Amit Bar-Or, MD, FRCPC-Heuroimmunology Unit, Montreal Neurological Institute, Montreal, QC, Canada

Introduction
There are two major body systems whose interactions are responsible for multiple sclerosis (MS). One is the central nervous system (CNS), whose cells are damaged or destroyed by the disease. The other is the immune system, whose cells are thought to perpetrate the damage. Information that is useful for understanding MS can be drawn from studying both of these systems separately and by looking at their interactions.

The immune system is responsible for the inflammation that is seen at active lesions in the CNS. Immune cells are thought to be somehow triggered in the periphery and then invade across the blood brain barrier (BBB), into brain, where they attack brain tissue as if it were a foreign invader. The cells that make the myelin sheathe that surrounds the nerve fibers are damaged in this attack, as are the nerve fibers, and the nerve cells may ultimately die. Repeated episodes of immune attack, tissue damage, and the gradual cessation of inflammation account for the “relapses” and “remissions” of relapsing-remitting (RR) MS.

In addition to having destructive properties, immune cells have a variety of normal functions that are meant to protect and repair tissue. In MS lesions, however, the immune cells are triggered to release inflammatory molecules that may cause damage as well as recruit other immune cells to the site. These molecules may also encourage the generation of proinflammatory cells.

The immune system’s role during the late, secondary progressive (SP) stage of the disease is less clear. During this stage, relapses are usually few or nonexistent, and disabilities increase without periods of recovery. MRIs taken during this stage of the disease generally do not show the formation of new active inflammatory lesions. Therefore, it is unlikely that ongoing inflammation (due to peripherally activated immune cells invading the CNS) is responsible for the progression of damage in the CNS (see Figure 1). Instead, this stage of the disease seems to depend on the biology of the CNS as it responds to decades of repeated immune attacks. It now seems likely that many neurons whose fibers were attacked earlier in the course of the disease die off during the progressive stage (See Trapp 2007 in MSQR Vol. 26/2, pp. 6-10). The dying cells disappear from the gray matter of the CNS, which houses the cell bodies of neurons, causing widespread abnormalities that are not readily visible on standard MRI.

How and why the immune attack begins in the first place is not yet clear. The immune system is normally separated from the CNS by an intact barrier, the BBB. Although, like all organs, the brain requires oxygen and nutrients from the blood, the BBB is designed to limit blood cells and many other substances from entering the brain. Immune cells, which are also known as white blood cells, travel in the blood to patrol the body for harmful invaders, like viruses and bacteria. However, they are equipped to make proteins that can open the BBB. At the start of an MS attack, they do just that, moving across the BBB to invade a CNS area that will ultimately become a lesion. Once the BBB has been breached, it is easier for other substances and immune cells to follow.

This description of how MS is believed to develop also suggests several points where intervention with treatments may slow or prevent continued damage. These interventions could involve the immune system, the CNS, or their interactions. With respect to targeting the immune attack, therapies might attempt to prevent the original activation of immune cells outside the CNS, to interfere with their recruitment to the lesion site, and/or alter the kind of molecules they release once in the lesion. Therapies that target the nervous system might be aimed at eliminating or hiding the molecules that trigger the immune cells or finding ways to help the neural cells (neurons, oligodendrocytes that make the myelin, etc.) repair themselves after they are damaged - rather than dying.

Current Research
Much of the research into understanding MS has been carried out in animal models, such as in rats or mice. Because MS is thought to be an autoimmune disorder (that is, a disorder in which the immune system recognizes proteins in the body as alien invaders), there has been great interest in understanding what might prompt immune cells to recognize and attack targets in the CNS. Immunizing rodents with certain myelin proteins can cause a very predictable demyelinating CNS disease that is similar to MS, which suggests that MS may indeed be initiated by a triggering event, where immune cells become activated in the periphery to some exposure, and then attack the CNS. Treatments that modify the rodent disease may also be effective in humans. There are limitations, however, inherent in animal models of diseases. Animals do not always react in the same way as humans, models of disease may not correctly reflect all the particulars of human disease, and humans are far more genetically diverse than lab-use rodents, who generally share the same genes.

Trying to determine the initiating event in adult MS patients has been difficult because they typically have had decades of exposure to many viral, bacterial, parasitic, and environmental antigens. Their immune systems show complex reactions to antigens, and there are several common viruses that most adults have been infected with and make antibodies against, which makes it impossible to discover whether any of these viruses might be associated with triggering of the autoimmune disease process.

There is a specific set of patients with MS a much simpler immune history: children. They have less exposure to pathogens and other environmental immune triggers than adults, and an analysis of the cells or antibodies in their blood may prove useful in terms of figuring out how MS is triggered or propagated in the early stages. Studies of children with MS have the potential to improve the care for the children as well as to provide a greater understanding of the triggering event for MS in general.

