharing a genetic risk factor and connection to the Epstein Barr Virus.
Scientists at the Institute of Cancer Research (ICR) in London have discovered a genetic link between Hodgkin's lymphoma and multiple sclerosis (MS), suggesting that there may be a shared mechanism of action the triggers the two diseases.
Analyzing the genes of more than 12,000 people, the researchers found two new gene variants that increase the risk of developing Hodgkin's lymphoma significantly.
According to the study, “One of these variants is linked to a gene known as EOMES that helps develop cell-mediated immunity, and is also a known risk factor for MS. This might explain why cases of Hodgkin's lymphoma and MS are found to cluster together in families.”
What Is Hodgkin's Lymphoma?
Hodgkin's lymphoma is a cancer that starts in the white blood cells, or lymphocytes, found in the lymphatic system, which is part of the body’s immune system. Lymph nodes, lymph fluid, and lymph vessels, which transport the fluid throughout the body, all make up the lymphatic system.
Because this system runs throughout the body, Hodgkin's lymphoma can start nearly anywhere. According to the American Cancer Society (ACS), the major sites are the lymph nodes, spleen, thymus, bone marrow, and digestive tract.
Lymphocytes are also thought to play an important role in MS. Normally, lymphocytes defend the body against foreign invaders like viruses and bacteria. In MS, the lymphocytes are misdirected and attack the protective covering of the nerves in the brain and spinal cord.
In a study conducted in Denmark and published in 2004, researchers followed 11,790 patients with multiple sclerosis and 19,599 of their first-degree relatives and monitored them for the development of Hodgkin's lymphoma.
They concluded that “the observed familial clustering of multiple sclerosis and young-adult-onset Hodgkin's lymphoma is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.” The discovery of a genetic connection between Hodgkin's lymphoma and MS is exciting progress toward understanding both, suggesting the possibility of a mutual trigger.
EBV: A Possible Culprit?
If finding an MS trigger were a “whodunit,” the Epstein Barr virus (EBV), responsible for mononucleosis, would look like a handsome suspect. It is one of the known risk factors for developing Hodgkin's lymphoma and is commonly found in people with MS. EBV and MS appear to relapse together in those who have both.
“Epstein Barr virus is the virus that causes glandular fever (mononucleosis),” explains Cancer Research U.K. on their website. “People who have had glandular fever have an increased risk of Hodgkin's lymphoma afterwards. A study published in December 2011 estimated that almost half of the cases of Hodgkin's lymphoma in the U.K. are related to EBV infection.”
Not all people with Hodgkin's lymphoma or MS have been exposed to EBV, however, suggesting that if the virus is a trigger for either, it’s certainly not the only factor.
Researchers are working on the first human trials for a vaccine to fight EBV. Further research is needed to explore the connection between Hodgkin's lymphoma and MS.
The fact that both involve the immune system, share a genetic risk factor, and seem to cluster in families suggests that we are getting closer to solving the mysteries surrounding both diseases and are perhaps one step closer to a cure.
Source: Healthline Copyright © 2005 - 2013 Healthline Networks, Inc (07/11/13)
A major milestone has been reached on the path to finding a cure for multiple sclerosis (MS), researchers say.
A group of international scientists, including an Australian contingent, has discovered 48 previously unknown genes that influence the risk of developing MS.
MS, which attacks a person’s central nervous system and can impact mobility, balance and sensation, affects 23,000 Australians.
The new discovery is a big step towards finding a cure and further treatment for the debilitating condition, says University of Sydney Associate Professor David Booth, who led the Australian and New Zealand component of the study.
“The exciting thing about this is we have doubled the number of genes that we now know are associated with MS,” he’s told Sydney media.
“What that means is every one of those new genes is potentially providing us with a new way to understand the disease and to come up with new therapies for the disease.”
Researchers say they believe the findings underline the central role the immune system plays in the development of MS.
The results also show an overlap with genes found to be linked to other auto-immune diseases, including inflammatory bowel disease and coeliac disease.
