Research

Scientists from Irvine, California and Toronto have just published an interesting study that explains how genetic and environmental factors may interact to cause MS. It's widely accepted that both types of factors are involved in triggering the disease, but so far very few ideas have been proposed and tested to show how this might happen. This study focused on a process called glycosylation, which is the attachment of certain sugars to proteins located on the surface of cells. The presence of these sugars affects how cells behave and respond to various signals, and in the case of immune cells, influences their ability to be activated to participate in an immune response. The research team had previously created a mouse model with genetic deficiences affecting glycosylation; these mice spontaneously developed an inflammatory demyelinating disease resembling MS, so the scientists hypothesized that this cellular function might also play a role in MS.

Through a series of studies, the team demonstrated that several MS risk factors (variants in the IL7RA, IL2RA, MGAT1 and CTLA-4 genes, and low levels of vitamin D) can alter the glycosylation process in ways that may both result in immune dysfunction and enhance the vulnerability of oligodendrocytes and neurons. In addition, these factors appear to have an increased effect when present together. The authors suggest that supplementation with vitamin D and N-acetylglucosamine may help to reduce the increase in MS risk associated with the glycosylation process.

Here's an article summarizing the paper, and here's the paper itself. The Accelerated Cure Project Repository provided DNA samples to Dr. Demetriou for this study, so we're pleased to have played a supporting role in generating these results.

ACP's Notes From the 2011 AAN Meeting in Honolulu

American Academy of Neurology meeting April 9-16, Honolulu, Hawaii

Each year staff from Accelerated Cure Project attend the American Academy of Neurology annual meeting. We try to take notes on as many presentations as we can, write them up, and make them available on MSNews for anyone to read.

You can see our notes below. By the way, if you're interested in seeing the abstracts for the posters and presentations from this conference, you can do so here: http://www.abstracts2view.com/aan

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Having identified several genetic and environmental factors that appear to affect the risk of MS, scientists are now starting to explore how these factors relate to one another in ways that contribute to the development of MS. Two recently published studies have focused on relationships between various factors that are thought to either increase or decrease the risk of MS. Another study is starting up to further explore this topic, and is reaching out to first-degree relatives of people with MS as potential participants.

The first study was conducted by a team of Swedish researchers, who were interested in whether smoking and immune system genes might interact in determining MS risk. In this study, 843 people with MS and 1209 controls donated DNA samples and completed questionnaires that asked about smoking history, in addition to other topics. The DNA was analyzed for the presence of immune system gene variants HLA-DRB1*15 and HLA-A*02, which have been found to increase and decrease the risk of MS, respectively. The risk of MS was 14 times higher in the group of smokers with DRB1*15 and without A*02 than in non-smokers negative for DRB1*15 and positive for A*02. This increase in risk was greater than if the individual risks for these factors were added together, suggesting that smoking has an especially significant effect on MS in people with certain immune gene variants. The authors suggested that smoking might set off an immune response in the lungs that leads to MS, perhaps involving irritation or infection.

The second study, performed in Australia, sought to clarify the relationship between ultraviolet radiation (UVR) and vitamin D in protecting against MS. Both have been associated with reducing the risk of MS -- but is the association with UVR due only to its vitamin D-producing effect? 216 cases with a first demyelinating event and 395 matched controls were compared in terms of past UV exposure (self-reported exposure and measured sun damage to the skin), and serum vitamin D levels. Increased UVR exposure and higher levels of serum vitamin D were both associated with a reduced risk of MS. However, analysis of the associations showed somewhat independent effects for UVR and vitamin D. This suggests that UVR may provide additional protection against MS via mechanisms that are separate from vitamin D production.

