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Myelin multiple sclerosis: Myelin | National Multiple Sclerosis Society


Myelin repair | Multiple Sclerosis Society UK

Nerve cells carry messages between the brain and spinal cord and the organs and limbs of the body. They control everything we do – from how we move to how we think and feel.

Myelin is the fatty protective coating that surrounds nerve fibres – a bit like the insulation on an electrical wire.

As well as protecting the fragile nerve fibres, myelin also allows messages to travel quickly along the nerves without being lost or interrupted.

For example, in the nerve cells that extend from the spinal cord to the muscles in your leg, the myelin coating allows messages to travel at up to 268 miles per hour. In nerve cells without myelin, the speed the message travels at can drop as low as 1 mile per hour.

What happens to myelin in MS?

In MS, immune cells enter the brain and spinal cord and attack both the myelin and the cells that make it. When myelin becomes damaged, messages find it harder to get through – or can’t get through at all. That’s what causes the symptoms of MS.

These symptoms can be very different for people, depending on where in the brain and spinal cord the attack has occurred.

Why do we need to repair myelin?

If myelin isn’t repaired properly, the nerve fibres become increasingly vulnerable to damage. And over time they may be lost. When this happens, messages can no longer get through and symptoms become permanent.

This gradual, steady accumulation of disability is what we call MS progression. It’s why we need to find ways to put myelin back on nerves, protecting them from damage and getting the messages flowing again.  

How can we repair and replace myelin?

The human body has an amazing natural ability to repair myelin and get nerves working properly again.

Myelin is repaired or replaced by special cells in the brain called oligodendrocytes. These cells are made from a type of stem cell found in the brain, called oligodendrocyte precursor cells (OPCs).

  •  Nerve cells signal for help when their myelin is damaged
  • When the signal reaches the OPCs, they travel to the site of damage and mature into oligodendrocytes
  • And then the damage can be repaired.

Early in the condition, this process works quite well. With the myelin replaced, the messages are able to travel down the nerve fibre again. Your MS symptoms may lessen or go away as the immune attack subsides.

But, with age and repeated attacks, this process stops working as effectively. It’s thought that OPCs stop responding to the nerve cell’s cry for help, and damaged oligodendrocytes can no longer effectively replace the lost myelin.

We need to find ways to kickstart this natural process again. This involves understanding everything about the process: from how nerve cells signal for help, to finding out what molecules help activate the myelin-making cells. Researchers then have to translate these findings into developing treatments that will help people with both relapsing and progressive MS.

This is no small task but we’re making good progress.

Our myelin repair research

With your help, we’re supporting world leading research into myelin repair for MS. This includes funding two dedicated centres of excellence and dozens of individual projects around the UK.

Read about all our current myelin repair projects

The MS Society Cambridge Centre for Myelin Repair is dedicated to understanding more about the myelin repair process, particularly focusing on the OPC response. The team are taking a ground-breaking approach to studying myelin repair, for the first time looking at the impact ageing and lifestyle factors (such as diet and exercise) can have on these OPCs.

The MS Society Edinburgh Centre for MS Research is using pioneering animal and tissue models to find the myelin repair treatments of tomorrow. The centre’s expertise includes screening drugs for their potential to help myelin repair and protect nerves from damage. Many researchers there also work closely with people living with MS attending their neurology clinics.

Working together, our Cambridge and Edinburgh centres have created a world-class research environment in which to understand myelin repair and identify drug targets for further testing. Recent breakthroughs include identifying molecules that are important in myelin repair and testing drugs that can target those molecules in clinical trials. And last year researchers found that the diabetes drug metformin could repair myelin in rats. Now we’re supporting a trial to test the drug on people with MS.

New compound promotes healing of myelin in nervous system disorders

Scientists have created a compound that promotes the rebuilding of the sheath around nerve cells damaged in conditions such as multiple sclerosis. (Getty Images)

Scientists have developed a compound that successfully promotes the rebuilding of the protective sheath around nerve cells that is damaged in conditions such as multiple sclerosis.

In a study published today in the journal Glia, scientists described successfully testing the compound in mice. Researchers at Oregon Health & Science University have already started to apply the compound on a rare population of macaque monkeys at the Oregon National Primate Research Center at OHSU who develop a disease that is similar to MS in humans.

Larry Sherman, Ph.D.

“I think we’ll know in about a year if this is the exact right drug to try in human clinical trials,” said senior author Larry Sherman, Ph.D., an OHSU professor in the Division of Neuroscience at the primate center. “If it’s not, we know from the mouse studies that this approach can work. The question is, can this drug be adapted to bigger human brains?”

Discovery culminates more than a decade of research

The discovery culminates more than a decade of research following a 2005 breakthrough by Sherman’s lab.

In that study, scientists discovered that a molecule called hyaluronic acid, or HA, accumulates in the brains of patients with MS. Further, the scientists linked this accumulation of HA to the failure of cells called oligodendrocytes to mature. Oligodendrocytes generate myelin.

Myelin, in turn, forms a protective sheath covering each nerve cell’s axon – the threadlike portion of a cell that transmits electrical signals between cells.

Damage to myelin is associated with MS, stroke, brain injuries, and certain forms of dementia such as Alzheimer’s disease. In addition, delay in myelination can affect infants born prematurely, leading to brain damage or cerebral palsy.

Subsequent studies led by the Sherman lab showed that HA is broken down into small fragments in multiple sclerosis lesions by enzymes called hyaluronidases. In collaboration with Stephen Back, M.D., Ph.D., a professor of pediatrics in the OHSU School of Medicine, Sherman discovered that the fragments of HA generated by hyaluronidases send a signal to immature oligodendrocytes not to turn on their myelin genes.

That led researchers to explore how they might block hyaluronidase activity and promote remyelination.

Development of a new healing compound

For the past decade, an international team of researchers led by OHSU has been working to develop a compound that neutralizes the hyaluronidase in the brains of patients with MS and other neurodegenerative diseases, thereby reviving the ability of progenitor cells to mature into myelin-producing oligodendrocytes.

The study published today describes a modified flavonoid – a class of chemicals found in fruits and vegetables – that does just that.

The compound, called S3, reverses the effect of HA in constraining the growth of oligodendrocytes and promotes functional remyelination in mice. Lead author Weiping Su, Ph.D., senior scientist in the Sherman lab, dedicated years of intensive research to make the discovery.

“It’s not only showing that the myelin is coming back, but it’s causing the axons to fire at a much higher speed,” Sherman said. “That’s exactly what you want functionally.”

The next phase of research involves testing, and potentially refining, the compound in macaque monkeys who carry a naturally occurring version of MS called Japanese macaque encephalomyelitis. The condition, which causes clinical symptoms similar to multiple sclerosis in people, is the only spontaneously occurring MS-like disease in nonhuman primates in the world.

The work was supported by the National Institutes of Health grant No. P51OD011092 for the operation of the Oregon National Primate Research Center; Congressionally Directed Medical Research Program grant No. MS160144; the National Multiple Sclerosis Society grant No. RG4843A5/1; the NIH’s National Institute of Neurological Disorders and Stroke award Nos. NS054044 and NS045737; and American Heart Grant in Aid award No. 17GRNT33370058.

The Multiple Sclerosis Process and Symptoms

Multiple sclerosis (MS) is a disease of the central nervous system (CNS). The CNS consists of the brain, optic nerves and spinal cord. With MS, areas of the CNS become inflamed, damaging the protective covering (known as “myelin“) that surrounds and insulates the nerves (known as “axons“). In addition to the myelin, over time, the axons and nerve cells (neurons) within the CNS may also become damaged.

The damage to the protective covering and also to the nerves disrupts the smooth flow of nerve impulses. As a result, messages from the brain and spinal cord going to other parts of the body may be delayed and have trouble reaching their destination – causing the symptoms of MS.

Shown above is an illustration of two nerve cells. The normal one on the left has a healthy nerve fiber, or axon, protected by myelin (insulation covering the nerve), and is able to transmit signals at a very fast speed – similar to electricity traveling along an electrical cord. The ms nerve cell on the right shows damage to the myelin, and as a result, signals do not travel well along the nerve.

When the myelin becomes damaged (as shown in the top illustration), or the nerve itself becomes damaged, signals can no longer travel across the nerve fiber efficiently. As signals slow down or are lost, the body cannot respond appropriately – causing the symptoms of ms.

Shown above is an illustration of a nerve cell. The nerve fiber, or axon, when protected by healthy myelin, is able to transmit signals at a very fast speed – similar to electricity traveling along an electrical cord.

Common symptoms include:

Areas of inflammation and damage are known as “lesions.” The changes in size, number, and location of these lesions may determine the type and severity of symptoms. While individuals with relapsing forms of MS are believed to experience more inflammation than those with progressive forms of MS, lesions still occur for individuals with all forms of MS. However, the lesions in progressive forms of MS may be less active and expand more slowly.

In addition to symptoms, disease activity may be evaluated from changes in the size or number of lesions. Frequently, MS may be “clinically silent,” showing no increase in symptoms, yet continuing to show signs of disease activity within the CNS. For individuals with relapsing forms of MS, early and continued treatment with a disease-modifying therapy (DMT) can often slow the “clinically silent” disease activity in the brain, reducing the size and number of active lesions. This is why most neurologists, as well as the American Academy of Neurology, recommend that individuals with relapsing forms of MS begin treatment as soon as possible after the diagnosis is established. More recent FDA approvals have brought new DMTs that also treat active secondary-progressive MS and primary-progressive MS.

Additionally, areas of thick scar tissue may eventually form along the areas of permanently damaged myelin. These areas of scar tissue are referred to as “plaques.” The term “multiple sclerosis” originates from the discovery of these hardened plaques. Multiple refers to “many;” sclerosis refers to “scars.”

Lesions and plaques are viewed on a magnetic resonance imaging (MRI) scanner. This technology is used to help diagnose MS and evaluate its progress at various intervals.

Previous: History of MS | Next: Who Gets MS

Identification of autoantibodies associated with myelin damage in multiple sclerosis

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  • Study finds a new line of drugs to stimulate myelin repair in multiple sclerosis

    In the nearly 1 million Americans living with multiple sclerosis, the fatty substance that insulates the nerves of the central nervous system—called myelin—is damaged. This slows the transmission of signals from their brain to the rest of their body, which causes movement difficulties, vision problems, and cognitive changes.

    Clinical trials are currently testing drugs that were shown in lab-based studies to stimulate the production of new myelin. However, in the brains of patients with multiple sclerosis, cells are surrounded by toxic elements from the blood and the immune system that inhibit the repair of damaged myelin, so it remains unclear whether the drugs can be effective in humans.

    A new study by scientists at Gladstone Institutes led by Senior Investigator Katerina Akassoglou, PhD, shows that many of the drugs currently in trials may not be sufficient to promote repair within these cells’ toxic environment and identifies a different treatment option that could improve the repair of myelin. The study, performed in collaboration with UC San Diego and the University of Vienna, Austria, is published in the journal Brain.

    We found a new line of drugs that could potentially be used to stimulate myelin repair even in the presence of toxic blood leaks in the brain.

    Katerina Akassoglou, PhD, Director of the Center for Neurovascular Brain Immunology at Gladstone and Professor of Neurology at UC San Francisco (UCSF)

    Blood leaks in the brain prevent repair

    Normally, in an attempt to restore insulation to damaged nerves, specialized repair cells in the brain can transform into cells called oligodendrocytes, which produce new myelin.

