By using computers to compare thousands of genomes, scientists are identifying genes that occur more frequently among people with multiple sclerosis. This new knowledge about the genetic underpinnings of the disease supports the hypothesis that malfunctions of the immune system drive the disease, and suggests more effective strategies for treating it.
At present, almost all treatment options involve suppressing the most conspicuous consequence of the disease—the inflammation that damages myelin, the fatty white coating that insulates the slender fibers known as axons that transmit electrochemical signals away from a neuron’s cell body.
The multiple layers of myelin wrapped tightly around an axon enable signals to travel rapidly, producing movement, sensation, perception and thought. When damaged by inflammation, the myelin sheath develops a lesion or scar that disrupts those signals. Since the myelin of any axon in the brain and the spinal cord is vulnerable to attack, people with MS can develop a wide array of symptoms, among them numbness and tingling, vision loss, weakness, paralysis, tremors, poor balance, bladder and bowel problems and cognitive changes such as memory loss, poor concentration or difficulty in planning tasks.
The disease also varies greatly in severity. Some people have mild symptoms that occur rarely, and may cease altogether, while others progress to profound disability that prevents them from walking, feeding themselves and performing other routine tasks. New genetic insights that reveal what makes some people more vulnerable to MS will undoubtedly help scientists treat the inflammation of the myelin that causes symptoms, and may also help them interrupt the disease before the inflammation causes problems.
Faulty Immune System May Be Tied to Genes
Axons in the brain and spinal cord, which constitute the central nervous system, or CNS, are protected by the blood-brain barrier, a tight layer of cells within blood vessels that prevents many substances from passing into the CNS from the blood, while allowing oxygen, glucose, other nutrients and a limited number of other substances to pass freely. Certain immune cells (T cells), which recognize and attack non-body molecules, are also blocked. In MS patients, however, these cells somehow get through the blood-brain barrier and attack the myelin as though it were a foreign substance. This attack triggers the inflammation that damages the myelin sheath. Cells known as oligodendrocytes produce new myelin and wrap it around the newly denuded portions of axons, but this process is imperfect, and signals have difficulty crossing the patched areas. Eventually, the inflammation and residual demyelination and axonal damage results in cumulative and debilitating deficits.
About half a million people in the United States have MS, which usually appears in young adulthood as the relapsing-remitting form of the disease. During a relapse or exacerbation, the patient develops a symptom—numbness and tingling in an arm, perhaps, or loss of vision, or vertigo—which usually improves gradually, with or without treatment.
About 10 to 20 percent of MS patients, however, begin with primary-progressive MS, which involves a continuous, gradual decline in physical abilities.
About half of the patients who begin with relapsing-remitting MS progress within ten years to secondary-progressive MS, characterized by frequent exacerbations that produce severe symptoms resulting in permanent disability.
And a few patients—less than 5 percent—display a combination of the relapsing-remitting and primary-progressive forms of MS. They experience a continuous gradual decline punctuated by severe exacerbations that accelerate disability.
Four patterns seen in the development of multiple sclerosis.(Wikimedia Commons, licensed under the GNU Free Documentation License)
Circumstantial evidence strongly suggests that genes confer susceptibility to MS: The disease is most common among people of Northern European ancestry, while other groups, including European Gypsies, Eskimos and African Bantu, rarely get MS. Also, if one identical twin gets MS, the other has a 30 percent chance of getting it too, whereas the fraternal twin of an MS patient acquires the disease only 4 percent of the time. MS occurs more frequently among family members of people who have it, and women get MS three times as often as men. All these statistics make a persuasive case for a genetic model of illness.
However, an environmental trigger such as a virus is believed to initiate the disease in people who are genetically susceptible to it.
Most existing treatments for MS attempt to adjust the immune system in some way so it won’t attack myelin, but insight into the genetic underpinnings of the disease may lead to methods of preventing immune cells from getting into the CNS in the first place—a treatment that would effectively halt the disease process.