To better understand how various types of risk factors contribute to MS, a team at Brigham & Women's Hospital in Boston MA is launching the "Genes and Environment in Multiple Sclerosis (GEMS) Study." They are enrolling people aged 18-50 who have a parent, child, or sibling who has been diagnosed with MS -- people with MS can also enroll as long as they have a first-degree relative with MS. Subjects will be asked to provide a saliva DNA sample and to complete a 15-minute online survey; some subjects will also be asked for a blood sample and an MRI, but this is optional. Additional surveys will be conducted every 3 years, and the study will run for up to 20 years. The scope (up to 5000 subjects) and long duration of the study mean that lots of data will be collected for MS risk research. One of the goals of the study is to develop an MS "risk score" which could be used to help identify people with the highest risk of MS -- who could then be given up-to-date advice about MS risk reduction. If you're interested in learning more about this study, you can contact the research coordinator, Irene Wood, at 617-264-5980 or at bwhmsstudy@partners.org.

A research team in Argentina has been studying the effect of helminth (worm) infections on MS for several years, reporting that people with these infections appear to have lower levels of MS disease activity and severity. A new study associates antihelminth treatment in people with MS with worsening disease, supporting the idea that certain parasitic infections could have a protective effect on MS.

This study includes twelve people with MS who had been diagnosed with intestinal worm infections of various types. Each was followed for several years, and eventually four of the subjects required anti-parasitic treatment due to symptoms such as fever, abdominal pain, anorexia, diarrhea, etc. The other eight were able to remain untreated. The researchers compared MS relapses, EDSS, and MRI measurements in the treated and untreated subjects, as well as in 12 uninfected MS subjects. Prior to antihelminth treatment, the infected subjects experienced minimal MS exacerbations, EDSS changes, or new MRI lesions. However, in the months following antihelminth treatment, those subjects who had been treated experienced increased clinical and MRI disease activity, with levels of disease activity rising to reach a level similar to that of the uninfected subjects.

Studies of immune system response (secretion of immune factors and number of inflammatory/anti-inflammatory cells) were also performed. These studies compared the treated subjects, untreated subjects, uninfected MS subjects, and healthy controls. Again, the antihelminth treatment was followed by a shift from an anti-inflammatory to a pro-inflammatory profile. Exposing the cells used in the assays to the antihelminth drugs that were used to treat the infections did not affect the results of these assays, suggesting that the worms have a protective effect on MS as opposed to the drugs having a harmful effect on MS.

The authors acknowledged certain limitations of this study, namely the small number of subjects and the fact that the investigators were not blinded as to the infection and treatment status of the subjects. They also caution against using parasitic infections to treat MS, stating that a better approach might be to identify which of the molecules that are produced by helminths are responsible for the therapeutic effect. (However, there are a couple of clinical trials taking place involving helminth infection -- it will be interesting to see the results generated by these studies.)

The disease-modifying drugs currently available for MS have well-established effects on relapse rate and white matter lesion development. Whether they also help to protect gray matter has been an open question, primarily due to the difficulties in imaging gray matter lesions. However, since gray matter pathology has been linked with disability and cognitive dysfunction, it is important to learn what effect standard therapies might have in these regions.

A team of scientists in Italy has performed a study on this topic using an MRI technique called double-inversion recovery (DIR), which is capable of imaging lesions in the cortex (the gray matter layer that constitutes the outer edge of the brain). (Click to see the abstract or open-access full text of their paper.) Their study included 165 people with MS randomized to one of three treatments (two forms of interferon-beta and glatiramer acetate). Also included were 50 people with MS who chose not to be treated (due to benign course, needle phobia, pregnancy plans, etc.). Subjects were imaged at baseline and at 12 and 24 months.

At both timepoints, the treated subjects were less likely to have developed new cortical lesions than the untreated subjects (45% vs. 74% at month 12, and 64% vs. 82% at month 24). The number of new cortical lesions was also lower in the treated vs. untreated subjects. Comparing across the different drugs, the largest effects were seen in those subjects taking IFN-b 1a 44 mcg subcutaneous 3x/week, followed by glatiramer acetate, followed by IFN-b 1a 30 mcg intramuscular 1x/week. These differences across drugs were greater at 12 months, and still present but less pronounced at 24 months. The treated subjects also had lower rates of gray matter atrophy compared with untreated subjects (no differences across drugs). As expected, white matter lesion development and relapse rates were also lower in the treated vs. untreated subjects.