The team of scientists, working under the umbrella of the International Multiple Sclerosis Genetics Consortium, has its findings published in medical journal Nature Genetics today (Monday, September 30).
As part of the study, the largest investigation of MS genetics to date, DNA from blood samples from 80,000 people with and without the condition were examined, including 1800 from Australia and New Zealand.
Professor Booth says the “milestone” provided specific research targets.
“So going forward we will try and find out why all of these genes affect MS,” he says.
“And particularly finding which processes are tagged by groups of genes and that will give us specific information on immune processes that are not functioning as they should.”
As a result of the new findings, there are now 110 genetic variants linked to MS.
MS Research Australia’s CEO Matthew Miles says the work is a huge contribution to understanding MS.
Source: Cowra Community News © 2013 Cowra Community News (30/09/13)
The National Institutes of Health (NIH) awarded Benaroya Research Institute at Virginia Mason (BRI) a $1.9 million grant to find marks in the human genome which can explain why some white blood cells cause damage to the spinal cord and brain in multiple sclerosis (MS). This is the first study to look for molecular changes in the genome of specific immune cells responsible for the devastation caused by MS. The broad-based study will determine the function of these cells, how they are generated and how they can be regulated in system models of MS and in humans.
"We want to understand the factors that make these cells target the spinal cord and brain to cause disease," says Estelle Bettelli, PhD, BRI Assistant Member and co-principal investigator of the study. Dr. Bettelli and other scientists have identified different types of T cells which they believe are potent inducers of MS and other autoimmune diseases. She has also developed system models to study different forms of multiple sclerosis.
"With Dr. Bettelli's research advances and with the new technological innovations in genome research, we can look at specific marks present in the genome of these cells and understand how they are generated and how they can be controlled," says co-principal investigator Steven Ziegler, PhD, Director of the BRI Immunology Research Program. Dr. Ziegler has used whole genome studies to investigate these cell types in healthy individuals. "We can then see how the genomic marks affect the cells in model systems of MS and how they operate in humans cells with and without the disease. We can also see how these cells behave once the patient receives treatment and if various treatments make the cells act differently."
"It is important to know how and when these cells are formed in the body to determine how to inhibit their harmful function," says Dr. Bettelli. "It is becoming clear that MS is not a unique disease entity but can present itself in different clinical forms and variants. Several factors, including the cell types involved, are believed to dictate the clinical progression of MS. The understanding of how and which cell populations of the immune system participate in the autoimmune attack is very important for determining current treatments and designing new therapeutics tailored to the different forms of MS. We hope to find ways to significantly inhibit these dangerous cells with new targeted medicines with fewer side effects.
"This work highlights a key mechanism for understanding and modifying the immune cells that cause autoimmune diseases like MS," says BRI Director Gerald Nepom, MD, PhD. "It is an exciting example of the power of merging new genomic technologies with state-of-the-art immunology research to address a major clinical need."
Other scientists collaborating in this effort are Jane Buckner, MD, BRI Associate Director, Damien Chaussabel, PhD, BRI Director of Systems Immunology, Mariko Kita, MD, BRI Affiliate Investigator and Director of the Virginia Mason Multiple Sclerosis Center, and John Stamatoyannopoulos, MD, Associate Professor of Genome Sciences and Medicine, University of Washington.
Multiple sclerosis is an autoimmune disease in which the body's immune system mistakenly attacks myelin, the fatty substance that surrounds and protects the nerve fibers in the central nervous system. When the myelin is damaged the nerve impulses are not transmitted as quickly or efficiently, resulting in symptoms such as numbness in the limbs, fatigue, dizziness, paralysis and/or loss of vision. Symptoms of MS will often improve and relapse with time and vary from one person to another. In progressive forms of multiple sclerosis, they gradually worsen.
MS affects approximately 400,000 Americans but is much more common in the Northwest. Some likely factors that contribute to this may be vitamin D deficiency, genetic predisposition and environmental triggers. Other factors are still unknown.