Genome Studies Provide Clues
The mapping of the human genome, combined with the massive computer power needed to analyze the DNA of vast numbers of people, is revealing subtle genetic differences among people with MS.
One ongoing study, for example, involves comparing the genomes of 22,000 people to find genes that occur more frequently in people with MS.1
So far only a few genes have been found that appear to make people more susceptible to MS, with each gene contributing slightly to overall susceptibility. This evidence makes scientists suspect that MS, like diabetes, autism and other genetically complex diseases, involves many genes working together. “There will certainly be a hundred genes, maybe more, that are serious players,” said Stephen L. Hauser of the University of California, San Francisco, who has created a DNA bank containing samples from MS patients and their relatives.
No single gene is likely to emerge as a major culprit, he added. “But I’m confident that genetic variants will lead us to novel pathways that will simplify our understanding of the disease and make a critical connection with environmental risk.”
The genetic findings so far support the prevailing theory that MS results when the immune system mistakenly attacks the myelin around axons.
“We now have about a dozen genes that have been implicated in MS, and they’re all immune genes,” said David A. Hafler of Harvard Medical School and Brigham and Women’s Hospital in Boston. “All are involved in dictating the immune response, and they all have incredible similarities genetically. Right now the genetics are explaining only a small part of the risk, and there are probably hundreds of variants working together, as in all complex genetic diseases, but we’re in the early stages. I think this is a very exciting time.”2
Hafler expects a better genetic understanding of the disease to explain the wide variability in the severity of symptoms that MS patients experience. This also will allow for customized treatments that consider each patient’s unique genetic endowment.
“Now patients undergo a process of trial and error to find the treatment that works best for them,” he said.
Still, the genetic evidence so far fails to settle a fundamental debate regarding the cause of MS: Is the immune system attack on the myelin the cause of the disease or the result of another form of dysfunction elsewhere in the brain and spinal cord?
Richard A. Rudick, director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, leads investigations into the root causes of the disease.(Courtesy of Richard A. Rudick / Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research)
Environment Leads to Inflammation
“We don’t know the cause of MS—that’s the bottom line,” said Richard A. Rudick, director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research. “And I think the two ideas about the disease are somewhat irreconcilable.”
The leading hypothesis maintains that an environmental trigger such as a virus causes the immune system to overreact and mistakenly initiate a persistent attack on myelin. (The Epstein-Barr virus, which causes infectious mononucleosis, is a leading contender.3) The resulting scar or lesion in the myelin disrupts the transmission of signals and eventually damages the neuron, producing the degeneration and permanent disability that appear in later stages of the disease.
The competing hypothesis asserts that the immune attack may be an appropriate response to defective myelin that is deteriorating for some reason and must be broken down and removed. In this model, the damage to the myelin results from an abnormality in the oligodendrocytes, the cells that produce myelin, or from dysfunction in the body of the neurons themselves, which supply the neurotransmitters that travel to the end of the axon and enable signals to jump from one neuron to the next.4
“In this hypothesis the immune system is responding to an abnormality, but also contributing to tissue injury,” said Rudick. “In this scenario, interrupting the inflammatory process might be partially effective, but it wouldn’t stop the underlying degenerative process.”
An Australian group led by John Prineas provided support for this idea with a 2004 paper that described the death of oligodendrocytes in MS lesions prior to any evidence of inflammation.5 Prineas argued that oligodendrocytes become sick before damage to the myelin appears.
While this idea has started to lose ground in the face of new genetic evidence that implicates immune dysfunction, MS clearly begins long before inflammation of myelin starts to cause symptoms. The widespread use of magnetic resonance imaging in recent years has found people who have “silent” MS lesions—damage that has never caused symptoms—and studies have confirmed that the loss of brain tissue in MS patients starts early in the disease process, even though neurological deficits don’t start to appear until years later.
“It seems as if patients compensate for considerable amounts of brain injury, but only up to a point,” Rudick said. “When they get past that point they start to deteriorate, and the disease looks more like a classic progressive neurodegenerative process. So there’s some evidence that the process underlying the disease changes from mostly inflammatory in the early stages to mostly degenerative in later stages of the disease.”