    Drugs in clinical trials are intended to boost this formation of mature oligodendrocytes as a way of increasing myelin production. However, many of these drugs were initially tested on cells grown in laboratory dishes, which didn’t account for the fact that, in disease, toxic elements are also present in a cell’s environment.

    In multiple sclerosis, one such element is fibrinogen, a blood-clotting protein that leaks into the brain.

    Blood leaks are abundant in the brain and spinal cord of multiple sclerosis patients, and are monitored with brain scans to establish a diagnosis for the disease. Akassoglou and her team previously showed that, in multiple sclerosis, fibrinogen leaking into the brain causes inflammation and loss of neurons, and blocks myelin repair.

    In this study, the researchers wanted to understand how to overcome fibrinogen’s harmful effect. In collaboration with Mark H. Ellisman, PhD, director of the National Center for Microscopy and Imaging Research (NCMIR) at UC San Diego, they developed an advanced microscopy technique that allows them to combine the high-resolving power and advanced 3D imaging capabilities of electron microscopy with light optics–based imaging inside a living mouse’s spinal cord.

    “We can image blood leaks and track repair cells in real-time, visualizing the structure of myelin at exactly the same sites, all in the same specimen,” says Reshmi Tognatta, PhD, a scientist in Akassoglou’s lab and one of the first authors of the study.

    The researchers found that, in mouse models of multiple sclerosis, the repair cells were clustering at sites of blood leaks in the brain, where fibrinogen is present. But instead of transforming into myelin-producing cells, they transformed into astrocytes, a type of cell that produces scar tissue.

    “We now understand that fibrinogen blocks the production of myelin by causing a chain of events that prevents the repair cells from transforming into myelin producers, forcing them instead to turn into cells that can make scar tissue,” says Tognatta. “Fibrinogen determines the cells’ fate.”

    Possible new drug to repair myelin

    The team decided to test whether the clinical trial drugs could overcome the detrimental effect caused by fibrinogen. To do so, they developed a new method to screen the drugs in the presence of fibrinogen, mimicking the inhibitory environment around the repair cells. The new assay was designed to test not only the production of new myelin, but also the formation of damaging cells in brain lesions.

    “Fibrinogen puts repair cells on a derailed path, stopping myelin production,” says Akassoglou. “We can now screen, in a single assay, the efficacy of drugs to put the cells back on track for myelin repair. Our new assay is ideal for the discovery of drugs that overcome the toxic lesion environment.”

    The scientists showed that while the trial drugs may increase myelin repair in a normal environment, they were not effective when fibrinogen was present.

    “None of the drugs we tested could reverse the effect of fibrinogen,” says the other first author of the study, Mark Petersen, MD, a visiting scientist in Akassoglou’s lab and an associate professor of neonatology at UCSF.

    The team then tested other compounds to see if any of them could increase the production of myelin even in the presence of fibrinogen. They identified one small molecule that could not only make the repair cells turn into myelin-producing oligodendrocytes, but could also stop them from becoming scar-producing astrocytes. They treated two different mouse models of multiple sclerosis with this compound, and discovered that it increased the production of myelin and prevented paralysis in these mice.

    “This compound completely overcame the effect of fibrinogen and restored myelin repair around leaky blood vessels,” says Petersen. “Even if the treatment started after they were already sick, the mice improved and we saw signs that the myelin was repairing faster and there was less damage to their nervous system.”

    Similar compounds to the one used by the scientists are being tested in clinical trials for other indications, and so far, they appear to be safe. These compounds could potentially be repurposed and tested in multiple sclerosis patients much sooner than new drugs that still must go through an extensive development process.

    Beyond multiple sclerosis

    The small molecule identified by Gladstone researchers could be combined with other available drugs to help better repair myelin. The team’s findings could also provide clinicians with a new option to enhance the production of myelin in the presence of a leaky blood-brain barrier in multiple sclerosis.

    And, beyond those diagnosed with multiple sclerosis, the study could help a much larger group of patients with other diseases.

    “The disruption of blood vessels and deposits of fibrinogen link many neurological diseases, from multiple sclerosis to neonatal brain injury-;so a discovery in one area gives us a lot of insight into other disease processes,” says Petersen, who takes care of infants in the intensive care nursery. “I’m now applying our findings and the tools we developed to the study of the developing brain.”

    There is also growing evidence that myelin damage plays a role in normal aging as well as Alzheimer’s disease. Indeed, Akassoglou’s team has spearheaded studies that identify fibrinogen as a new culprit for cognitive decline in Alzheimer’s disease. Akassoglou and Ellisman also recently expanded their collaboration in Alzheimer’s disease research with the support of a new grant.

    “It’s crucial to take into account the blood leaks in the diseased brain in order to design treatments that can benefit a broad set of patients,” says Akassoglou. “We discovered that fibrinogen gains access to the diseased brain, acting as a gas pedal for toxic inflammation and as a break for repair. We are continuing to investigate its deleterious effects in the brain in hopes that we can develop effective therapies for multiple sclerosis and other devastating neurological diseases.”

    “Identifying and blocking the mechanisms by which fibrinogen contributes to major diseases of the brain and spinal cord is an important objective for us and the field at large,” says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease. “Dr. Akassoglou’s research program has pioneered this mission and-;through this groundbreaking study-;has opened new avenues for the development of urgently needed novel therapeutics.”


    Journal reference:

    Petersen, M.A., et al. (2021) BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis. Brain. doi.org/10.1093/brain/awab106.

    Is MS affecting the CNS only?


    MS is regarded as a disease of the CNS where a combination of demyelination, inflammation, and axonal degeneration results in neurologic disability. However, various studies have also shown that the peripheral nervous system (PNS) can be involved in MS, expanding the consequences of this disorder outside the brain and spinal cord, and providing food for thought to the still unanswered questions about MS origin and treatment. Here, we review the emerging concept of PNS involvement in MS by looking at it from a clinical, molecular, and biochemical point of view. Clinical, pathologic, electrophysiologic, and imaging studies give evidence that the PNS is functionally affected during MS and suggest that the disease might be part of a spectrum of demyelinating disorders instead of being a distinct entity. At the molecular level, similarities between the anatomic structure of the myelin and its interaction with axons in CNS and PNS are evident. In addition, a number of biochemical alterations that affect the myelin during MS can be assumed to be shared between CNS and PNS. Involvement of the PNS as a relevant disease target in MS pathology may have consequences for reaching the diagnosis and for therapeutic approaches of patients with MS. Hence, future MS studies should pay attention to the involvement of the PNS, i.e., its myelin, in MS pathogenesis, which could advance MS research.


    axo-myelinic synapse;
    combined central and peripheral demyelination;
    cyclic nucleotide phosphodiesterase;
    degraded form of MAG;
    immunoglobulin-like cell adhesion molecule;
    myelin-associated glycoprotein;
    myelin basic protein;
    NMDA receptor;
    NRG1 type III=
    oligodendrocyte progenitor cell;
    peptidyl arginine deiminase;
    proteolipid protein;
    peripheral nervous system;
    myelin protein 0;
    relapsing-remitting MS

    MS is the most common cause of acquired neurologic disability in young adults. 1 It is pathologically characterized by a combination of inflammation, demyelination, and axonal degeneration in the CNS, which, ultimately, results in neurologic disability.2 Clinically, MS is very heterogeneous, resulting in an array of symptoms.3 Although it is generally regarded as a disease restricted to the CNS, several studies have reported that some patients with MS also have demyelination in the peripheral nervous system (PNS),4,–,8 where axonal fiber demyelination is correlated with a reduced mean myelin sheath thickness and internode length.4 For instance, conduction abnormalities in peripheral nerves suggestive of demyelination were observed in patients with MS,7 and magnetic resonance neurography has shown a higher occurrence of PNS abnormalities in patients with MS compared with controls.8 These observations suggest that a common pathologic process may underlie CNS and PNS demyelination in a subset of patients with MS. 9 Furthermore, central and peripheral myelin share many molecules, such as myelin basic protein (MBP) and myelin-associated glycoprotein (MAG),10,–,13 which could lead to autoimmune reactivity to myelin antigens in both the CNS and the PNS.

    Based on these findings, it is tempting to hypothesize that MS, despite being considered a canonical CNS disorder, can also affect the PNS. Therefore, in this review, we focus on the myelin composition and axo-myelin interaction in the CNS vs PNS, the biochemical myelin alterations that contribute to MS pathology, and a number of MS clinical observations supporting impaired functioning of the PNS in addition to the CNS, which could have an impact on disease monitoring and treatment.

    Clinical observations in MS: the overlooked involvement of the PNS

    The onset of MS is usually during early adulthood, and the prognosis of the disease is highly variable.14 Currently, 3 main types of clinical MS are acknowledged with common patterns of symptoms associated with various levels of inflammation: relapsing-remitting MS (RRMS), primary progressive MS, and secondary progressive MS. 15 In patients with MS, CNS dysfunction can cause a wide range of symptoms and results in the considerable clinical heterogeneity of MS. For example, patients can have sensory disturbances, optic neuritis, limb weakness, fatigue, cognitive impairment, depression, pain, bladder, bowel and sexual dysfunction, and/or spasticity.16,–,18 At the moment, there is still no curative treatment available for MS. Several drug therapies have been approved during the last 20 years, which mainly aim to reduce inflammation in the CNS. However, there is increasing evidence that these therapies are most effective during the early phases of the disease, while there is active inflammation of the brain and spinal cord.19 The diagnosis of MS is based on established clinical, imaging, and spinal fluid observations, also known as the 2017 McDonald criteria.20 Of interest is that the criteria used for the diagnosis of MS are all focused on CNS pathology and related clinical dysfunction, which are at the forefront of the disease.

