It is an interplay of unfavorable gene variants and mysterious environmental influences that triggers multiple sclerosis. Researchers are now on the trail of both genetic and environmental causes.
Multiple sclerosis is an autoimmune disease that involves not only the attack of misdirected immune cells on the myelin sheaths of nerve fibers, but also on nerve cell processes and nerve cells.
- Multiple sclerosis develops in people who have a genetic predisposition and are exposed to certain (as yet unknown) environmental factors.
- Experiments in mice show that the intestinal flora plays a role in the development of MS, since mice without intestinal bacteria do not develop MS.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs mainly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from completely different symptoms. Particularly common are visual disturbances and numbness in the limbs.
Neuron
The neuron is a cell of the body specialized in signal transmission. It is characterized by the reception and transmission of electrical or chemical signals.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
a common neurological disease that occurs mainly in young adults. For reasons still unknown, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from completely different symptoms. Visual disturbances and numbness in the limbs are particularly common.
In germany, there are about 130.000 MS patients (prevalence 1:1000), worldwide about 2.5 million people are affected. Women are twice to three times more likely to develop the disease than men. In most cases, the first symptoms of the disease appear between the age of 20. And 40. Multiple sclerosis is a disease that affects more than one person, but can take different courses: an aggressive form with rapid successive attacks, in which the nerve damage becomes apparent in increasingly severe physical disabilities, and the recovery time between attacks is limited. A type with longer recovery times between relapses. And a relapse-free form in which nerve damage and physical disability progress continuously.
Not many research offices look as tidy as frauke zipp’s. An orchid is standing accurately and in full bloom on the sideboard in which medical journals and books are sorted, which are piled up in stacks on the desk of many a colleague. White suit, white walls, clear speech – with a double dose of discipline and order, the doctor, senior neurologist, professor at the Johannes Gutenberg university, mother of two and wife seems to fight against the chaos in the brain of multiple sclerosis patients.
every day, zipp, director of the neurology clinic at the university of mainz, stands in front of patients to whom, despite more than a hundred years of MS research, she still can’t explain why their immune cells eventually turn against the body’s own tissue, attack the insulating layer of the nerve cell processes and, over the years, fewer and fewer nerve impulses reach the body. But the scientist, who moved from berlin to mainz in 2009, is now able to say which genes are predisposing to the development of multiple sclerosis. And that it is not only the nerve fiber insulating layer against which the immune system runs amok.
Gene
Information unit on the DNA. Specialized enzymes translate the core component of a gene into ribonucleic acid (RNA). While some ribonucleic acids themselves carry out important functions in the cell, others specify the order in which the cell should assemble individual amino acids to form a particular protein. The gene thus provides the code for this protein. In addition, regulatory elements on the DNA belong to a gene, which ensure that the gene is read exactly when the cell or the organism actually needs its product.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For reasons that are still unknown, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. this can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Visual disturbances and numbness in the limbs are particularly common.
More than one point of attack
As early as the end of the 19th century. At the beginning of the twentieth century, medicine thought it had found the cause of multiple sclerosis: the french doctor jean-marie charcot observed at that time that the so-called myelin sheaths, which are mainly composed of the protein myelin and form a kind of electrical insulating layer around the nerve cell processes, were being lost. As a result, the transmission of nerve impulses slows down or stops altogether. The current hypothesis on the causes of this destructive process is that the patient’s immune system mistakenly classifies myelin as a foreign body, attacks it and degrades it. This so-called autoimmune reaction against myelin is supported by the fact that the hardenings characteristic of MS – the scleroses that give the disease its name – are found primarily in the white matter of the brain, where there is a particularly large amount of myelin. In addition, an MS-like disease can be induced in healthy mice by injecting the animals with fragments of myelin protein.
"but charcot himself already recognized that not only the myelin, but also the nerve cells and fibers are attacked," says frauke zipp. One hundred years later, in the late 1990s, this was confirmed in tissue samples from the brains of MS patients, and the accompanying inflammatory process was also observed. "it appears that the progression of the disease and the increasing disability are more related to this nerve fiber damage than to the demyelination," says zipp. In an animal model, the neuroscientist and her team have demonstrated that immune cells not only directly attack the myelin sheaths, but also nerve cells and processes independently of them.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can occur throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Particularly common are impaired vision and numbness in the limbs.
Myelin
Myelin is a fatty substance that is formed from glial cells. It coats the axons (long fiber-like extensions) of nerve cells and isolates them so that messages cannot pass unhindered to neighboring nerve cells. In addition, signal conduction is accelerated enormously.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For a still unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from completely different symptoms. Particularly common are visual disturbances and numbness in the limbs.
Neuron
The neuron is a cell of the body that is specialized in signal transmission. It is characterized by the reception and transmission of electrical or chemical signals.
