Research Studies
Epstein-Barr Virus Linked to MS

May 4, 2009

Infection with Epstein-Barr virus (EBV) appears to raise the risk of developing multiple sclerosis (MS). It's widely known that almost everyone is infected with EBV by the time they reach adulthood. Infection early in childhood typically doesn't cause severe illness but infection that occurs in adolescence often leads to mononucleosis (mono).

Researchers have searched for a viral or bacterial agent that may trigger MS in people who are genetically susceptible. Epidemiology professor Alberto Ascherio, MD, DrPH, and colleagues at the Harvard School of Public Health in Boston have published several studies suggesting that the EBV may be that agent.

The study showed that people who are not infected with EBV didn't get MS. The study also says that 100% of the people who got MS in the study were infected with EBV.

The findings were presented at the annual meeting of the American Academy of Neurology.

The researchers were granted access to more than 7 million blood specimens stored in the Department of Defense Serum Repository. The U.S. military maintains service members' medical records in electronic databases.

The researchers identified 305 service members who were diagnosed with MS and had up to three blood samples taken prior to their diagnosis. Researchers compared these blood specimens with samples from 610 people who didn't develop MS but were similar in age, race, sex, and other characteristics to those who did.

The initial blood sample tested negative for EBV-fighting antibodies in 10 (3.2%) of people who developed MS and 32 (5.3%) of people who didn't. Measuring antibodies, which are proteins produced by the body to fight specific infections, is one way to determine the intensity of infection.

More important was that all 10 of the people who developed MS went on to test positive for EBV antibodies before the onset of neurological symptoms. They tested EBV-positive an average of four years before symptoms of the disorder first appeared.

In contrast, only 30% of the people who didn't develop MS later tested positive for EBV.

Further analysis showed about a 50-fold increased risk of MS among people with the highest levels of EBV antibodies, compared with those with the lowest levels.

The study shows that EBV most likely works in concert with environmental factors to trigger MS in people who are genetically vulnerable to the disease. The researchers also believe that one of those factors may be vitamin D deficiency.


Epstein-Barr Virus is Associated with Gray Matter Atrophy in Multiple Sclerosis

January 23, 2009

Researchers from the University of Buffalo and the University of Trieste, in Italy, published a study that looked at 135 MS patients who underwent both an MRI and testing for the levels of EBV antibodies which is a sign of prior infection.

The study set out to determine whether the presence of anti-EBV antibodies is associated with MRI measures of brain injury and neurodegeneration in MS patients. The study had the 135 MS patients undergo MRI's of the brain and testing for antibodies against EBV. The MRI measurements included gadolinium-enhancing (Gd) lesion volume, T1 and T2 lesion volumes and fractions of whole brain parenchyma (BPF), white matter (WMF) and gray matter (GMF).

The anti-EBV panel included anti-EBV early antigen (EA) IgG, anti-EBV nuclear antigen (EBNA) IgG, and anti-EBV viral capsid antigen (VCA) IgG levels. The relationships between antibody levels and MRI measurements were assessed in regression analysis. Repeated measurements of anti-EBV VCA IgG and MRI measures were available for a subset of 50 patients after mean follow-up of 3.1 years.

The findings showed negative associations with anti-EBV-VCA IgG levels. Higher decline in BPF was significantly associated with increased 3 year time point anti-EBV VCA IgG levels. The conclusions of the findings suggest that the presence of anti-EBV antibodies is associated with MRI markers of GM atrophy in MS and with increased loss of brain volume over 3 year follow-up.

To summarize, the people with the EBV antibodies were more likely to show MRIs that had increased loss of gray matter and total brain volume. This gives more support to the possible link between prior infection with Epstein-Barr and MS.


New Imaging Technique Could Promote Early Detection of Multiple Sclerosis

June 27, 2007

Researchers from Purdue University have studied and recorded how myelin degrades real-time in live mice using a new imaging technique. Myelin is the fatty sheath coating the axons, or nerve cells, that insulate and aid in efficient nerve fiber conduction. In diseases such as MS, the myelin sheath has been found to degrade.