    Although the majority of clinical and pathologic studies on MS have specifically concentrated on the CNS, the involvement of the PNS in MS is not an entirely new concept, being already reported early in the 20th century.4,–,6,9,21 In these studies, the pathology observed in the PNS could be due to confounding factors such as malnutrition and vitamin deficiency.5,6,22 In addition, the presence of PNS pathology was considered exceptionally rare in chronic MS23 and more associated with a specific acute, aggressive form of MS.4,24 In those early days, the in vivo diagnosis of MS was uniquely based on clinical observations and not confirmed by MRI. Therefore, it is possible that the diagnosis of MS in those patients was not correct. Conversely, more recent investigations examining PNS involvement in patients diagnosed with MS according to the McDonald criteria exclude those patients with risk factors for neuropathy and for vitamin deficiency or malnutrition. 8,25,26

    Clinical and neurophysiologic observations have repeatedly described peripheral nerve dysfunction in MS, and pathologic studies have confirmed peripheral nerve demyelination in biopsies or autopsies of patients with MS. For example, single pathologic studies described a reduction of myelin thickness21 and demyelinating activity, including the invasion of myelin sheaths by macrophages and by inflammation involving mononuclear cells4 in the peripheral nerves of patients with MS. In addition, neurophysiologic investigations have mentioned that almost 30% of the examined patients with RRMS presented at least 1 abnormality on standard nerve conduction velocity of the tibial, sural, or peroneal nerve.25 In another study, electrophysiologic abnormalities of the peripheral nerves were observed in 28% of the participating patients with MS with concomitant clinical signs in 12% of the patients with MS.26 In addition, magnetic resonance neurography investigations have highlighted that patients with MS have significantly more lesions in the sciatic nerve, tibial, and peroneal nerves compared with healthy controls. 8 Also by MRI in 79.2% of the patients with MS, contrast enhancement of the trigeminal nerve extended to the distal part of the nerve was found, which indicated pathology of peripheral myelin.27 Recently, a patient with established MS in our MS Center Amsterdam presented with radicular pain that coincided with MRI abnormalities in the nerve root L4. Other possible diagnoses (such as compression, infection, or inflammatory disorders other than MS) were excluded (figure 1). Overall, these findings indicate that the PNS is affected in, at least a subset of, patients with MS based on clinical symptoms, neurophysiologic examinations, and on imaging and pathologic observations. It could also be argued that the common concept about inflammatory demyelinating diseases of the CNS and PNS being distinct entities should be revised. Instead, they could represent a broad spectrum of possible manifestations of CNS and PNS demyelination. These diseases would vary in regional distribution, clinical course, and pathology. Prototypical MS would be at one end of the spectrum (demyelination in CNS), chronic inflammatory demyelinating polyneuropathy at the other end of the spectrum (demyelination in PNS), and combined central and peripheral demyelination (CCPD) in between (demyelination in both the CNS and the PNS).28,–,32 Hence, the spectrum view is a potential explanation for the heterogeneity observed within the diseases and the overlapping features reported between the diseases.28,30,33 PNS involvement in MS can then be placed between prototypical MS and CCPD on the spectrum. Of interest, also CNS involvement can affect a PNS disease, namely acute motor axon neuropathy, which might be caused by molecular mimicry.34 Notably, the spectrum view of MS would have important consequences for the pathophysiologic concepts, disease monitoring, and future treatments of the diseases. By focusing on patients with MS who have both CNS and PNS demyelination, we may gain insight into the mechanisms underlying demyelination. To this end, it is relevant to compare CNS and PNS myelin to indicate possible target sites.

    Figure 1 MRI observations in the CNS and PNS of a patient with MS

    MRI scans of a patient who was diagnosed with MS based on clinical presentation in combination with the presence of CNS lesions suggestive of demyelination with dissemination in space and time. The diagnosis was confirmed by the presence of unique oligoclonal bands in the spinal fluid, in the absence of any other inflammatory signs that are atypical for MS such as a severe pleiocytosis. In addition, we excluded a diagnosis of neurosarcoidosis, systemic inflammatory condition, or central nervous infection. At 18 months after the diagnosis of MS, the patient developed severe radicular pain in the trajectory of L4 on the right side, with an absent patellar tendon reflex. Subsequent MRI and laboratory investigations systematically ruled out neurosarcoidosis, infection of the CNS, or a systemic inflammatory condition. (A–C) FLAIR images of multiple confluent lesions periventricular, juxtacortical, and in the corpus callosum with a Dawson finger aspect. (D) Focal hyperintensity (arrow) on the T2-PD-weighted image of the spinal cord at the level of C4. There was also a smaller lesion (not depicted) at the level of Th8-Th9. A follow-up scan 1 year after these images showed a new, small, focal lesion at the level of C2-C3. (E) At 6 months after the images shown in (A–D), 3 axial T1-weighted images after contrast enhancement on the level of the exit of root L4 of the spinal cord were made. We observed isolated intradural contrast enhancement of the nerve root L4 with some postganglionic nerve root enhancement (arrow). There was neither spinal disc protrusion nor nerve root compression. No leptomeningeal enhancement was seen. The patient with MS gave permission to present the imaging data as shown in this figure.

    Composition of CNS and PNS myelin

    The loss of myelin during MS is of critical clinical and pathologic importance. Myelin produced by either oligodendrocytes (CNS) or Schwann cells (PNS) extends from the glial plasma membrane and spirally enwraps axonal segments.35 The myelinated axonal segments are also known as internodes, whereas the unmyelinated axonal segments are called the nodes of Ranvier (figure 2A).2 The node of Ranvier lies between the outermost paranodal loops of adjacent myelin sheaths. The innermost paranodal loop is adjacent to the juxtaparanode, which borders the internode proper.36 Myelin in the CNS and PNS is thought to have the same vital function, namely saltatory impulse propagation along the axon.2 As demyelination has been established in the PNS as is in the CNS, it is of interest to compare the anatomic structure and molecular constituents of CNS myelin to PNS myelin, which may give insight into possible overlapping or divergent factors attacked during the demyelination process.

    Figure 2 The periaxonal region of a myelinated axon in the CNS is similar to the PNS

    (A) Overview of the myelinated axonal domains in the CNS and PNS. The upper half shows an axon that is myelinated by a Schwann cell, including the basal lamina, microvilli, Schmidt-Lanterman incisures, sodium (Na+) channels and potassium (K+) channels, and myelin proteins that are highly abundant in the PNS. The lower half represents an axon that is myelinated by an oligodendrocyte, including the process from a perinodal astrocyte/oligodendrocyte progenitor cells (OPCs), Na+ channels and K+ channels, and myelin proteins that are highly abundant in the CNS. (B) NFasc155 and NFasc186 are required to ensure the integrity of the clustered Na+ and K+ channels in the CNS and PNS. Paranodal NFasc155 binds to axolemmal Caspr and Contactin to form the paranodal complex and ensure paranodal integrity. Axolemmal NFasc186 ensures nodal integrity by clustering Na+ channels at the node of Ranvier. (C) The periaxonal region is suggested to function as a synapse in the CNS and PNS. The upper half represents a myelinated axon in the PNS. On arrival of the action potential, the voltage-gated K+ channel opens, resulting in a potassium efflux into the periaxonal region. Potassium is taken up by the myelin sheaths and eventually exits the myelin via nodal abaxonal voltage-gated K+ channels. The lower half represents a myelinated axon in the CNS. On arrival of the action potential, the voltage-gated periaxonal calcium (Ca2+) channel initiates subsequent calcium release from the axoplasmic reticulum. This results in the release of glutamate into the periaxonal region, which in turn binds to myelinic AMPA receptors (AMPARs) and NMDA receptors (NMDARs) to stimulate Ca2+ release in the myelin.58,e18 CLDN11 = claudin 11; CNP = cyclic nucleotide phosphodiesterase; FASN = fatty acid synthase; MAG = myelin-associated glycoprotein; MOG = myelin oligodendrocyte glycoprotein; P0 = myelin protein 0; PLP = proteolipid protein; SIRT2 = sirtuin 2; 4.1 G = band 4.1-like protein G.

    Anatomic structure

    Myelin sheaths in the CNS and PNS exist of a compact and a noncompact domain. Compact myelin consists of double-layered glial plasma membranes that are closely apposed at both intracellular and extracellular surfaces. These surfaces can be visualized by major dense lines and intraperiod lines, respectively. In noncompact myelin, the double-layered membranes do not compact. The majority of PNS myelin consists of compact myelin; noncompact myelin is found in paranodes and Schmidt-Lanterman incisures. The most external layer of myelin apposes to the Schwann cell basal lamina.37 The lateral borders of the Schwann cell cytoplasm are tipped with microvilli, which are in contact with the nodal axolemma.38,39 In the CNS, myelin is compact except for the myelinic channel system, consisting of a single channel of cytoplasm around the perimeter of the oligodendrocytic process, which includes both the abaxonal (portion of myelin far from the axonal process) and adaxonal (portion of the myelin close to axonal process) surface, as well as paranodes and transient openings of previously compacted myelin in some CNS fibers. It connects the most distal part of the myelin sheath with the soma of the oligodendrocyte.36 A distinctive structural feature of CNS myelin are the radial components. These structures consist of a series of radially arranged intralamellar strands spanning the myelin sheath and resemble tight junctions.37 Hence, radial components primarily hinder the diffusion of material through the CNS myelin sheath and make it less permeable.40 Unlike the PNS, myelin sheaths in the CNS do not have a basal lamina or microvilli. Some nodes are in contact with perinodal astrocytes or oligodendrocyte progenitor cell (OPC) processes, but the function remains unknown.41 Thus, CNS myelin and PNS myelin both exist of compact and noncompact domains, but they also have distinctive components.

    Molecular constituents

    Myelin consists of multiple components and has a high lipid-to-protein ratio comprising about 70%–85% of the dry weight in both CNS and PNS myelin.42,–,44 Only small quantitative differences between the lipid composition of the 2 types of myelin have been reported. In both CNS and PNS myelin, the most abundant lipids present are cholesterol, glycolipids (cerebroside and cerebroside sulfate), and ethanolamine glycerophosphatides. Of interest is that CNS myelin contains more glycolipids and less sphingomyelin compared with myelin in the PNS (table).42,43


    Overview of the lipid and protein composition in CNS and PNS myelin

    Proteomic studies have identified the presence of over 1,200 different proteins in CNS myelin and 545 different proteins in PNS myelin using mass spectrometry.13,45 CNS and PNS myelin each express a distinct set of proteins (table).37,46 However, 44% of the identified myelin proteins are shared by PNS and CNS myelin.13 The most dominant proteins of CNS and PNS myelin are proteolipid protein (PLP) and myelin protein 0 (P0), respectively, and might be involved in the myelin compaction.2,12,13 PLP is a tetraspan transmembrane protein,12 which is important for various myelin-related cellular events, and several mutated myelin tetraspans are known to cause neuropathies. Transmembrane protein P0 is an immunoglobulin-like cell adhesion molecule (Ig-CAM) and mediates the adhesion of the extracellular myelin surfaces.13,47,48 Periaxin is the second most abundant protein in PNS myelin and is a scaffolding protein.2,13,49 Periaxin is expressed before P0, MBP, or MAG and is suggested to play an important role during ensheathment and myelination in the PNS.49 In the CNS and PNS, MBP accounts for 8% of the myelin proteins and mediates the intracellular adhesion of cytoplasmic surfaces between individual layers of compact myelin.12,13,50 MBP is a highly heterogeneous protein as a result of alternative splicing and posttranslational modifications such as N-terminal acylation, GTP- and ADP-ribose binding sites, deamidation, methylated arginine, methionine sulfoxide, phosphorylation, and deimination of arginyl residues.51,52 In the CNS of shiverer mutant mice, which do not express MBP, major dense lines are missing. This can be rescued by expressing the MBP gene in transgenic shiverer mice.53 Of interest, loss of major dense lines is not observed in the PNS of shiverer mice because the cytoplasmic domain of P0 can compensate for MBP loss.54,55 The remaining identified myelin proteins have a relative low abundance compared with the CNS and PNS myelin proteins described above.12,13

    An example of a protein, which despite its low abundance (0.2%) is thought to play an important role in PNS myelin, is the myelin protein P2.13 In particular, P2 seems to be strongly involved in lipid homeostasis of myelinated Schwann cells.56 The protein is sufficient to induce clinical, electrophysiologic, and neuropathologic characteristics of experimental allergic neuritis.57

    Thus, CNS and PNS myelin each have a unique but also partly overlapping lipid and protein profile. In particular, the overlapping or functional compensating lipids and proteins may be considered as common target in the demyelination process of CNS and PNS during MS.