Epstein Barr Virus (EBV), best known as the cause of mononucleosis, is one of the viruses that most adults have antibodies against. It can cause other illnesses as well, and there has been some interest in finding out if it might be a trigger for MS. One theory behind this is called molecular mimicry. The idea is that if a protein fragment of a virus (or other pathogen) resembles a protein in the body, the immune system might be triggered to attack its own tissues, while it is trying to respond to the pathogen. In fact, everyone has some immune cells in their blood that recognize the myelin proteins often targeted in MS. They don’t attack the body, though, because the immune system has a mechanism for recognizing “self” antigens, and blocks any such attack. If, however, some external antigen triggered an immune reaction from these cells, the activated immune system might now perceive the body’s own tissues to be an appropriate immune target. In this case, T-cells that normally don’t respond to “self” antigens would instead be activated or “primed” by the molecular mimic, which could then lead to a pro-inflammatory immune response.

One research group (Alotaibi et al., 2004; Banwell et al., 2007) measured EBV antibodies in blood samples from children with MS and compared the results with samples from healthy children, children with some other autoimmune disease, or children with a different neurological disorder. They found that more than 80% of the children with MS showed antibodies to EBV, and that their exposure to EBV had happened a considerable time earlier. In the other groups of children, only about 40% showed such an antibody response to EBV. Although this is certainly not proof of a role for EBV in MS, it is consistent with the idea that
EBV could cause an immune response that might, over time, lead to an attack on the nervous system.

Another way immune cells might be primed to attack “self” antigens is through exposure to protein fragments in the blood or lymph system (which contains immune cells but no red blood cells). The lymphatic fluid is intended to carry antigens to lymph nodes, where T-cells can encounter them.

In a study of children with diabetes (an autoimmune disorder) or MS, researchers found that the children carried T-cells in their blood that were “primed” to react with specific antigens in the affected tissues. That is, patients with MS had T-cells primed to react with myelin proteins, and patients with diabetes had T-cells primed to react with the pancreas. Another group of children, who had had a single MS-like neurological episode, which means that they also had a strong likelihood of developing MS, had many more Tcells primed to react with myelin antigens than did healthy children. Moreover, the three groups with these autoreactive T-cells also had increased T-cell responses to antigens from foods (dietary antigens), suggesting that their immune system was generally more reactive to novel antigens than that of healthy children. It is possible that early exposure to dietary antigens enhances the immune response to self-antigens as well, though this relationship requires further investigation.

Understanding pediatric MS will help in understanding adult-onset MS, because these two forms of the disease are likely to share at least some of the same disease mechanisms.

New Treatment Approaches
Several new treatments for MS are being developed. One treatment (called APL for ‘altered peptide ligands’) involves injection of small, altered peptides that are very similar to pieces of myelin proteins into patients to “trick” T-cells into binding them (see Markovic-Plese, 2005 in MSQR Vol. 24/2, pp. 5-9). The intent of this trickery is to alterthe way T-cells respond after binding that antigen. This is possible because immature T-cells can divide and differentiate into different kinds of activated T-cells, including ones producing either pro-inflammatory or anti-inflammatory molecules. The so called Th1-cells promote inflammation by recruiting other immune cells and releasing molecules that attack the source of the antigen. Th2-cells, on the other hand, tend to decrease Th1-mediated inflammation. The idea behind the APL strategy is to drive the T-cells to differentiate into Th2-cells, rather than Th1-cells, and thereby prevent inflammationinduced damage. Clinical trials suggest that this approach may prove at least partially effective, although more studies are needed since there is some concern that APLs may inadvertently trigger a pro-inflammatory response in certain situations.