This unprecedented feat of looking real-time at the actual progress of demyelination will advance understanding of and perhaps promote early detection of conditions such as MS.

Using a technique called coherent anti-Stokes Raman scattering microscopy, or CARS, scientists observed the injection of a compound called lysophosphatidylcholine (LPC) into the myelin of a mouse. Then, using CARS, they observed an influx of calcium ions into the myelin. This influx is now believed to start the process of myelin degradation.

The research was supported and reported by the National Science Foundation.


KLK6

Kallikrein-related peptidase 6, also known as KLK6, is a human gene.

A recent study has been looking into two enzymes that could indicate the progression of MS. Higher than normal levels of a kallifrein enzyme now known as KLK1 and KLK6 were found in people with secondary-progressive MS (SPMS). This could at least give a warning as to the activity and possible progression of the disease.

Current MS therapies reduce relapses and new magnetic resonance imaging (MRI) lesions, but are less effective in attenuating progression. Further understanding the pathophysiology of progressive MS is therefore needed for the rational design of novel appropriate therapies.

Kallikreins are a subgroup of serine endopeptidases having diverse physiological functions. It's felt that many kallikreins have potential as cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. The encoded enzyme is regulated by steroid hormones.

Although immunopathogenic mechanisms of MS initiation and progression are not completely understood, members of several protease families called the MS degradome, likely contribute. Proteolytic events participate in the development of inflammatory responses, including immune cell activation and extravasation, demyelination, cytokine, chemokine and complement activation, apoptosis, axon injury, and epitope spreading.

With the abundance of kallikreins in MS disease activity, the goal of the study was to determine whether serum kallikrein levels are altered in MS patients. It was also looked at whether serum kallikrein levels correlate with the Expanded Disability Status Scale (EDSS) as a measure of neurologic impairment, and/or the relapsing-remitting MS (RRMS), or more progressive stages of disease.

The data from this study suggested that KLK1 and KLK6 may represent important new therapeutic targets for the development of novel treatments for progressive MS patients. This doesn't solve the puzzle, but rather provides an additional clue to puzzle.


HDAC

Histone deacetylases, also known as HDAC, are a class of enzymes.

These enzymes remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone.

A study involving HDAC enzymes has been looking into oligodendrocyte progenitors, or young myelin-making cells. Enough of these cells are needed so they can then go to the site were myelin has been damaged and needs to be repaired. Once there, they are then instructed that they are there to make and repair the myelin. It is being looked into that if specific molecules might possibly be blocking or inhibiting the genes activation.

The study showed that a HDAC inhibitor drug called trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and improves disability in the relapsing phase of experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

It was found that the drug TSA up-regulates antioxidant, anti-excitotoxicity and pro-neuronal growth and differentiation mRNAs. TSA also inhibits caspase activation and down-regulates gene targets of the pro-apoptotic E2F transcription factor pathway. A transcriptional imbalance in MS may contribute to immune dysregulation and neurodegeneration. The study identified the HDAC inhibition as a transcriptional intervention, or blocking the synthesis of RNA to improve this imbalance.


TREM-2

Triggering receptor expressed on myeloid cells 2, also known as TREM2, is a human gene.

TREM-2 is a receptor protein, which means that another molecule activates it and has been found in higher amounts in spinal fluid. It's typical to find it on the surface of immune cells where it keeps things calm and quiet.

The fact that they are floating freely in the spinal fluid gives some indication that it may actually be binding to an unknown cell and not an immune cell, reducing the chances that it will bind to and activate TREM-2 attached to immune cells. When activated, TREM-2 has been found to reduce immune inflammation when it is not confused or interfered with.

If this theory is confirmed, the TREM-2 in the spinal fluid or its unknown partner could become targets for new MS treatments.