Images of neuronal mass death
Whether the nerve damage is only a consequence of the demyelination or whether, in addition to the myelin sheaths, nerve cells themselves are also attacked from the outset, is an open question in humans, says zipp. After all, researchers can’t just look inside the central nervous system of a living person. "but in mice, where we can look into the CNS while the early phase of the disease is going on, we have observed that very aggressive lymphocytes attack the nerve cell processes – even when there is no myelin at all." frauke zipp impatiently jumps up from the black sofa and runs to the computer. "come on, i’ll show you."
One click and dozens of file folders appear on the screen. But despite her orderliness, the professor does not immediately find what she wants to show. Only seconds pass, but she already grumbles an annoyed apology. A few clicks later she finds what she is looking for. A film starts, red and green spots – cells – flit across the screen. "there, look, this is the nerve cell and there the immune cell attacks and then here you see the injury." zipp points enthusiastically at the screen – a look into the brains of mice in which the equivalent of multiple sclerosis in humans has been induced. She is sure that similar things happen in the approximately 2.5 million patients with multiple sclerosis worldwide.
"in MS patients, we see atrophies, i.e. the disappearance of nerve cells and their fibers, at a very early stage in magnetic resonance imaging, which suggests that the attack on the myelin sheaths and on the nerve cell components occurs independently of each other or at least in parallel," says zipp. She expects this finding to open up new therapeutic possibilities, because it appears that the physical disability associated with MS is mainly due to neuronal damage and inflammation.
Neuron
The neuron is a cell in the body that specializes in signal transmission. It is characterized by the reception and transmission of electrical or chemical signals.
Myelin
myelin is a fatty substance formed by glial cells. It coats the axons (long fiber-like extensions) of nerve cells and isolates them so that messages cannot pass unhindered to neighboring nerve cells. In addition, signal conduction is accelerated enormously.
Neuron
The neuron is a cell in the body that specializes in signal transduction. It is characterized by the reception and transmission of electrical or chemical signals.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. It can occur throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Genes influence disease risk
that MS is based on an immune system run amok, frauke zipp and 22 other international MS research groups were able to confirm by comparing the genes of more than 9,700 MS patients. In addition to 28 already known variants, they discovered 29 new genetic variants that occur significantly more frequently in MS patients and mostly affect genes that influence the immune system, in particular the development of the so-called T cells. "the results support what has only ever been probable: multiple sclerosis is an autoimmune disease," says zipp.
Although MS is not a hereditary disease caused by single gene mutations like hemophilia, for example, it is a disease of the brain. But there is a genetic predisposition that results from the interaction of many gene variants. For example, an identical twin of an MS patient is 300 times more likely than the rest of the population to also develop the disease. And even with a fraternal twin, the probability is still increased by about 40 to 50 times. "we assume that due to a genetic predisposition, infections and environmental influences, there is a random activation of immune cells that mistakenly target the central nervous system," says zipp.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs mainly in young adults. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Vision problems and numbness in the limbs are particularly common.
Gene
Information unit on the DNA. Specialized enzymes translate the core component of a gene into ribonucleic acid (RNA). While some ribonucleic acids themselves perform important functions in the cell, others dictate the order in which the cell should assemble individual amino acids into a particular protein. The gene therefore provides the code for this protein. In addition, a gene has regulatory elements on its DNA that ensure that the gene is read exactly when the cell or organism needs its product.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For reasons still unknown, the body’s own cells attack and destroy the myelin sheaths of the nerve cells. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from completely different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Neurodegeneration
Collective term for diseases in the course of which nerve cells gradually lose their structure or function until they sometimes even die as a result. In many cases, misfolded proteins are the trigger – such as certain forms of the proteins beta-amyloid and tau in the case of alzheimer’s disease. In other diseases, such as Parkinson’s disease or chorea huntington’s disease, proteins within the neurons are not properly degraded. As a result, toxic aggregates are deposited there, which leads to the respective symptoms of the disease. While chorea Huntington’s is clearly genetic, in Parkinson’s and Alzheimer’s disease there seem to be at best certain forms of genes that favor their development. None of these neurodegenerative diseases can yet be cured.
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interaction of unfavorable genes and mysterious environmental influences – multiple sclerosis.
Environmental influences play a role – but which ones??
No one knows which environmental factors could trigger the disease, says zipp, shrugging his shoulders: "the frequency of MS increases with distance from the equator, but whether this is related to solar radiation and vitamin D production in the skin is not known for sure."Among the associated gene variants, the researchers found two that play a role in vitamin D metabolism. viruses, especially the widespread epstein-barr virus, have long been suspected of being at the root of MS disease. "our genome analysis can’t answer this question either," says zipp. "the gene variants correlated with MS suggest an inflammatory immune response, but this does not suggest the cause of that inflammation."experiments by zipp’s colleagues hartmut wekerle and gurumoorthy krishnamoorthy of the max planck institute for neurobiology in munich, on the other hand, support the hypothesis that microorganisms are involved in the development of ms.