Another treatment under development attempts to modulate how the immune system responds by injecting DNA that carries instructions to make human myelin proteins into the muscles of patients with MS . This “DNA vaccine” is analogous to allergy shots, in that the DNA encodes proteins that are normally targeted by the anti-myelin antibodies and reactive T-cells in MS patients, and the intent is to modify the immune response by “teaching” the immune system to tolerate these proteins (similar to ‘desensitizing’ the immune system). This has been used effectively in a rodent model of MS, and an early clinical trial in MS has shown promising results without obvious toxicities, though the numbers remain small (Bar-Or, Vollmer, Antel, Arnold, Bodner et al., 2007). Instead of changing how immune cells behave, it is also possible to change which immune cells are present in the body. An antibody called rituximab, which has been used for some time to treat B-cell lymphomas, binds to B-cells, thus signaling other immune components to destroy them. B-cells appear to be involved in MS lesions and like T-cells, release molecules that can increase or suppress inflammation. In patients with MS, the B-cells behave abnormally, making relatively small amounts of a molecule that tends to suppress inflammation and relatively more of those that exacerbate it. The concept behind using rituximab to treat MS, then, is to reduce the numbers of B-cells in the body so that they cannot add to the inflammation by secreting harmful molecules. When patients with MS are given rituximab the number of B-cells in their blood drops precipitously. MRI studies showed that within a week or so of rituximab treatment, the number of new lesions in the patients with MS given rituximab was significantly lower compared with the number in patients with MS given placebo. The number of new lesions continued to drop in the rituximab treated group, reaching zero by 20 weeks after treatment, and remaining at zero through at least 24 weeks. In contrast, the placebo-treated group had about one new lesion at every 4-week interval when the MRIs were performed. These results indicate that rituximab may be very useful in reducing the damaging inflammation that characterizes the early years of MS. With respect to potential toxicity, rituximab use in patients with MS did not reveal unexpected safety signals. Infusion related reactions were quite common, but none rated as serious. There was probably a mild increase in the frequency of infections (such as upper respiratory) in the rituximab treated patients, though none were deemed serious. (Bar-Or et al. 2007; Hauser et al. 2007)

Another treatment that has been under investigation involves a very aggressive destruction of the immune system (including the autoimmune cells), and replacing it with transplanted bone marrow stem cells, usually from the patient’s own bone marrow. The hope has been that the bone marrow transplant would serve as a fresh start for the immune system, and that it would not again make cells that would attack the CNS. The results at the moment are mixed. The Canadian Collaborative Study Group on Bone Marrow Transplantation (BMT) reported no new relapses or new lesions among eight patients whose BMT was carried out an average of about 4 years ago. These patients were all young with very active MS that was not responding to other treatment. Their brains, however, seemed to continue to atrophy (shrink) after BMT. This observation may be due to a toxic effect of the chemotherapy, but may also demonstrate that this therapy does not entirely prevent the progressive or degenerative component of the disease process. In many patients, T-cells that recognized myelin proteins did return to the blood stream after BMT, and these cells secreted the same potentially damaging molecules as they did in the patients with MS before the treatment. All–in all, BMT does not appear to offer a cure for MS and because of its potentially significant risk (including fatal complications), it may only be appropriate to carry out in the most aggressive cases.

Summary and Conclusions
The state of MS research today indicates that MS is a disease where responses of two systems are important, both alone and in combination: the immune system and the CNS. An aberrant immune system that attacks CNS tissue, specifically myelin proteins, likely contributes to inflammation within lesions in the MS brain and damages myelin as well as nerve fibers. Over time, inflammation becomes a less dominant part of the disease, as the role of the CNS neurobiology takes over. Widespread abnormalities appear including the gray matter, the brain atrophies, and disabilities accumulate inexorably. Therefore, research approaches that consider both the immunology and the neurobiology of MS are needed.

Studies of special groups of patients, such as children, can help shed light on MS disease mechanisms, and some of these mechanisms are likely to be shared between populations of patients—for example, between childhood onset and adult-onset MS.

Several developing therapies that target different points in the disease cycle show promise. In particular, methods for altering the immune response or for removing harmful cells from the body may prove very beneficial.

References
Alotaibi, S., Kennedy, J., Tellier, R., Stephens, D., & Banwell, B. (2004). Epstain-Barr virus in pediatric multiple sclerosis. The Journal of the American Medical Association, 291(15), 1875-1879.

Banwell, B., Ghezzi A., Bar-Or A., Mikaeloff Y., & Tardieu M. (2007). Multiple Sclerosis in Children: Clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurology (in press).

Bar-Or, A., Calabresi, P., Arnold, D., Markovitz, C., Shafer, S., Kasper, L., et al (2007). A phase I, open-label, multicenter study to evaluate the safety and activity of rituximab in adults with relapsing-remitting multiple sclerosis (RRMS). Presented at the AAN meeting in Boston. Abstract S02.001 published in Neurology, 68, Suppl 1, A84.

Bar-Or, A., Vollmer, T., Antel, J.P., Arnold, D.L., Bodner, C.A., Campagnolo, D., et al. (2007). Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase I/II trial. Archives of Neurology (in press).

Hauser, S., Waubant, E., Arnold, D., Vollmer, T., Antel, J., Fox, R., et al. (2007). A phase II randomized, placebo-controlled, multicenter trial of rituximab in adults with relapsing remitting multiple sclerosis (RRMS). Presented at the AAN meeting in Boston. Abstract S12.003 published in Neurology, 68, Suppl 1, A99.

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