Finding New Ways to Modulate the Immune System
Even if the inflammation of myelin—the hallmark of MS—turns out to be a consequence of dysfunction in neurons or oligodendrocytes, suppressing the inflammation clearly helps control symptoms, and that’s what existing treatments as well as most new medications in the pipeline attempt to do.
Drugs such as interferon beta-1b (Betaseron), interferon beta-1a (Avonex, Rebif), along with glatiramer acetate, a synthetic product sold as Copaxone, interfere with the inflammatory hormones called interferons, substances produced by cells in response to viral infections. Known as immunomodulators, these drugs are believed to discourage T cells in the immune system from attacking myelin. They reduce relapses or exacerbations, as well as new lesions in the myelin, by up to one third, and their long history of use has shown them to be very safe. Patients may respond better to one drug than to others because of their unique genetic makeup, “but thus far we don’t have a way to individualize treatment,” said Rudick.
Several oral medications now in the pipeline are expected to be approved shortly, including cladribine (Leustatin), fingolimod, teriflunomide and laquinimod. Like drugs given to transplant patients to prevent rejection, these drugs suppress the immune system and thereby weaken its ability to attack the myelin of MS patients. While these drugs work primarily by destroying immune cells, fingolimod, also known as FTY-720, suppresses the immune system by confining lymphocytes to lymph nodes, thereby muting their ability to trigger inflammation.
|Macrophages, or immune cells, stained brown here, crowd around a demyelinating MS-lesion. (Wikimedia Commons, licensed under the GNU Free Documentation License.) |
Another drug recently approved by the FDA, natalizumab, is a highly specific type of antibody known as a monoclonal antibody. Administered every twenty-eight days, natalizumab acts on the walls of the blood-brain barrier to block inflammatory cells in the immune system from crossing into the central nervous system. It is also used to treat Crohn’s disease, a severe immune-mediated inflammation of the lining of the intestines.
Sold under the brand name Tysabri, natalizumab aroused high hopes when it was approved by the FDA in 2004 because it appeared to work nearly twice as well as existing drugs in preventing relapses and new lesions in MS patients. However, it was temporarily withdrawn from the market when three people taking it developed progressive multifocal leukoencephalopathy, or PML, a disease much like MS that causes inflammation in the myelin of the brain. Normally seen only in people with weakened immune systems, such as AIDS patients or those taking immunosuppressive drugs to prevent rejection of a transplanted organ, PML usually causes death. After a study, the FDA allowed natalizumab to return to the market in 2006. Since then about ten patients out of more than 40,000 who have taken it have developed PML, but none have died.
“The good news is that neurologists can recognize PML early,” said Peter Calabresi, director of the Johns Hopkins Multiple Sclerosis Center. “You can wash the Tysabri [natalizumab] out with leukopheresis and most patients do not die from PML. Even if we must use non-specific immunosuppressive drugs [on MS patients], the drugs that are reversible are much more appealing than ones that have sustained effects.”
But PML is not the only serious complication of natalizumab, according to Joseph Berger, chairman of the department of neurology at the University of Kentucky College of Medicine.
“For instance, there’s also an increased risk of herpes infections,” said Berger, who addressed the May 2009 convention of the Consortium of MS Centers on the risk/benefit considerations of MS therapies. “What we typically see are recrudescences [revivals] of latent infections. Eighty percent of us carry JC virus, the cause of PML, yet PML is a vanishingly rare disease in the absence of an immunosuppressive condition or the administration of an immunosuppressant drug. The risk for developing infectious complications will likely be increased with many of these drugs being developed for MS besides natalizumab. As the efficacy of a therapy improves, the risks associated with it will increase as well.”
Nevertheless, by preventing immune cells from crossing the bloodbrain barrier, natalizumab could conceivably slow or even halt the progression of symptoms if it is administered early in the course of the disease. However, because of the heavy side effects, neurologists tend to reserve the drug for those patients with the most severe disease, who have failed to respond well to all other treatments.