However, the munich researchers have not identified viruses but rather harmless bacteria from the intestine as a possible cause of MS: if mice that actually develop an MS-like disease due to genetic modification are raised free of any intestinal bacteria, then they are protected from the disease. Based on these experiments, wekerle and krishnamoorthy suspect that in people with a genetic predisposition, certain immune cells develop an autoimmune reaction against myelin as a result of contact with normally harmless clostridia bacteria. "whether the human intestinal flora plays a role in the development of multiple sclerosis is to be clarified in a study in collaboration with several scientists and clinics in germany," reports frauke zipp.
Since the influence of the intestinal flora is also observed in other autoimmune diseases, such as rheumatoid arthritis or type 1 diabetes, nutrition is now becoming the focus of attention. Food plays a decisive role in determining the composition of the various intestinal bacteria. "changing eating habits could be one explanation for why multiple sclerosis has increased in asian countries in recent years," speculates hartmut wekerle.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from completely different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Myelin
Myelin is a fatty substance formed from glial cells. It coats the axons (long fiber-like extensions) of nerve cells and isolates them so that messages cannot pass freely to neighboring nerve cells. In addition, signal conduction is accelerated enormously.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Visual disturbances and numbness in the limbs are especially common.
Attention
Attention serves as a tool to consciously perceive internal and external stimuli. We can do this by concentrating our mental resources on a limited number of awareness items. While some stimuli automatically attract our attention, we can select others in a controlled way. The brain unconsciously processes stimuli that are not the focus of our attention.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For reasons that are still unclear, the body’s own cells attack the myelin sheaths of nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Early and aggressive?
For zipp, who as a doctor has to make treatment decisions every day, the result of the genetic study is not just a research result like any other. "this changes my approach to patients," she says, "because i am now even more convinced that MS is an inflammatory disease and that our anti-inflammatory therapies are correct, even though they cannot yet stop the disease." now she can also make a more forceful case for starting anti-inflammatory treatment as early as possible when patients are initially hesitant and want to "wait and see" how the disease develops.
Zipp has high hopes for the future use of new nerve cell-protecting agents to preserve as many neurons as possible right from the start. including flavonoids or similar active ingredients such as EGCG (epigallocatechin gallate) or luteolin. "EGCG has both anti-inflammatory and neuroprotective effects and has shown a strong effect in animal models," says the neurologist. Zipp expects initial results from a phase II study in patients in 2012. "we now know that neuronal damage occurs at a very early age, but it is an open question whether we should therefore treat aggressively at a very early stage."
Until now, treatment has tended to be restrained at the beginning of the disease and more "radical" drugs have only been used when the patient shows clearer MS symptoms. One such drug is tysabri, which blocks all immune cells from the brain. However, this carries considerable risks, because dangerous infections in the brain are then not combated. An alternative is the monoclonal antibody alemtuzumab, which scavenges all white blood cells and kept 78 percent of patients free of MS relapses for two years in a phase III study. Here, too, side effects were not absent. But zipp and colleagues wonder whether the earliest possible administration of such preparations might not nip multiple sclerosis in the bud.
Ideally, the autoimmune disease should be detected in the early stages, when the damage to the nerve cells is still minimal. Current international genome analysis cannot yet help directly, because even if a person has all the gene variants relevant to MS, he or she does not necessarily develop the disease. "but we hope to use genetic fingerprints from patients to predict not only the individual course of the disease, but perhaps even the likelihood of success of certain therapies," says the researcher. Corresponding studies are already underway.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
a common neurological disease that occurs predominantly in young adulthood. For reasons that are still unclear, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from completely different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Neuron
The neuron is a cell of the body specialized in signal transduction. It is characterized by the reception and transmission of electrical or chemical signals.
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For an as yet unexplained reason, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from very different symptoms. Visual disturbances and numbness in the limbs are particularly common.
Neuron
The neuron is a cell in the body that specializes in signal transmission. It is characterized by the reception and transmission of electrical or chemical signals.
To read on:
- Berer, K. Et al.: commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011; 479:538 – 541 (to abstract).
- International multiple sclerosis genetics consortium: genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011; 476 (7359):214 – 219 (go to abstract).
- Max planck society: natural intestinal flora involved in the development of multiple sclerosis. 26. October 2011 (to abstract).
Multiple sclerosis
Multiple sclerosis/encephalomyelitis disseminata/multiple sclerosis
A common neurological disease that occurs predominantly in young adulthood. For reasons that are still unclear, the body’s own cells attack the myelin sheaths of the nerve cells and destroy them. This can happen throughout the central nervous system, which is why two different multiple sclerosis patients can suffer from completely different symptoms. Particularly common are visual disturbances and numbness in the limbs.