This study suggests that the first-line disease-modifying drugs for MS may curb lesion-promoting inflammation in the cortex as well as in the white matter. It is encouraging to think that this critical area of the brain could receive some protection by available MS drugs. Hopefully this line of investigation will be continued, and expanded to include the emerging MS drugs as well.

The nonprofit group CCSVI Alliance is hosting an educational meeting on the topic of CCSVI at Brandeis University in Waltham, MA on the evening of January 10, 2011. The title of the meeting is "MS and the CCSVI Connection: What do we know? What don't we know? Where do we go from here?" and the speaker will be Dr. Michael Dake, professor of cardiothoracic surgery at Stanford University. Dr. Dake was one of the first doctors to try surgical treatment of CCSVI in people with MS. He placed stents in 35 people but had to stop performing this procedure after one person died following the procedure and another required emergency open-heart surgery to retrieve a dislodged stent.

You can visit this Evite page set up by the CCSVI Alliance for more information and registration (admission is free).

Much of the immunology research in MS has focused on the immune system's potentially harmful activities and behaviors, such as the role of pro-inflammatory Th17 cells which have been associated with EAE and MS. However, the immune system also has potentially helpful activities and behaviors, and one line of thought is that these beneficial responses are ineffective or muted in MS. Two papers that were recently published support that idea.

The first study reports that T cells from MS subjects produce less of a protein called "noggin" than T cells from unaffected controls. In the brain, noggin has the effect of encouraging neural precursor cells to differentiate into astrocytes, neurons, and oligodendrocytes. Noggin is expressed by cells in the lining of the brain but is also expressed by immune cells. The authors hypothesized that impaired secretion of noggin by immune cells might hold back attempts at remyelination in MS lesions. They studied blood samples from people with MS (either treated with interferon-beta or untreated) and controls. Their analyses indeed showed lower levels of noggin production by T cells in the MS subjects vs. the controls, both under normal conditions and after stimulation with various factors. IFN-beta didn't seem to affect noggin production one way or the other.

The second study focused on the ability of regulatory T cells to migrate within the body and specifically through the blood-brain barrier. Regulatory T cells help to control the inflammatory response and are thus thought of as being helpful in limiting MS disease activity. Compared with other (non-regulatory) T cells, regulatory T cells from mice and healthy humans demonstrated an enhanced ability to migrate and pass through a simulated blood-brain barrier in lab experiments. In fact, these cells have a strong presence in central nervous system tissues of normal mice, indicating that they play a surveillance role there. However, regulatory T cells taken from people with MS had impaired migration abilities under noninflammatory conditions. Perhaps regulatory T cells in people with MS have a harder time entering the central nervous system, which results in a decreased regulatory response at sites of inflammation.

Hollie's Notes From the 2010 ECTRIMS Meeting in Gothenburg, Sweden

Each year Accelerated Cure Project attends the ECTRIMS conference. We try to take notes on as many presentations as we can, write them up, and make them available on MSNews for anyone to read.

You can see our notes below. By the way, if you're interested in seeing the abstracts for the posters and presentations from this conference, you can do so here: http://registration.akm.ch/einsicht.php?XNKONGRESS_ID=126&XNSPRACHE_ID=2n

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The University of California San Francisco has a substantial MS research program, with particular strengths in genetics and imaging. Scientists from both of these disciplines recently collaborated on a project to learn more about the role of inherited gene variants in MS. In addition to influencing who gets MS and who doesn't, genes may also affect the course or severity of disease, but this aspect of MS has not yet been as extensively explored.

This project focused on the role of glutamate. Glutamate plays an important role in nerve signal transmission in the central nervous system, but it can be harmful to cells if concentrations are too high. Normally oligodendrocytes help to regulate glutamate concentrations by taking in excess glutamate, but this process is impaired in MS, and past research has documented elevated levels of glutamate in MS brains.