    Axo-myelin interaction in the CNS vs PNS

    The interaction between axons and myelinating glial cells is required for the initiation of myelination and subsequent maintenance to protect the axon and seems to be affected in MS.35,58 Myelinating glia determine the axonal diameter,59,60 help define the nodal and internodal domains of the axolemma,e1,e2 and provide survival signals to neurons.35 In turn, axons provide signals to regulate myelin formation.2,35 In the PNS, the initiation of myelination is completely controlled by axonal signals.35 Axon caliber is a key signal for myelination by Schwann cells, and axons above a threshold size of ∼1 μm diameter are typically myelinated.e3 The axon diameter can be measured based on the abundance of neuregulins, for example, neuregulin-1 (NRG1 type III) present on the axon surface, which is sensed by Schwann cell receptor tyrosine kinases erbB2 and erbB3.e4,e5 Similar to the PNS, only a selection of axons in the CNS becomes myelinated.2 The threshold axonal diameter for myelination in the CNS is 0.4 μm.e6 Although NRG1-ErbB signaling is not essential for CNS myelination, overexpression of NRG1 also stimulates myelination by oligodendrocytes.e7,e8 Beside axonal signals, CNS myelination is also controlled by additional mechanisms such as spatial density of OPCs, electrical activity, and cues from other glial cells.2 This difference in myelination initiation of the CNS and PNS suggests that oligodendrocytes have acquired additional mechanisms to control myelination.

    After myelination has been initiated, myelinating glia maintain neuronal health, axonal diameter, and axolemmal organization. In turn, axons are responsible for the myelin integrity.35 For instance, a tight association between axons and myelinating glia is essential for the integrity of the molecular domains of the axolemma.e1,e2 In both the CNS and the PNS, paranodal neurofascin (NFasc)155 binds to axolemmal Caspr and contactin to form the paranodal complex (figure 2b). This complex is essential for the formation of the septate-like axo-myelinic junctions that prevent the invasion of sodium and potassium channels into the paranode. Furthermore, axolemmal NFasc186 is required to ensure nodal integrity by clustering sodium channels at the node of Ranvier.e1,e2 P0 has been identified as an additional binding partner of NFasc155 and NFasc186 in peripheral myelin. Loss of its transcriptional regulators histone deacetylase 1 and 2 resulted in impaired axon-Schwann cell interaction.e1 It is unknown whether NFasc155 and NFasc186 also have an additional binding partner in CNS myelin. In addition, myelin protein cyclic nucleotide phosphodiesterase (CNP) is required to maintain the integrity of the specialized domains. In the CNS, loss of CNP disrupts the axoglial interactions and results in the disorganization of nodal sodium channels and paranodal Caspr.e9 It has not been reported whether CNP deficiency in the PNS also disorganizes nodal and paranodal components. However, it has been shown that loss of CNP causes peripheral hypermyelination and axonal loss and reduces noncompact myelin.e10 This suggests that CNP is required for axo-myelin maintenance in both the CNS and the PNS.

    In contrast to degenerated axons in the PNS, degenerated axons poorly regenerate in the CNS.e11 For instance, inhibitors of regeneration, called myelin-associated inhibitors, have been found specifically in CNS myelin. These include ephrin-B3, MAG, Nogo-A, and myelin oligodendrocyte glycoprotein. MAG is the only myelin-associated inhibitor that is also expressed in the PNS myelin.e12 However, the high concentration of laminin in the PNS overrides the inhibitory effect of MAG.e10 There are also myelin components that seem to prevent axon degeneration, such as oligodendrocytic peroxisomes or myelin proteins PLP and CNP. Loss of these components results in the formation of axonal spheroids and subsequent axonal degeneration.e14–e16

    According to new discoveries in the CNS, axons are able to form an axo-myelinic synapse (AMS) with myelin (figure 2c). Action potentials depolarize the internodal axolemma, which is detected by voltage-gated calcium channels located on the axonal surface. These calcium channels initiate subsequent calcium release from the axoplasmic reticulum, resulting in the release of glutamate in the periaxonal space located between the myelin sheath and axolemma. Glutamate then activates the myelinic AMPA and NMDA receptors (NMDARs) leading to a calcium influx into the myelin.e17 It is postulated that the AMS is responsible for the myelin structural dynamics and couples electrical activity to the metabolic output of the oligodendrocyte.58 In the PNS, the periaxonal space also seems to function as a synapse. Action potentials result in the opening of axonal potassium channels, leading to an increase of potassium in the periaxonal space, which is subsequently taken up by myelin via tight junctions.e18

    In conclusion, reciprocal signaling between neurons and oligodendrocytes or Schwann cells is required for myelination and the maintenance of the myelinated axons. An important distinction between myelination in the CNS and PNS is that axonal expression of NRG1 type III alone is sufficient to initiate myelination by Schwann cells but not by oligodendrocytes. Although the CNS and PNS use similar mechanisms to maintain the interaction between the axon and myelin, such as paranodal complexes and AMSs, differences have been observed. Furthermore, the axons in the CNS are more prone to degeneration, which can be partly be explained by CNS-specific axo-glial signaling.

    Biochemical alterations in CNS vs PNS myelin during MS

    Damage to myelin can result in demyelination of the axon, which makes the neuron prone to degeneration. Hence, remyelination is required to restore normal neural signaling. Most people have the innate ability to reestablish any damaged myelin in the CNS. However, patients with MS eventually lose this ability for reasons that are not entirely understood yet.e19 Several biochemical changes affecting CNS myelin have been identified in patients with MS. Unlike the CNS, far less studies have been performed that investigated the biochemical alterations in the PNS myelin of patients with MS. This might be the result of the persisting dogma according to which MS exquisitely affects the CNS.8

    White matter MS lesions are heterogeneous and can be divided into 4 fundamentally different types of demyelinating lesions. One group of lesions, accounting for 25% of all active lesions, was characterized by preferential loss of the periaxonal Ig-CAM MAG. Other highly abundant CNS myelin proteins (PLP, MBP, and CNP) were still present within the partly damaged myelin.e20 In studies using MAG-deficient mice, it was found that in face of a normal CNS/PNS myelination process, the periaxonal myelin sheath contained intracytoplasmic depositions and inclusion bodies.e21 Of interest, a uniform widening of the periaxonal myelin sheath was also observed during the pathologic examination of MS brains. In contrast, the outer myelin sheaths are often still intact in early lesions.e22,e23 These findings all suggest that demyelination can be initiated by a process starting in the innermost myelin layers, also called a dying-back oligodendropathy.

    Consistent with this hypothesis are the findings from a study that investigated the breakdown of myelin sheaths in several CNS demyelination models. In this study, the myelin protein required for compact myelin formation, MBP, was targeted by elevating the intracellular calcium levels. This led to the displacement of MBP and subsequent myelin fragmentation by the breakdown of the innermost myelin lamellae into vesicular structures.e24 As mentioned, MBP is a very heterogeneous protein due to alternative splicing and posttranslational modifications.51 A mass spectrometry study found that phosphorylation of MBP is strongly reduced or even absent in myelin of patients with MS compared with healthy myelin. Furthermore, arginine methylation of most MBP components is decreased in MS.e25 Moreover, citrullinated MBP levels are increased in patients with MS compared with healthy individuals.e25,e26 Because these posttranslational modifications affect the charge, conformation, and hydrogen bonding of MBP, it is suggested that these alterations compromise the ability of MBP to form stable myelin multilayers and compact myelin. Hence, the altered levels of MBP observed in patients with MS would result in a loss of compact myelin and unstable myelin multilayers. Citrullination/deimination of MBP is an enzymatic reaction involving the conversion of arginine to citrulline by a family of 5 citrullinating enzymes known as peptidyl arginine deiminases (PADs).e25 Mice exhibiting upregulation of PAD2 have increased levels of citrullinated MBP and show subsequent demyelination. Clusters of PAD2 were found in the periaxonal regions of these mice, which supports the theory of a dying-back pathology.52 It has been shown that citrullinated MBP has lost its ability to compact myelin and that it is more vulnerable to proteolytic attack. Hence, MBP citrullination might increase myelin breakdown during MS.e27 Increased citrullinated MBP is found in areas of ongoing demyelination and strongly correlates with the severity of MS.e28,e29 This suggests a central role for deimination of MBP in the pathogenesis of MS.e29 Recently, a new mouse model was introduced showing that a primary myelinopathy can trigger secondary pathologic inflammation. In this model, called cuprizone autoimmune encephalitis, a brief cuprizone treatment increased MBP citrullination. This led to biochemically destabilized myelin followed by a pathologic demyelinating immune response comparable to active MS plaques.e30 Of interest, drugs targeting PAD are able to attenuate inflammatory demyelination in animal models and may hold promise for MS.52,e30 It is possible that certain patients with MS have increased amounts of citrullinated MBP in PNS myelin. As mentioned, deimination of MBP hinders its ability to compact CNS myelin.52 It has been shown that PAD2 and PAD3, the enzymes responsible for deimination, are coexpressed with MBP in cultured rat and human Schwann cells. Furthermore, citrullinated proteins were observed in cultured Schwann cells of patients having peripheral lesions.e31

    Besides the role of MBP in MS pathology, the role of the MAG is also attracting a lot of interest. As mentioned above, pathologic studies in newly forming MS lesions often show a preferential loss of MAG,e20 and other investigations have underlined a higher degree of formation of a degraded form of MAG (dMAG) in the brain of patients with MS compared with non-neurologic controls.e32,e33 MAG is proteolyzed into dMAG by a putative cysteine protease (cathepsin-L) acting on the amino acid sequence 512–513 of the MAG depriving the molecule of the majority of its intracellular myelin compartment, making it soluble and allegedly less functional.e34 MAG being a sialic acid binding lectin and playing a role as an adhesion molecule to hold axon and myelin together,e35 it is then possible that a reduced MAG functionality might affect the stability of the AMS, contributing to the pathologic cascade of mechanisms that might lead to demyelination. Because this protein has a similar periaxonal distribution in healthy CNS and PNS myelin (MAG is additionally located in the paranodal and incisure membranes of PNS myelin),e36 its expression may also be decreased in peripheral myelin. For example, Mag-null mice show dysmyelination and axonal degeneration in both the CNS and the PNS.e37 Furthermore, a disrupted organization of central and peripheral periaxonal regions is observed in Mag-null mice.e38 Hence, these studies suggest that MAG might not only be reduced in central myelin but also in peripheral myelin.

    Because the myelin pathology seems to start at the most distal myelin compartment, it has recently been hypothesized that the AMS is involved in the pathogenesis of MS.58 MS genome-wide association studies have identified mutations that are important for glutamate homeostasis.e39 An altered glutamatergic transmission might establish an environment of chronic excitotoxicity, via myelinic NMDARs or additional mechanisms, resulting in biochemically altered myelin.58 Myelinating oligodendrocytes provide metabolic support for mitochondria by transporting lactate to the axons.e40 Lactate is reconverted into pyruvate and subsequently used by axonal mitochondria for ATP production.e41 Thus, the inability of oligodendrocytes to transport lactate would reduce the axonal ATP production. This results in a pathologic depolarization of axons due to ion transporter failure. This would in turn activate the voltage-gated calcium channels and excessive release of calcium from stores, leading to glutamate excitotoxicity in the periaxonal space (figure 3).58 The resulting excessive calcium entry through myelinic receptors can lead to the deimination of MBP by the calcium-dependent enzyme PAD and subsequent breakdown of the adaxonal myelin into vesicular structures.52,58,e24,e30 Schwann cells also express NMDARs, suggesting that the overactivation of myelinic NMDARs might also result in hypercitrullination of MBP in the PNS myelin.e31,e42 However, whether patients with MS also experience glutamate toxicity in the PNS remains unknown.