Source: EurekaAlert! Copyright ©2013 by AAAS (04/09/13)
MicroRNA are small noncoding RNA molecules that are involved in the control of gene expression. To investigate the role of microRNA in multiple sclerosis (MS), we performed genome-wide expression analyses of mRNA and microRNA in T-cells from MS patients and controls.
Methods: Heparin-anticoagulated peripheral blood was collected from MS-patients and healthy controls followed by isolation of T-cells.
MicroRNA and RNA from T-cells was prepared and hybridized to Affymetrix miR 2.0 array and Affymetrix U133Plus 2.0 Human Genome array (Santa Clara, CA), respectively. Verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).
Results: We identified 2,452 differentially expressed genes and 21 differentially expressed microRNA between MS patients and controls.
By Kolmogorov-Smirnov test, 20 of 21 differentially expressed microRNA were shown to affect the expression of their target genes, many of which were involved in the immune system. Tumor necrosis factor ligand superfamily member 14 (TNFSF14) was a microRNA target gene significantly decreased in MS.
The differential expression of mir-494, mir-197 and the predicted microRNA target gene TNFSF14 was verified by real-time PCR and ELISA.
Conclusion: These findings indicate that microRNA may be important regulatory molecules in T-cells in MS.
Author: Margareta JernÃ¥sClas MalmestrÃ¶mMarkus AxelssonIntawat NookaewHans WadenvikJan LyckeBob Olsson
Credits/Source: BMC Immunology 2013, 14:32
Source: 7thSpace Interactive © 2013 7thSpace Interactive (30/07/13)
A Western Australia-cohort of patients has been used to study the risk modifying role of specific genes suspected to contribute to one’s predisposition to multiple sclerosis (MS).
MS is the most common cause of neurological disabilities in young adults with an estimated 25,000 cases nationwide and a higher prevalence among women than men in most Western countries.
The Australian Neuro-muscular Research Institute’s Allan Kermode says this candidate gene selection study is validation research based on previously identified gene-disease associations.
“It needs to be interpreted in the context of other studies done,” Dr Kermode says.
Genome-wide association studies may have generated unforeseeable genetic associations but, “their weakness is that they use large groups of patients from diverse geographical and ethnic backgrounds—such patients can contaminate the group”.
Dr Kermode says the confirmation of individual gene variation effects on MS development in a highly categorised MS cohort of Anglo-Celtic origin—like the WA cohort, is valuable.
The study also provides evidence for interactive influences of gene combinations not studied before, some of which are described as protective.
“It could well be that certain genes are risk factors in some populations but not others,” says Dr Kermode.
“Lots of [immune regulatory] genes associated with MS are common and many people have them, but most of us do not get MS.
“The Human Leukocyte Antigen (HLA)-gene association remains the strongest association with MS risk,” and relates to the general understanding that autoimmunity underpins disease progression in this disorder.
But the idea that non-HLA genes contribute in parallel is well established now, supporting Dr Kermode’s interest in interactive effects of non-HLA with HLA-genes on MS risk.
He took a subset of the WA MS patients, who were selected for being carriers of the best known HLA-DRB1 risk gene in an Anglo-Celtic population, and studied its interaction with 10 non-HLA genes showing 16 sequence variations in MS patients and controls.
Dr Kermode says it also makes sense to consider interactions of environment stimuli and infections with HLA-genes, defining our immunity.
But their contribution to MS risk is dependent on one’s genotype, explaining why some do and others don’t develop MS.
He has started using the MS database to further investigate whether MS risk may be affected by vitamin D, as an immune modulator, or Epstein-Barr virus infections, which are 100 per cent prevalent in MS patients.
The inclusion of gene-environment interactions is hoped to improve stratification of MS patients and, in turn, the risk assessment of developing MS.
Notes: The Australian Neuromuscular Disease Research Institute (ANRI) is affiliated with the University of Western Australia and Murdoch University.
Source: Science Network Western Australia (15/07/13)