The imaging researchers scanned the brains of 382 MS subjects using spectroscopy, which measures the level of different molecules in tissue. The geneticists performed a genome-wide genetics screen on the same subjects. The team then analyzed the genetic results with respect to the glutamate levels determined by spectroscopy. They found several variants in genes associated with glutamate biology that were more common in subjects having the highest concentrations of glutamate. Further analysis showed similar genetic associations in subjects with higher brain atrophy (shrinkage) and lower concentrations of a molecule found in axons (N-acetylaspartate).

These results suggest that inherent genetic differences in nervous system biology among people with MS may influence concentrations of glutamate within the central nervous system, which may then affect survival or death of axons. It is encouraging to see scientists from different disciplines coming together in MS research, because looking at a question from more than one angle can lead to a much better understanding of the disease.

Vitamin D deficiency has been associated with increased risk of MS in several studies. However, the basis for this relationship remains unknown. A study published last year provided evidence that vitamin D affects the expression of the leading MS susceptibility gene (HLA DRB1*1501), indicating that gene expression effects may at least partially account for vitamin D's connection with MS. Now a new study appearing in the journal Genome Research further explores the connection between vitamin D, gene expression, and MS (as well as other diseases). Click here for the abstract and here for the full-text PDF.

Gene expression is the process by which a DNA sequence is copied into messenger RNA, which is then decoded by cellular structures to manufacture a protein needed by the cell. Whether and when a particular gene is expressed can be affected by different factors. Some of these factors are molecules that bind to DNA to increase or decrease copying of a gene sequence into mRNA. One of these factors, called Vitamin D receptor (VDR), becomes activated after it binds to a form of vitamin D called calcitriol. Once activated, VDR can then latch on to certain sequences on the chromosome which affects (increases or decreases) the expression of nearby genes. Therefore, being deficient in vitamin D can directly affect the level of production for certain proteins in a person's cells.

In this new study, a team of researchers used cell lines from two people to find 623 places in the genome where VDR binds. These locations are called vitamin D response elements, or VDREs. They found many more VDREs (2776) after exposing the cells to calcitriol. They also measured gene expression within these cells before and after exposure to calcitriol, and found 226 genes for which gene expression was increased and 3 for which it was decreased. Many of these genes play a role in immune function, and about a quarter of these genes had a VDRE nearby.

Next, the team analyzed the locations of the VDREs they had detected to see if they were located near to disease susceptibility genes (genes for which certain variants are more frequently found in people with a condition -- like HLA DRB1*1501 and MS). They found that many VDREs were located near genes that had been previously associated with MS and other autoimmune diseases as well as certain cancers. For example, one of the new VDREs was found in the IRF8 gene, which has been associated with MS -- and IRF8 was also one of the genes for which calcitriol enhanced gene expression. They did not find that the actual variants associated with these diseases had the potential to directly disrupt VDRE function, which would have helped solidify this line of investigation. However, perhaps they are inherited along with other nearby genetic variants that do affect VDR binding.

Finally, the researchers analyzed data from another study that had measured gene expression in people with MS and control subjects. They compared the list of genes that were expressed to a greater or lesser degree in MS subjects with their list of genes that had nearby VDREs. They found that VDR binding was indeed enriched in those genes that were differentially expressed in the MS subjects.

This study moves us a little farther along in understanding why vitamin D deficiency has been linked with MS. If vitamin D does play an active role in the disease -- by affecting expression of several genes -- then it may be helpful to correct any deficiency even after MS has been established since these genes may also influence the course of MS. In fact, another recent paper has found that vitamin D levels were connected with subsequent risk of relapse in people with MS. It would be interesting to extend this type of study to also include gene expression analysis. In the meantime, if you have MS and haven't yet discussed vitamin D with your doctor, perhaps that would be a good topic to bring up.