    Figure 3 The axo-myelinic synapse in the CNS might be involved in the pathogenesis of MS

    It is thought that oligodendrocytes produce lactate that is transported to the axonal mitochondria for the production of ATP. If the oligodendrocyte is unable to transport lactate, this would result in a reduction of axonal ATP. This in turn results in the pathologic depolarization of the axon. As a consequence, voltage-gated calcium (Ca2+) channels become activated and cause an increased release of Ca2+ from the axoplasmic reticulum and a subsequent increase of glutamate release into the periaxonal region. Glutamate activates the myelinic NMDA receptor (NMDAR), resulting in the activation of Ca2+-dependent peptidyl arginine deiminases (PADs). PADs will citrullinate myelin basic protein (MBP), which hinders the function of MBPs and might lead to the breakdown of myelin.58

    It has also been shown that paranodal and juxtaparanodal tethering proteins are diffusely distributed in demyelinated lesions of patients with MS.e43,e44,e45 Disruption of paranodal and nodal structures was also observed in a model of PNS demyelination. This resulted in the loss of septate-like junctions, allegedly affecting the stability of the axon-myelinic unit. Thus, demyelination in the PNS might be related to an altered expression of nodal, paranodal, and juxtaparanodal molecular structures. These findings suggest that the myelin integrity is harmed, which negatively affects the induction and fast propagation of electric signals along axons in the CNS and PNS.e1

    To conclude, multiple biochemical alterations have been discovered in CNS myelin of patients with MS. Several of the alterations are related to the periaxonal region, suggesting that the CNS demyelination observed in MS might be initiated by a dying-back oligodendropathy. Multiple studies have shown that patients with MS may experience PNS demyelination in addition to loss of myelin in the CNS,4,–,6,8,9,21,25,26 but how this pathology relates to each other needs to be elucidated.

    Summary and outlook for PNS myelin impairment in MS

    To date, the prevalent dogma is that MS is a demyelinating disorder of the CNS,8 leaving the PNS relatively unaffected. However, multiple studies reported clinical symptoms, pathologic findings, electrophysiologic examinations, and imaging data that are indicative of PNS dysfunction, i.e., peripheral demyelination in patients with MS.4,–,9,25 Whether there are common pathologic processes underlying demyelination in the CNS and PNS (in a subset of) patients with MS is currently unknown. Of interest is that the myelin lipid composition is very similar between the CNS and PNS42,e46 and that 44% of the proteins are similarly present in CNS and PNS myelin.12,13 The initial process of PNS myelination is completely regulated by axonal signals, whereas CNS myelination has acquired additional mechanisms.2,35 In both the CNS and the PNS, axonal and myelin components are required to ensure the integrity of nodal and internodal domains.e1,e2 Furthermore, the periaxonal space seems to function as a synapse in CNS and PNS myelin.e17,e18

    Myelinated axons depend on myelinating glia for support and maintenance. Any disturbance in the myelin has the potential to hinder axo-myelin interaction. During MS, several biochemical alterations have been observed in CNS myelin that affect this interaction. For example, a subtype of MS lesions shows preferential loss of MAG.e20 Furthermore, increased levels of citrullinated MBP are found in MS, which might be caused by glutamate excitotoxicity in the AMS.58,e28,e29 Moreover, several autoantigenic myelin proteins have been identified.10,11 Besides that, it has recently been observed that myelin lipids are globally altered in MS brains.e47 In addition, the nodal, paranodal, and juxtaparanodal domains are disrupted during MS.e44 Because numerous biochemical alterations in myelin of the CNS suggest a dying-back oligodendropathy,52,e20,e22–e24 it might be interesting to focus on the periaxonal region as an important disease target during future studies.

    Based on the overlap in myelin content between the CNS and PNS, and on studies in animal models of MS, we propose that several alterations in CNS myelin can also take place in PNS myelin and subsequently affect the axo-myelin interaction. For example, the PNS myelin can be affected by loss of MAG,e38–e40 hypercitrullination of MBP,e41,e42 and disturbed myelin domains.e1,e2 Because multiple clinical observations suggest that the PNS is affected during MS, it is important to further examine potential biochemical alterations in PNS myelin during MS.

    What is the consequence of PNS involvement in MS?

    PNS involvement in MS might be more frequent than is generally assumed. We propose that clinical observations of PNS dysfunction should be more explicitly questioned and tested for. In addition, PNS involvement also has consequences for research studies on MS. Studies on the PNS should be taken into account to accomplish better understanding of the pathophysiologic mechanism underlying MS and possibly also other demyelinating diseases. It will enable new concepts including the search for a possible common pathologic mechanism for PNS and CNS demyelination. When using human material in this search, future studies could study the myelinated or demyelinated peripheral nerves from patients with MS and controls, which will be accessible through biopsy which the CNS is not.e48 Furthermore, longitudinal studies examining both CNS and PNS dysfunction may be beneficial to unravel the primary or secondary PNS involvement to CNS pathology. When including PNS analysis in the diagnostic protocol, it may direct to a subtype of patients with MS that has not be recognized thus far and offers opportunities for lower strain disease monitoring and a therapeutic approach that fits with the spectrum of demyelinating pathology.

    Study funding

    No targeted funding reported.


    The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.

    Appendix Authors


    • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

    • The Article Processing Charge was funded by the authors.

    • Received June 2, 2020.
    • Accepted in final form September 23, 2020.
    • Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

    Compound Created To Help Reconstruct Myelin in Multiple Sclerosis

    Researchers have created a compound, that when tested in mice, was able to promote the reconstruction of the myelin sheath surrounding neuronal axons. These findings could pave the way to a new treatment for combating demyelinating conditions such as multiple sclerosis (MS). The findings were published in Glia.

    “I think we’ll know in about a year if this is the exact right drug to try in human clinical trials,” explained senior study author Larry Sherman, Ph.D., in a recent press release.

    “If it’s not, we know from the mouse studies that this approach can work. The question is, can this drug be adapted to bigger human brains?”

    What is myelin?

    Myelin is a membranous structure that surrounds neuronal axons (the part of the cell responsible for transmitting electrical signals). Myelin lamellae (cellular protrusions) are formed by fusion of the plasma membrane in glial cells. The lamellae repeat radially at a distance of approximately 12 nm along the length of the axon forming a “sheath”.

    Distribution of myelin along an axon. Credit: Pixabay

    Myelin is formed by different glial cell types depending on location. In the central nervous system (CNS) myelin is formed by oligodendrocytes, and in the peripheral nervous system (PNS) by Schwann cells.

    Demyelination in MS

    MS is an inflammatory condition that involves the loss of myelin (demyelination) around axons, disrupting the ability of the nerves to conduct electrical impulses. Only nerves in the CNS are affected by MS. The regions of the CNS where myelin is lost are referred to as “lesions” and appear as hardened scars. The translation of “multiple sclerosis” literally means “many scars”.

    Hyaluronic acid and multiple sclerosis

    The team had previously discovered a molecule called hyaluronic acid (HA) that accumulates in the brains of MS patients. This accumulation of HA inhibits the maturation of oligodendrocytes. Further studies revealed that HA is broken down into small fragments in MS lesions by hyaluronidases. These fragments act as a signal to immature oligodendrocytes not to “activate” their myelin-producing genes.

    The team set out to explore whether it was possible to block the hyaluronidase activity to promote remyelination.

    In the most recent study, the team report that the compound S3 (a modified flavonoid) is able to reverse the effects of HA, leading to the remyelination of axons in mice.

    “It’s not only showing that the myelin is coming back, but it’s causing the axons to fire at a much higher speed,” says Sherman. “That’s exactly what you want functionally.”

    The team are now beginning to apply the compound to a rare population of macaque monkeys with a multiple sclerosis-like disease known as Japanese macaque encephalomyelitis.

     Japanese Macaque. Credit: PixabayReference: Su, et al. (2019) A Modified Flavonoid Accelerates Oligodendrocyte Maturation and Functional Remyelination. Glia

    Scientists have figured out how to get the brain to get rid of multiple sclerosis


    Scientists have figured out how to get the brain to get rid of multiple sclerosis

    Scientists have figured out how to get the brain to get rid of multiple sclerosis – RIA Novosti, 07/05/2019

    Scientists have figured out how to make the brain get rid of multiple sclerosis

    American molecular biologists have discovered a gene, the removal of which makes the auxiliary cells of the nervous tissue especially actively restore “isolation”… RIA Novosti, 05.07.2019

    2019-07-05T14: 23

    2019-07-05T14: 23

    2019-07-05T14: 23




    discoveries – RIA Science

    health – society




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    MOSCOW, July 5 – RIA Novosti. American molecular biologists have discovered a gene, the removal of which makes the auxiliary cells of the nervous tissue especially actively restore the “isolation” of neurons when it is damaged. Managing its activity will help suppress the symptoms of multiple sclerosis, researchers write in the journal Nature Communications. Multiple sclerosis is a disease of the nervous system in which immune cells begin to attack the sheath of nerve fibers called myelin.Without myelin, the nerves conduct the signal worse and begin to “close”, which leads to various consequences from mild numbness of the limbs to paralysis or blindness. According to WHO statistics, almost 2.3 million people suffer from the disease. Today, dozens of scientific teams around the world are working to create treatments for this disease. Several years ago, Russian scientists from the Institute of Bioorganic Chemistry of the Russian Academy of Sciences proposed the first potential “vaccine” for multiple sclerosis, teaching immune cells not to attack the brain and not kill its cells.Despite these successes, it remains unclear why the immune system begins to consider the brain “the enemy”. Some scientists believe that this is due to the penetration of infections into the brain, while others believe that the causes of the development of multiple sclerosis are associated with disturbances in the functioning of the body itself. Myelin, as Monk notes, is produced not by the nerve cells themselves, but by special auxiliary bodies. There are two types of such “helpers” – oligodendrocytes and lemmocytes, the so-called Schwann cells. The former are responsible for restoring the “isolation” of brain neurons, while the latter are responsible for repairing similar damage in the lining of peripheral nerve cells.The first observations of their work showed that these cells work in slightly different ways and perform different tasks. The auxiliary bodies that live in the brain specialized in “packing” several axons, nerve endings at once, while Schwann cells selected and processed only one of them. These differences, as the researchers suggested, were the main reason why all attempts to cure multiple sclerosis with aid cultures of Schwann cells ended in vain. They simply did not take root in the brains of rats and other animals and did not participate in repairing injuries.Monk and her colleagues accidentally found out what exactly differs in the functioning of oligodendrocytes and their peripheral “cousins”, experimenting on fish, in which various genes associated with the formation of the nervous system were randomly damaged. By observing their life, scientists noticed that peripheral nervous the cells and brains of zebra fish in which the fbxw7 gene was damaged had significantly more myelin than similar body parts in other experimental animals. Having become interested in this feature of fish, biologists tried to uncover the reasons for its appearance, following the work of lemmocytes and oligodendrocytes, devoid of this piece of DNA.It turned out that this mutation changed the way Schwann cells work in an unusual way. In fact, they became indistinguishable from oligodendrocytes in their demeanor – they stopped focusing on only one nerve ending and began to process several axons at once. As a result, both the mass and the thickness of the myelin sheath in many peripheral nerve cells increased. After uncovering the mechanisms of the fbxw7 gene, Monk and her team tested what would happen if similar changes were made to the genome of mice.Removing this piece of DNA in an interesting way changed their behavior – they became less mobile and dexterous, as well as more sensitive to cold, but in general they were not much different from other rodents. Scientists hope that further experiments with these mice and fish will help them understand What else distinguishes oligodendrocytes and Schwann cells, and how you can make the former more actively fight damage or adapt the latter to work in the brain. All this will help not only create a therapy for multiple sclerosis, but also other diseases of the nervous system, for example, Charcot’s syndrome. Marie-Tooth, associated with excessively high immune activity.





