Medicine & Research

MS NEWS and What It Means to You

By Dr. Ben Thrower

Study Suggests New B Cell Role in MS

A new study points a finger at a subset of B cells – the GM-CSF-producing B cells – as a key contributor in the inflammatory immune cell responses in multiple sclerosis. The results offer new insights into the role of B cells and their interaction with other immune cells in MS.

The authors, led by Dr. Amit Bar-Or at the Montreal Neurological Institute  and Hospital, discovered that GM-CSF-producing B cells were more frequent and more prone to activation in MS patients. This subset of B cells activated inflammatory responses of myeloid cells of the immune system. They also found that after B cell depletion therapy, the myeloid cells became much less inflammatory. This suggests that BCDT may work by lowering the number of GM-CSF-producing B cells, limiting both myeloid cell and T cell contribution to new disease activity.

According to Bar-Or, “The study is significant in discovering a new way by which B cells can contribute to abnormal immune responses in MS, which reinforces the rationale for the use of B cell depletion therapy. Furthermore, by better identifying the particular subset of B cells responsible for new disease activity, we can look forward to more selectively targeting the ‘bad’ B cells while leaving ‘good’ B cells intact. This is important because B cells normally play key roles in our immune system, so more selective therapies offer the prospect of decreasing the risk of impairing the patients’ immune system in the long run.” 

The findings were published in the journal Science Translational Medicine.  

Dr. Thrower: Our understanding of the immune system and how it goes awry in conditions like MS, continues to grow. Two of the major cell lines of the human immune system are T cells and B cells. In the past, much of the focus on MS management has been on the T cells. Clearly, B cells play a role as well. The timing of this renewed interest in the role of B cells is perfect given the likely approval of ocrelizumab in the future. It should be noted that the human immune system is complex and many components have multiple functions. While we typically think of B cells as mainly producing antibodies, they also serve as antigen presenting cells to the T cells. So, if a therapy like ocrelizumab targets B cell function, does it also indirectly affect T cell function? Adding to the complexity is the variation in how one individual’s immune system works versus another’s. Research has suggested that MS in one person may result more from T cell dysfunction while in others, it may result from B cell dysfunction and on others still, a combination of both. Understanding this complexity and variability will hopefully lead to more, and better, therapies and customized therapies based upon your unique immune profile.

Study: Estriol Helps Reduce Relapses, Protects Brain in Women with MS

Taking the pregnancy hormone estriol along with conventional medications helped patients with relapsing-remitting multiple sclerosis avoid relapses, according to results of a Phase II randomized, placebo-controlled study led by UCLA researchers.

The study’s lead author Dr. Rhonda Voskuhl, professor in the UCLA Department of Neurology and director of UCLA’s Multiple Sclerosis Program, and her team discovered that estriol reduces the ability of immune cells to attack the brain, while also making brain cells more resistant to damage if any immune cells do make it through. They also showed that estriol treatment improved cognition and prevented atrophy of the cognitive region of the brain. It seems that during pregnancy, estriol can both suppress the immune system and protect the brain.

In 2002, Voskuhl completed the pilot study, in which 10 nonpregnant women with MS were given estriol, yielding a greater than 70 percent drop in inflammatory lesions in the brain within only six months of treatment. In the Phase II study, researchers enrolled 164 female patients, with 83 allocated to the estriol group and 81 to the placebo group. (Both groups were also treated with Copaxone 20 mg subcutaneously.) The team found that the patients taking estriol had a third to a half as many relapses compared to those taking the placebo, with this improvement occurring over and above that provided by their conventional treatment. In addition, when estriol levels were the highest, there was improved cognitive function and less atrophy of the brain area related to cognition. The treatment was well tolerated during the two years the volunteers took estriol and the only significant side effect was irregular menstruation. Voskuhl hopes to see a Phase III trial conducted to replicate these findings.

The study was published in Lancet Neurology.

Dr. Thrower: It has long been noted that there is a hormonal relationship in MS. Women are diagnosed with MS three times more frequently than men. MS relapses frequently stop during pregnancy, especially during the second and third trimesters. Relapses become more common during the three to six months following pregnancy. Estriol seems to be at least part of the explanation for the protective effect of pregnancy in MS. Estriol is an estrogen that seems to be at its highest levels during pregnancy and should not be confused with estradiol, the estrogen typically used in oral contraceptives or in hormone replacement. Dr. Voskuhl has focused much of her MS research career on confirming the protective effects of estriol, determining the long-term safety and hopefully giving us another tool in the fight against MS.