“If you put patients from the beginning of the disease on Tysabri and stop inflammatory lesions, do you stop the disease?” said Bruce D. Trapp, chairman of the department of neurosciences at the Cleveland Clinic Lerner Research Institute. “That is an experiment I would like to see. It could determine if the inflammation is primary or secondary.”
Trapp was the lead author of a 1998 article in the New England Journal of Medicine that transformed thinking about MS, which up to that time was thought to affect only myelin. He showed that MS also damages the nerve fibers themselves, which probably accounts for the severe long-term disability that afflicts some patients.
This conception of MS suggests that discovering how to protect the delicate nerve fibers and promote the body’s own efforts to repair myelin might be an effective way to stave off or even halt the degeneration that produces disability in MS patients. However, the development of such therapies is hindered by the lack of a technique to detect myelin non-invasively and thereby determine the effectiveness of such treatments.
“The best MS imaging labs in the world are working on this,” Trapp said, “but as of now we have no way of measuring an effective repair.”
Bruce D. Trapp changed the way researchers view MS by showing that not only myelin, but the nerve fibers themselves, are damaged in the course of the disease. (Courtesy of Bruce D. Trapp / Cleveland Clinic Lerner Research Institute).
In a paper published in the Journal of Neuroscience in 2009, however, Trapp and his colleagues reported the existence of a previously unidentified type of cell in the brain that gives rise to oligodendrocytes, which restore myelin that has been damaged by inflammation.6
“We developed a method to purify this cell, and we showed in a mouse model that fails to make myelin that it has a significant ability to generate oligodendrocytes,” Trapp said. “If we transplant the same number of these cells as we transplant progenitor cells, we get more myelination, suggesting that the repair capacity of this cell may be greater than that of an oligodendrocyte progenitor cell.”
Stem Cells Provide Blank Slate
A team at Northwestern University’s Feinberg School of Medicine, led by Dr. Richard Burt, has been “resetting” the immune system of MS patients by transplanting their own immune stem cells.7
In one study, eighteen of twenty-one MS patients with the relapsing-remitting form of the disease improved significantly for twenty-four months after the stem cell transplant, and none got worse. Most patients with relapsing-remitting MS get progressively worse as irreversible damage to their neurons accumulates.
The procedure involves harvesting immune stem cells from the patient’s bone marrow, and then destroying the immune component of the bone marrow with chemotherapy. When the stem cells are transplanted, the patient develops a new immune system apparently free of disease.
“The stem cells are not immune cells,” Burt said. “They have to be educated. They have to differentiate and grow into immune cells. The reset [after transplantation] results in an immune system like a newborn child’s.”
Burt has applied this technique to other diseases, including type 1 diabetes,8,9 lupus,10 scleroderma, Crohn’s, and a form of vision loss known as autoimmune-related retinopathy and optic neuropathy syndrome, or ARRON.11
Fixing Faulty Immune System Remains a Tough Challenge
What will the treatment of MS look like in the years ahead?
A deeper understanding of MS will almost certainly lead to the creation of a subspecialty within neurology dedicated to the treatment of the disease. “Management of patients with MS will become increasingly complex in the next five to ten years,” said Berger. “While neurologists will always make the diagnosis of MS, the treatment may become sufficiently complex that the average neurologist will defer to a specialist or a specialty group for the management of the MS patient. That’s where I see it going with the panoply of drugs likely to make it to market. I would also predict that genetic analysis of these individuals will enable us to predict who is going to respond to those therapies that are less aggressive.”
And if the past decade is any indication, the years ahead will bring much more effective treatments, according to Trapp.
“I don’t see a cure until we know the cause, and we don’t know the cause,” he said. “But we are making strides. What we’ve accomplished in the last ten years has been remarkable. The existing therapies, while not perfect, make a real difference in quality of life of MS patients.”