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    medicine, usa, discoveries – RIA science, health – society, health, neurophysiology, genetics

    MOSCOW, July 5 – RIA Novosti .American molecular biologists have discovered a gene, the removal of which makes the auxiliary cells of the nervous tissue especially actively restore the “isolation” of neurons when it is damaged. Managing its activity will help suppress the symptoms of multiple sclerosis, the researchers write in the journal Nature Communications.

    “This completely overturns our understanding of how Schwann cells work. Their repertoire of actions is much richer than previously thought. We now know that controlling the activity of the fbxw7 gene will help us restore the myelin sheath of nerves in the human brain,” said Kelly Monk (Kelly Monk) from Oregon Medical University in Portland (USA).

    Multiple sclerosis is a disease of the nervous system, during the development of which immune cells begin to attack the sheath of nerve fibers, the so-called myelin. Without myelin, the nerves conduct the signal worse and begin to “close”, which leads to various consequences from mild numbness of the limbs to paralysis or blindness. According to WHO statistics, almost 2.3 million people suffer from this disease.

    Today, dozens of scientific teams around the world are working to create treatments for this disease. Several years ago, Russian scientists from the Institute of Bioorganic Chemistry of the Russian Academy of Sciences proposed the first potential “vaccine” for multiple sclerosis, teaching immune cells not to attack the brain and not kill its cells.

    5 December 2018, 11:22 Some scientists believe that this is due to the penetration of infections into the brain, while others believe that the causes of the development of multiple sclerosis are associated with disturbances in the functioning of the body itself.

    Myelin, as Monk notes, is not produced by the nerve cells themselves, but by special auxiliary bodies.There are two types of such “helpers” – oligodendrocytes and lemmocytes, the so-called Schwann cells. The former are responsible for restoring the “isolation” of brain neurons, while the latter are responsible for repairing similar damage in the lining of peripheral nerve cells.

    The first observations of their work showed that these cells work in slightly different ways and perform different tasks. The auxiliary bodies living in the brain specialized in “packing” several axons and nerve endings at once, while Schwann cells selected and processed only one of them.

    These differences, the researchers speculated, were the main reason why all attempts to cure multiple sclerosis with Schwann cell cultures have failed. They simply did not take root in the brains of rats and other animals and did not participate in repairing injuries.

    Monk and her colleagues accidentally found out what exactly differs in the work of oligodendrocytes and their peripheral “cousins”, experimenting on fish, in which various genes associated with the formation of the nervous system were randomly damaged.

    May 6, 2016, 16:30 disease – Charcot-Marie-Tooth syndrome, which deprived her of mobility.

    Observing their lives, scientists noticed that peripheral nerve cells and the brain of zebra fish, which had a damaged fbxw7 gene, had significantly more myelin than similar body parts in other experimental animals.Having become interested in this feature of fish, biologists tried to uncover the reasons for its appearance, following the work of lemmocytes and oligodendrocytes, devoid of this piece of DNA.

    This mutation turned out to change the way Schwann cells work in an unusual way. In fact, they became indistinguishable from oligodendrocytes in their demeanor – they stopped focusing on only one nerve ending and began to process several axons at once. As a result, both the mass and the thickness of the myelin sheath increased in many peripheral nerve cells.

    After uncovering how the fbxw7 gene works, Monk and her team tested what would happen if similar changes were made to the genome of mice. The removal of this DNA segment changed their behavior in an interesting way – they became less mobile and dexterous, as well as more sensitive to cold, but in general they differed little from other rodents.

    Scientists hope that further experiments with these mice and fish will help them understand what else distinguishes oligodendrocytes and Schwann cells, and how the former can be made to actively fight damage or adapt the latter to work in the brain.

    All this will help not only to create a therapy for multiple sclerosis, but also other diseases of the nervous system, for example, Charcot-Marie-Tooth syndrome, associated with excessively high immune activity.

    June 21, 2016, 18:46 The new vaccine does not have these side effects. 90,000 Modern therapy can stop the progression of multiple sclerosis

    Multiple sclerosis is a chronic autoimmune disease in which the myelin sheath of nerve fibers in the brain and spinal cord is affected.Most often, it affects young people. But with timely correct treatment, the patient can lead a full life – study, work, create a family. However, some of these patients develop secondary progressive multiple sclerosis (SPMS), a special form of the disease. About how it is dangerous and how it is being treated today, “RG” was told by the professor of the Department of Neurology of the Faculty of Advanced Training for Doctors of the Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, Doctor of Medical Sciences Rinat Bogdanov.

    Rinat Ravilevich, what are the features of secondary progressive multiple sclerosis?

    Rinat Bogdanov: In multiple sclerosis (MS), the myelin sheath of nerve cells is damaged. There are several variants of the disease. Clinical manifestations depend on where in the nerve tissue a focus of nerve cell damage has formed. The peculiarity of myelin is that it can be restored. The remitting form is a wave-like course of the disease, when exacerbations alternate with the restoration of the myelin sheath and, therefore, functions.It occurs in about three quarters of patients. But with secondary progressive multiple sclerosis, not only the nerve sheath begins to suffer, but also the peripheral nerves themselves, or the processes of neurons. And this situation is often irreversible or partially reversible, so a progression occurs: in the period between exacerbations, clinical symptoms increase. The remitting form can also turn into a secondary progressive form over time.

    What are the causes of secondary progressive multiple sclerosis and what are its main symptoms?

    Rinat Bogdanov: The patient himself begins to feel the main signs, because the neurologist, unfortunately, does not see him every day.The patient feels that after the next exacerbation, complete recovery does not occur: he has difficulties with controlling his body, it becomes difficult to walk long distances, tactile sensations change, vision may deteriorate. And the more neuronal processes are damaged, the more pronounced this clinical symptomatology will be.

    What are the statistics of this form of MS in the world and in our country?

    Rinat Bogdanov: There are now more than three million patients with multiple sclerosis in the world.In recent years, there are more of them. Basically, it was believed that this disease is typical for the population of northern latitudes, and its causes may be not only genetic breakdowns, but also environmental factors, unfavorable ecology. There is an assumption that one of the reasons may be a deficiency of vitamin D, as well as external infectious effects – viruses that are genetically similar to myelin. According to this theory, in genetically predisposed people, the immune system begins to confuse such viruses with myelin and, attacking it with antibodies, destroy myelin.

    Russia belongs to the regions with a high prevalence of multiple sclerosis. We have registered more than 150 thousand patients, that is, more than 50 cases per 100 thousand of the population. The most common variant is the recurrent form, which affects about 75 percent of patients. But of them, up to half can go into the future in a secondary progressive form.

    What tests are carried out to make an accurate diagnosis?

    Rinat Bogdanov: The sooner we detect the transition of the remitting form with exacerbations to the secondary progression, the better the long-term prognosis will be, since the possibility of an earlier therapeutic intervention appears.Therefore, diagnostic criteria are now being developed – special scales, questionnaires, including in electronic format, are used, which make it possible to identify the secondary progression of the disease by a set of signs. And, consequently, and on time to prescribe adequate therapy, since drugs have appeared that can affect this process.

    What is the prognosis for the development of the disease without adequate treatment?

    Rinat Bogdanov: Previously, there was no opportunity to influence the secondary progressive form.When new drugs appeared, scientists were able to compare the condition of patients who could not receive such therapy with those who receive it. It turned out that over time, those who received the new drugs had fewer movement problems and other impairments. And for those who did not receive it, disability set in faster.

    How does therapy work that can stop or slow down the progression of the disease?

    Rinat Bogdanov: New drugs affect the neurodegenerative process.That is, not on inflammation, which gives an exacerbation, but on the process of damage to the nerve processes, thereby postponing the death of nerve cells. They actually inhibit the neurodegeneration process.

    What are the guidelines for organizing the life of MS patients? What should their loved ones know in order to provide timely assistance?

    Rinat Bogdanov: The first task is to immediately consult a doctor when the condition changes in order to detect progression in time. Then therapy is needed with the help of special drugs.It is good that the state has taken upon itself the function of providing these drugs; under the program of high-cost nosologies, it provides these patients with them. The second important component is rehabilitation, regular physical activity. It should also be remembered that, in general, most MS patients do not tolerate heat well, their ability to move is reduced, and weakness increases. By the way, this symptom is even used in the diagnosis of MS: when a patient first comes to the doctor, he is usually asked how he tolerates heat, a bath, a hot bath.

    In general, a healthy lifestyle is very important for patients with MS, especially physical activity, adequate nutrition, and adequate sleep. And the correct alternation of work and rest so that the body has time to recover. Plus special trainings for both motor and cognitive rehabilitation. That is, it is necessary to train not only the muscles that are controlled by the nervous system, but also to make the brain work more actively, to form new neural connections in it, on which memory, attention, etc. depend.

    Do primary care physicians know how to recognize multiple sclerosis when a patient comes to them?

    Rinat Bogdanov: Everything depends on the level of education. Now work is underway to improve the level of knowledge of general practitioners and general practitioners. Their main task is to suspect this disease and refer the patient to a neurologist to clarify the diagnosis. This will allow you to prescribe adequate therapy earlier.

    Are there any scientific studies on SPM now?

    Rinat Bogdanov: Of course.We have learned to influence the formation of MS foci, to treat exacerbations. But the main problem of SPMS is the gradual accumulation of often irreversible damage, which leads to disability, and scientists are trying to solve the main problem – to learn how to influence the process of neurodegeneration. Research is underway to develop gene therapy that will target this very process. Moreover, the problem of neurodegeneration is broader than SPMS; this also includes Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases.In principle, similar mechanisms are involved in their development. Science does not stand still, so the process of neurodegeneration itself is being studied in more detail, points of application are looked for that can be influenced in order to slow down or, ideally, stop this process. But in our arsenal have already appeared drugs that are used to treat SPMS, and quite successfully, which is good news.

    Multiple sclerosis: a new step in diagnosis | Scientific discoveries and technical innovations from Germany | DW

    Multiple sclerosis is a severe and so far incurable chronic disease of the central nervous system, characterized by destruction of the myelin sheath of the nerve fibers of the spinal cord and brain.Today it is known that this progressive disease is autoimmune, but in general it poses many mysteries for doctors: the causes of multiple sclerosis are still unknown, the mechanism of development is not fully understood, and the available drugs can, at best, slow down somewhat, but by no means stop the course of the disease.

    Problems of early diagnosis

    The situation with early diagnosis is also unimportant: by the time doctors can definitely inform the patient of this sad news, the damage to his central nervous system is usually already so significant that it is clearly visible on the magnetic resonance tomogram.