Vitamin D Receptors May be Key to Remyelination

A new study suggests vitamin D might affect multiple sclerosis disease progression by controlling myelin sheath regeneration. The authors suggest drugs that activate vitamin D receptors might be able to enhance remyelination in MS patients.

A nuclear receptor protein called retinoid X receptor gamma is known to promote differentiation in oligodendrocyte precursor cells and remyelination. Because these receptors function in pairs, researchers, led by Robin Franklin at the University of Cambridge, UK, set out to identify RXR gamma’s binding partners and investigate their possible role in remyelination.

RXR gamma bound to several receptors, including vitamin D receptors, in oligodendrocyte precursor cells and mature oligodendrocytes. Inhibiting vitamin D receptors impaired oligodendrocyte precursor cell differentiation and reduced the cells’ ability to remyelinate axons. In contrast, vitamin D, which binds and activates vitamin D receptors, boosted oligo-dendrocyte precursor cell differentiation.

The findings were published in the Journal of Cell Biology.

Dr. Thrower: Where vitamin D was once just thought of as something that helped promote strong bones, its role in the immune system is becoming increasingly apparent. What do we know so far?
  1. The majority of people with MS have low serum vitamin D levels.
  2. Low vitamin D levels are associated with a higher risk of developing MS and may be associated with a more severe course of MS.
  3. Correction of low vitamin D levels seems to be associated with fewer relapses and new lesions on MRI.
  4. Many of the genes associated with MS play a role in vitamin D metabolism.

In our center, we routinely check 25-hydroxy vitamin D levels. Our goal is to get those levels up to 50 to 70. Supplemental vitamin D doses vary greatly and it must be kept in mind, that excessive vitamin D has health risks, including kidney stones. Many of our patients take an over-the-counter vitamin D3 50,000 unit dose, typically once weekly. The need for regular blood monitoring at these higher doses cannot be overstated.

Research has shown that optimal vitamin D doses are associated with higher numbers of T-regulatory cells, sort of like the traffic police of the immune system. This recent research suggests that vitamin D may play a role in remyelination as well – very exciting.

Study Suggests Possible Inside-out Origin for MS

A new study suggests an inside-out theory of multiple sclerosis in which the disease may be triggered by the death of brain cells that make the insulation around nerve fibers, according to a new study from Northwestern Medicine and the University of Chicago researchers. Creating a mouse-model of progressive MS, scientists also used a specially developed nanoparticle that prevented MS even after the death of those brain cells.

The new study shows the possibility that MS can begin from the inside out, in which damage to oligodendrocytes in the central nervous system can trigger an immune response directly. Oligodendrocytes can possibly be destroyed by developmental abnormalities, viruses, bacterial toxins or environmental pollutants. Oligodendrocytes are responsible for the maintenance of myelin. If they die, the myelin sheath falls apart. The death of these cells can activate the autoimmune response against myelin, which is the main feature of MS. The inside-out hypothesis suggests that when myelin falls apart, the immune system interprets the products of its degradation as foreign bodies or antigens, erroneously viewing them as invaders and beginning a full-scale attack on myelin, initiating MS.

“Protecting oligodendrocytes in susceptible individuals might help delay or prevent MS from initiating. It’s likely that therapeutic strategies that intervene early in the disease process will have greater impact,” Brian Popko, the Jack Miller Professor of Neurological Disorders at the University of Chicago and one of the lead investigators in the study said.

The scientists also developed the first mouse model of the progressive form of the autoimmune disease, which will enable the testing of new drugs against progressive MS. In the study, nanoparticles creating tolerance to the myelin antigen were administered and prevented progressive MS from developing. The nanoparticles are being developed for clinical trials that could lead to new treatments – without the side effects of current therapies – in adults. 

The study was published in Nature Neuroscience.

Dr. Thrower: It has long been suspected that there is lots of variation under the umbrella of MS. This means not only variation in how MS presents and progresses, but even variation in how it comes to exist and how the immune system goes off the rails. Earlier, we discussed the role of B cells and T cells and how that may vary from person to person. Another interesting line of argument is about which comes first; damage to the myelin or damage to the underlying axon (nerve fiber). Prior to 1998, there really was not much thought that MS did anything more than damage the myelin that insulates the axon. Since that time, we know that the axon can be damaged as well and that this axonal damage may be the underlying cause for permanent disability.

Traditionally, we have thought that damage to the myelin leads to secondary damage to the axon. Studies such as this one from the University of Chicago ask, “What if we have the order backwards? What if the real initial event is something going wrong with the axon and that leads to a breakdown of myelin? This myelin breakdown may then initiate an immune response leading to further damage.” If this situation is true, it may be true only for some people with MS and not all. If it is true, it could also mean that we need to take a different approach to stop progression.