    These lesions – the inflammatory breakdown of myelin protein and the formation of sclerotic plaques – resemble a rapidly expanding fire, says American neurologist Katerina Akassoglou, professor at the University of California, San Francisco: significant destruction. But if the source of fire is found in time, then the damage from the fire can be prevented to a certain extent. ”

    Damage to the blood-brain barrier

    Today, most researchers agree that the spark that generates this fire enters the brain from the blood vessels.The fact is that the development of multiple sclerosis, like many other neurological diseases, begins with damage to the so-called blood-brain barrier – the physiological barrier between the circulatory system and the central nervous system.

    In the body of a healthy person, this barrier protects the nervous tissue from toxins circulating in the blood, infectious agents, as well as factors of the immune system, which perceive the brain tissue as foreign. That is, the vessels of the brain of a healthy person are impermeable to blood cells, including immune cells.But in patients with multiple sclerosis, lymphocytes, having overcome the blood-brain barrier, migrate to the brain, as a result of which the synthesis of antibodies to myelin begins, which leads to the formation of foci of inflammatory demyelination.

    Thrombin and fibrinogen in the patient’s brain

    But not only immune cells, but also a number of other substances penetrate into the brain of a patient with multiple sclerosis from the bloodstream – for example, the proteins thrombin and fibrinogen. One of the stages of the blood coagulation process – the so-called coagulation phase – consists in the breakdown of fibrinogen under the influence of thrombin, resulting in the formation of fibrin, from which a dense clot is then formed.

    This process is vital because it stops bleeding in case of violation of the integrity of the vascular system of the body. However, in the brain tissues, thrombin and fibrinogen cause uncontrolled inflammatory reactions that are so characteristic of patients with multiple sclerosis. Simply put, the presence of these proteins in the brain is highly likely to indicate some pathological condition. They can serve as indicators of impending damage to nerve cells – as smoke indicates an incipient fire.

    Fluorescence reveals the presence of thrombin

    This is the reasoning behind the new method for early diagnosis of multiple sclerosis developed by Katerina Akassoglu and her colleagues. The researcher explains: “Thrombin belongs to the class of proteases – special enzymes that cleave peptide bonds between amino acids in protein molecules. That is, it is a kind of scissors that cut proteins into their component parts. And we decided to use this property of thrombin to detect it, create a molecular indicator of the presence thrombin in tissues “.

    To this end, the researchers hung molecules of a fluorescent substance on protein fragments that are usually targeted by thrombin. Where thrombin is actually present, it begins to cut this marker protein into pieces, and they accumulate in the surrounding cells and are well identified due to fluorescence. Experiments on laboratory mice, which serve as a model for the study of multiple sclerosis, have confirmed the effectiveness of this method.

    If not a diagnosis, then at least a prognosis of an exacerbation

    True, there is one problem, Professor Akassoglu admits: “The fact that blood components enter the brain is typical for many neurological diseases, and not only for multiple sclerosis.In other words, our test is not very specific. But in the case of patients already diagnosed with multiple sclerosis, our test may be able to predict the next flare-up. ”

    This view is shared by a non-multiple sclerosis specialist, a researcher at the Mayo Clinic in Rochester, Minnesota. Brian Sauer: “It is extremely difficult to determine which patient will end in remission and start another exacerbation. This means that it is usually impossible to take appropriate measures in advance.The new test combined with magnetic resonance imaging is, if anything, better than tomography alone. Perhaps it will make it possible to achieve some progress in therapy: after all, today we can only state an exacerbation when it has already occurred. ” everyone is beginning to better understand the cellular and molecular mechanisms of multiple sclerosis, there is no doubt.

    90,000 Demyelinating diseases of the nervous system

    Neurological department

    Demyelinating diseases are autoimmune diseases in which the white matter myelin of the central or peripheral nervous system is destroyed. The disease is caused by the interaction of external (viruses, infections, intoxication, diet, stress, poor ecology) and hereditary factors.

    The most common demyelinating disease is multiple sclerosis , characterized by damage to several parts of the central nervous system.

    Demyelinating diseases include:

    • acute disseminated encephalomyelitis;
    • diffuse disseminated sclerosis;
    • acute optic neuromyelitis, concentric sclerosis.

    Young able-bodied people often suffer from demyelinating diseases.

    Reasons for occurrence:

    1. Immune response to proteins , which are part of myelin. These proteins begin to be perceived by the immune system as foreign and are attacked, resulting in their destruction.This is the most dangerous cause of the disease. The impetus for starting such a mechanism can be an infection or congenital features of the immune system: multiple encephalomyelitis, multiple sclerosis, Guillain-Barré syndrome, rheumatic diseases and chronic infections.
    2. Neuroinfection: Some viruses can infect myelin, resulting in demyelination of the brain.
    3. Failure in the metabolic mechanism . This process can be accompanied by a malnutrition of myelin and its subsequent death.This is typical for pathologies such as thyroid disease, diabetes mellitus.
    4. Intoxication with chemical substances of various nature: alcoholic, narcotic, psychotropic strong action, toxic substances, paint and varnish products, acetone, drying oil, or poisoning with the waste products of your own body: peroxides, free radicals.
    5. Paraneoplastic processes – pathologies that are a complication of tumor processes.Recent studies confirm that the interaction of environmental factors and a hereditary predisposition play an important role in triggering the mechanism of this disease. A relationship has been established between geographic location and the likelihood of disease occurrence. In addition, viruses (rubella, measles, Epstein-Barr, herpes), bacterial infections, eating habits, stress, ecology play an important role.

    Diagnosis of demyelinating diseases:

    The diagnosis is made if, by magnetic resonance imaging of the brain and spinal cord, foci of increased intensity of a round or oval shape are found.MRI can diagnose the development of brain atrophy, impaired conduction of impulses in the visual tract, brain stem and spinal cord. Myelin destruction and axonal degeneration can be detected by electroneuromyography.
    Immunological studies are also carried out (a high concentration of IgG indicates a demyelinating process).


    Measures for the treatment of demyelinating diseases are specific and symptomatic. New medical research has led to good advances in specific treatments.Beta-interferons are considered one of the most effective drugs: they include Rebif, Betaferon, Avanex. Clinical studies of betaferon have shown that its use reduces the rate of progression of the disease by 30%, prevents the development of disability and reduces the frequency of exacerbations.
    Experts increasingly prefer the method of intravenous administration of immunoglobulins (bioven, sandoglobulin, venoglobulin). Thus, exacerbations of this ailment are treated. More than 20 years ago, a new, rather effective method for the treatment of demyelinating diseases was developed – immunofiltration of cerebrospinal fluid.As means of specific treatment, corticosteroids, plasmapheresis, cytostatics are used. Also widely used are nootropics, neuroprotectors, amino acids, muscle relaxants.

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    A fundamentally new way of treating multiple sclerosis has been proposed

    Scientists are investigating a new agent that helps restore the myelin sheaths of nerve cells, which could theoretically be a cure for multiple sclerosis.

    Multiple sclerosis is an autoimmune disease in which nerve fibers lose the insulating myelin sheath , and with it the ability to effectively transmit signals. Patients complain of fatigue, their limbs, vision and memory weaken, speech becomes slurred, depression develops. Multiple sclerosis is now treated with immunosuppressants, mainly interferon beta and fingolimod, but these drugs are not very effective and have unwanted side effects.

    American researchers, led by Luke Leirson , Professor at Scripps Research Institute , have proposed a different approach, cell-regenerative. In an article published in the journal Nature , they described the action of a drug that stimulates the differentiation of progenitor cells of those cells that are supposed to ensure the restoration of destroyed myelin sheaths.

    Multiple sclerosis affects more than 2.5 million inhabitants of the planet, mostly women.The causes of its occurrence are unknown, but the development of the disease is provoked by some infections and the lack of vitamin D.

    In multiple sclerosis, cells of the immune system, known as T-lymphocytes , invade the brain and upper spinal cord, causing inflammation and eventually loss of the myelin sheath.

    Myelin is produced by special cells called oligodendrocytes (a long word, but you have to remember it). They must restore damaged membranes, but they cannot do this, because in multiple sclerosis their number is sharply reduced: for reasons that have not yet been clarified, progenitor cells stop turning into oligodendrocytes.

    Researchers have tried to find a substance that would stimulate the differentiation of progenitor cells. To do this, they tested the effect of about 100 thousand molecules on the culture of precursor cells of rat optic nerve neurons.Among several selected substances with unexplored properties was the familiar drug benztropine, a drug prescribed for Parkinson’s disease. Since many of the properties of benztropine were already known, scientists continued to work with it.

    Further studies were carried out on mice. A small amount of the demyelinating drug cuprizone was added to their diet and a mouse model of multiple sclerosis was produced.

    Benztropine appears to have no effect on the inflammatory response, but it helps mice restore the population of mature oligodendrocytes, which, in turn, recreate the myelin sheath of damaged nerves despite ongoing T-cell attacks.

    And, probably, the restoration of myelin occurs at the same rate as its destruction. Benztropine is known for multiple effects on brain neurons, but it causes differentiation of oligodendrocyte precursors by binding to some muscarinic (acetylcholine) receptors. The mechanism of its action is still to be studied in more detail.

    Benztropine has another extremely valuable property: it is an excellent complement to the traditional treatment of multiple sclerosis.Its reception allows you to reduce the dose of immunosuppressants by almost 90% without loss of effectiveness. Because these drugs have undesirable side effects, it is important to be able to reduce the dosage. Thus,

    medicine relieves the symptoms of multiple sclerosis, enhancing the effect of immunosuppressants and at the same time activating the restoration of myelin.

    Researchers plan to learn more about the mechanisms of this process and, possibly, modify the structure of benztropine to enhance its effect.They will also study the effects of other molecules that stimulate the differentiation of oligodendrocyte progenitor cells. It is possible that they will be more effective than benztropine.

    Benztropin is a drug prescribed for Parkinson’s disease; it is sold in pharmacies under a different name, but is not registered in Russia. His research as a cure for multiple sclerosis is just beginning, with long preclinical and clinical trials ahead. Scientists warn that benztropine also has unwanted dose-related side effects, neurological and psychiatric, and could harm MS patients if they self-medicate after reading this post.

    Antibodies to myelin antigens, IgG

    Determination of autoantibodies to myelin antigens in the blood, used for diagnosis, assessment of prognosis and control of treatment of multiple sclerosis and other demyelinating diseases of the central nervous system.

    Synonyms Russian

    Autoantibodies to myelin antigens

    Antibodies to myelin

    English synonyms

    Anti-myelin antibodies

    Myelin specific autoantibodies

    Research method

    Indirect immunofluorescence reaction.

    Which biomaterial can be used for research?

    Venous blood.

    How to properly prepare for the study?

    • Do not smoke within 30 minutes prior to examination.

    General information about the study

    Demyelinating diseases of the central nervous system are a heterogeneous group of diseases characterized by destruction of the myelin sheath (demyelination) of the nerve fibers of the brain and spinal cord.The most prominent representative of this group of diseases is multiple sclerosis. At the moment, demyelinating diseases are considered as autoimmune diseases, mainly mediated by T cells, however, recently there are new data on the role of the humoral response mediated by autoantibodies to CNS antigens. The most well studied antibodies to antigens of myelin – the protein-lipid membrane of neuronal axons. Determination of autoantibodies to myelin antigens in the blood can be used to diagnose, assess the prognosis and control the treatment of multiple sclerosis and other demyelinating diseases of the central nervous system.There are several variants of antibodies to myelin antigens:

    1. Antibodies to myelin glycoprotein oligodendrocytes (anti-myelin oligodendrocyte glycoprotein, Anti-MOG)

    A protein called myelin glycoprotein of oligodendrocytes (MOG) accounts for only 0.05% of all proteins in myelin. MOG, however, is located in the outer layer of the myelin sheath, making it a readily available antigen for autoantibody attack. In fact, MOG is a target for both humoral and cellular autoimmune responses.The physiological role of MOG is not completely clear, although, apparently, it is necessary for the “sticking” of myelin fibers. MOG is also able to bind the C1q fragment of the complement and thus participate in the regulation of the classical pathway of complement activation. It has been shown that antibodies to MOG directly lead to demyelination, that is, they have encephalitogenic properties. It is important to note that the MGO antigen has several conformations that differ in the degree of immunogenicity. The most pronounced demyelination is caused by antibodies directed against the glycosylated epitopes of MGO.

    Antibodies to MGO are found in the blood and cerebrospinal fluid of patients with multiple sclerosis, but can also be detected in healthy people. Interestingly, anti-MGOs are more commonly found in cases of childhood multiple sclerosis (in children under 10 years of age).

    Some studies have shown that the level of anti-MGO reflects the activity of multiple sclerosis and therefore can be used to predict and control the treatment of the disease. It has also been shown that healthy people who have anti-MGO in their blood have a slightly increased risk of developing multiple sclerosis in the future.

    2. Antibodies to myelin basic protein (anti-myelin basic protein, anti-MBP)

    Myelin basic protein (MBP) is one of the main components of the inner layer of the myelin sheath. Located internally, MBP is less accessible to autoantibodies, provided the myelin fiber is intact. Antibodies to MBP are found at elevated concentrations in the blood and cerebrospinal fluid of patients with multiple sclerosis. Unlike anti-MGO, anti-MBP does not have encephalitogenic properties and their role in the pathogenesis of multiple sclerosis is not clear.Some scientists have shown that anti-MBP in combination with anti-MGO can be used as markers for the early transformation of clinical isolated syndrome (CIS) into multiple sclerosis.

    3. Antibodies to myelin-associated glycoprotein (anti-myelin associated glycoprotein, anti-MAG)

    A protein called myelin-associated glycoprotein (MAG) accounts for about 3% of all proteins in myelin. However, MAG, like the myelin glycoprotein of oligodendrocytes MOG, is located in the outer layer of the myelin sheath and is therefore available for autoantibodies.Anti-MAG is well known as a clinical and laboratory marker of peripheral neuropathies associated with monoclonal gammopathies and other lymphoproliferative diseases. It has been shown that these autoantibodies are also found in patients with multiple sclerosis and may be associated with the progression of this disease.

    4. Antibodies to galactocerebrosidase (anti-galactocerebrosidase, anti-Galc)

    Galactocerebrosidase (Galc) is the most important lipid component of myelin, accounting for about 30% of myelin.As well as anti-MGO, anti-Galc can directly lead to demyelination. Anti-Galc is more common in relapsing-remitting multiple sclerosis and is not found in healthy individuals. Since anti-Galc is uncommon for the early stages of multiple sclerosis (clinically isolated syndrome) and is more often detected during disease progression, some scientists have suggested using this marker to determine the stage of the disease.

    5. Anti-proteolipid protein (anti-PLP)

    Proteolipid Protein (PLP) is another major component of myelin.Anti-PLP antibodies are found at elevated concentrations in the blood and cerebrospinal fluid of patients with multiple sclerosis.

    6. Antibodies to phosphatidylcholine (anti-phosphatidylcholine)

    In the composition of oligoclonal immunoglobulins, determined in the cerebrospinal fluid of patients with multiple sclerosis, specific antibodies of the IgM class, selectively interacting with phosphatidylcholine, can be detected. These autoantibodies are associated with a more aggressive course of the disease and therefore can be used as a prognostic marker.

    It should be emphasized again that antibodies to myelin antigens are nonspecific for multiple sclerosis. They are also found in some other demyelinating diseases (for example, in Marburg disease and acute disseminated encephalomyelitis) and in post-stroke conditions. For this reason, they are used as additional clinical and laboratory markers of multiple sclerosis and other diseases of the central nervous system.

    What is the research used for?

    • For the diagnosis, prognosis and control of the treatment of multiple sclerosis and other demyelinating diseases of the central nervous system.

    When is the study ordered?

    • If you have symptoms of multiple sclerosis: visual impairment (blurred, double vision), feelings of weakness, numbness, tingling in the hands and feet, imbalance, increased urination, especially if the symptoms are intermittent and are observed in a young woman;
    • upon receiving ambiguous results from magnetic resonance imaging of the brain (MRI).

    What do the results mean?

    Reference values ​​


    Increased result:

    • multiple sclerosis;
    • post-stroke condition;
    • Marburg disease;
    • acute disseminated encephalomyelitis.

    Reduced result:

    • norm;
    • effective treatment of the disease.

    What can influence the result?

    • Age: Antibodies to myelin antigens are more common in childhood multiple sclerosis;
    • The presence of concomitant diseases: antibodies to myelin antigens can be detected for a long time after a stroke.

    Download an example of the result

    Important notes

    • Antibodies to myelin antigens are nonspecific markers of multiple sclerosis and other demyelinating diseases;
    • the results of the analysis should be interpreted taking into account additional clinical, laboratory and instrumental data.

    Also recommended

    [13-058] Diagnostics of multiple sclerosis (isoelectric focusing of oligoclonal IgG in cerebrospinal fluid and serum)

    Who orders the study?

    Neurologist, general practitioner.


    • Lalive PH. Autoantibodies in inflammatory demyelinating diseases of the central nervous system. Swiss Med Wkly. 2008 Nov 29; 138 (47-48): 692-707. doi: / aop / smw-aop12283.Review.
    • Marie Cathrin Mayer, Edgar Meinl. Glycoproteins as targets of autoantibodies in CNS inflammation: MOG and more. Ther Adv Neurol Disord. 2012 May; 5 (3): 147-159.
    • Mirshafiey A, Kianiaslani M. Autoantigens and autoantibodies in multiple sclerosis. Iran J Allergy Asthma Immunol. 2013 Aug 28; 12 (4): 292-303.

    Science: Science and technology: Lenta.ru

    Partner material

    There is a widespread belief that multiple sclerosis is a senile memory disorder.In reality, this diagnosis has nothing to do with sclerosis and age-related forgetfulness. “Lenta.ru” tells about the danger of multiple sclerosis, how approaches to its treatment have changed in recent years, and how you can get help in Russia.

    Multiple sclerosis is a disease of young people. The first symptoms may appear at the age of 16–40 years, there are cases of illness in children in adolescence. The disease is characterized by multiple lesions of the nervous system with a large number of foci in the brain.Motor function, coordination, vision suffer most noticeably, memory is impaired over time

    Klara Bakhtiyarova

    Honored Doctor of the Republic of Bashkortostan, Head of the Multiple Sclerosis Center

    Klara Zakievna Bakhtiyarova – Professor, Doctor of Science, Honored Doctor of the Republic of Bashkortostan, author of more than 200 scientific papers, member of the All-Russian Society of Neurologists and the European Academy of Neurology, member of the Expert Council Russian Committee of Researchers of Multiple Sclerosis (RUCTRIMS), head of the Republican Center for Multiple Sclerosis.

    Multiple sclerosis is an autoimmune disease with a complex development mechanism. It occurs due to disorders in the immune system, the causes of which are not fully understood, and leads to the destruction of the myelin sheath of the nerve fibers of the central nervous system. This process gradually spreads and more and more affects the brain and spinal cord.

    If we compare nerves with electrical wires through which the central nervous system transmits signals to the entire body, then myelin performs an insulating role, so that the impulse propagates along the fiber without loss.Myelin multiplies the speed of impulse transmission from one nerve cell to another. When the membrane is damaged due to an attack by antibodies, “bald spots” appear in it, and the transmission rate slows down, the impulse between cells is transmitted worse or may not be transmitted at all.

    Of course, myelin at the onset of the disease is restored by itself, but not in all fibers. When there is no active inflammation in the foci of multiple sclerosis, two constant processes occur: demyelination (destruction of myelin) and remyelination (its restoration).As the attacks recur from time to time, damaged fibers accumulate in the nervous system – and the symptoms of the disease become more noticeable. Because of this, a person begins to experience more and more restrictions in everyday life.

    “All this leads to the fact,” explains Professor Klara Zakievna Bakhtiyarova, “that at first a person may feel only slight numbness in the fingers, a feeling of squeezing the body, disturbed gait, dizziness, but later may be confined to a wheelchair.This often happens at working age, when you want to lead an active life, you need to raise children. Why this breakdown occurs in the immune system and its own immune cells begin to attack the tissues of the body, we still do not know. As well as the reasons why women are more often affected by the disease are not quite clear. There are families where several siblings are sick, but there is no evidence that the disease is inherited. Geneticists are working in this direction, but so far it has not been possible to find the gene responsible for the occurrence of multiple sclerosis. “

    Unfortunately, it is impossible to completely cure multiple sclerosis, but today it is possible to achieve stable remission, smoothing the course of the disease, reducing the area of ​​damage and, as a consequence, slowing down the disability. Therapy must be applied throughout life.

    Many drugs that alter the course of multiple sclerosis (MSID) are aimed at reducing the activity of the inflammatory process in multiple sclerosis. Currently, much attention is paid not only to reducing exacerbations, but also to slowing down neurodegenerative and atrophic processes in the central nervous system in multiple sclerosis.

    Relapsing-remitting type of multiple sclerosis is the most common type, with exacerbation attacks followed by recovery periods. During remission, all symptoms may disappear or decrease significantly. There are a number of medications that can help reduce the frequency and harm of flare-ups.

    “Nowadays, it is possible to diagnose multiple sclerosis with the help of MRI already at the very first, barely noticeable symptoms. The earlier treatment is started, the more favorable and milder the course of the disease will be.The treatment regimen is selected individually, taking into account all the features of the manifestation and type of multiple sclerosis. Before the appointment of therapy, the patient is carefully examined, and then all changes in the state of health are monitored throughout life, ”explains Professor Bakhtiyarova.

    Approximately half of patients with a relapsing-remitting course pass into the secondary progressive stage of multiple sclerosis. This type of disease develops five to ten years after the onset of the disease. It is characterized by a persistent deterioration in neurological function.

    The average age of patients with this course of multiple sclerosis is from 40 years. The rate of progression of the disease is different for each patient, however, in most cases, the secondary progressive type of multiple sclerosis leads to disability. At this stage, the drugs used for the remitting type no longer work, and therapy must be changed.

    A new targeted drug has recently appeared in Russia. It is intended for the treatment of secondary progressive multiple sclerosis, regardless of the presence of exacerbations.This fundamentally distinguishes the drug from others that affect inflammatory activity and are indicated for reducing the frequency of relapses in RMS.

    The idea of ​​the method is to recognize autoaggressive cells and prevent them from leaving the lymph nodes. Thus, the central nervous system is protected from attacks from lymphocytes, while other links of the immune system are not affected. This selective intervention in immune mechanisms causes fewer side effects and improves the quality of life of patients.Studies show that the use of targeted therapy significantly slows down the progression of the disease, and therefore the onset of disability.

    The possibilities of modern therapy for secondary progressive multiple sclerosis have significantly expanded, which will improve the quality of life of people suffering from this serious disease.