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How does de-myelination occur in multiple sclerosis?

How does de-myelination occur in multiple sclerosis?


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From what I understand, only the oligodendrocytes are affected in multiple sclerosis, and they are attacked by T cells which cross the blood-brain barrier. This leads me to two questions:

  1. How is the blood-brain barrier affected in MS that allows T lymphocytes to cross the barrier?
  2. Why do the T lymphocytes attack the oligodendroccytes? And when they do, what is the mechanism for de-myelination?

Thank you in advance!


T-cell migration to the brain is very limited and occurs at a very low level in healthy conditions, however during diseases the number of T cells passing through the blood-brain barrier is elevate due to increased expression of traffic signals and adhesive molecules. I've found two good articles on how T-cells migrate through blood-brain barrier:

J Neural Transm (2006) 113: 477-485 Molecular mechanisms involved in T cell migration across the blood-brain barrier, B. Engelhardt

and D. W. Miller, “Immunobiology of the blood-brain barrier.,” J. Neurovirol., vol. 5, no. 6, pp. 570-578, 1999.

During T-cell maturation, those that react too heavily to antigens of the body are killed to avoid having T-cells that would kill the body's own cells. But in rare cases this process fails and auto-reactive T-cell get released from the thymus (This short paper is good for starters). So the (simplified) reason why T-cells attack oligodendrocytes is that they falsely recognize them as pathogens, and therefore kill them. The loss of oligodendrocytes results in loss of myelin sheats.

Also in this paper (it holds many info on demyelination and multiple sclerosis) it is shown that even non-specicfic T-cells can open the way for antibodies through the blood-brain barried, and this results in extended demyelination.


How Does MS Affect the Nervous System

In contrast to many diseases that affect a single part of the human body, MS affects two different body systems: the immune system and the nervous system. The immune system is not a distinct organ like the brain or liver. Instead, it is composed of many different types of molecules and cells (known as white blood cells) that travel through the bloodstream. The immune cells use chemical messages to protect the body from attack by bacteria, viruses, and cancers. MS is believed to be an autoimmune condition in which the immune system is excessively active and actually attacks the nervous system.

The central nervous system (CNS) is the part of the nervous system involved in MS. The CNS includes the brain and spinal cord. The nerves in the CNS communicate with each other through long, wire-like processes that have a central fiber (axon) surrounded by an insulating material (myelin). In MS, the immune system cells produce inflammation that injures the myelin. In addition, damage occurs to the axon. This damage is known as degeneration, which is the process that occurs in aging-related neurologic diseases such as Alzheimer's and Parkinson's disease. The injury to the myelin and axons results in a slowing or blocking of nerve impulses that prevents the affected parts of the nervous system from functioning normally.

The cause of MS is not entirely clear. It is believed that two important factors are involved in developing the disease, one of which is environmental and the other genetic. The characteristic geographic distribution of MS indicates that an environmental factor is present. One hypothesis is that individuals are exposed to a particular virus during childhood. This viral infection may be more common in cooler climates that are more distant from the equator. Another theory relates the geographic distribution to vitamin D, which mildly suppresses the immune system and thus could be protective against MS. Because vitamin D becomes active with sunlight exposure, those who live farther from the equator (with less-direct sunlight exposure) may have lower levels of vitamin D levels and higher risks of developing MS.

The presence of a genetic factor is suggested by family studies that demonstrate a hereditary predisposition to MS. Some genetic diseases are "dominant" and are clearly passed down through generations. MS usually is not passed on in such a well-defined pattern. Rather, there may exist an inherited predisposition to the disease that must be present in addition to an environmental agent to cause disease. Ongoing, intensive research efforts are aimed at identifying specific genes that increase the risk of developing MS or affect the severity of the disease.


Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS that affects approximately 0.1%–0.2% of the population in North America and Europe. Smoking has been recognized as a risk factor in development of MS. Interestingly, snus consumers and combined snus and cigarette consumers appear to have a reduced risk of developing MS compared to smokers who have never used snus, based on several studies in the Swedish population. From preclinical studies using experimental autoimmune encephalomyelitis model (EAE), nicotine appears to delay disease onset and reduce severity. Further epidemiological studies on noncombustible tobacco and nicotine-containing products will certainly give new interesting insights into correlations between MS and consumption of those products. Given the importance of various nAChRs in modulating disease exacerbation or ameliorating inflammatory and/or immune processes, nAChRs should be further investigated as possible drug targets. In this chapter, the impact of smoking, snus, and nicotine on MS are discussed.


Psychological aspects of multiple sclerosis

A significant incidence and prevalence of psychological disorders in multiple sclerosis (MS) has been reported. Their underlying mechanisms and the extent to which they are reactive to psychosocial factors or symptoms of the pathological process itself, remain unclear. Depression is the predominant psychological disturbance with lifetime prevalence around 50% and annual prevalence of 20%. Depression is commoner during relapses, may exacerbate fatigue and cognitive dysfunction and no firm evidence exists of its induction by interferon instead, treating depression improves adherence to disease-modifying drugs. Anxiety is also frequent, occurs in newly diagnosed patients, and its co-morbidity with depression has been suggested to increase the rate of suicidal ideation. The relationship between stress and MS is an attractive issue because some studies pointed to an association between stressful life-events and MS onset/relapses however, the evidence supporting this hypothesis is not conclusive so far. Other psychiatric illnesses, as bipolar affective disorder, pathological laughing and crying or psychosis occur less frequently in MS. Therapeutic strategies include psychotherapy, cognitive behavioural therapy, strengthen of coping, and specific medications. The "art" of the MS team in providing the best individualized care is emphasized, aiming to reduce the burden of the disease and improve the patients' quality of life.


Can nerve damage be repaired?

Once the inflammation caused by the immune attack is over, it is possible for the body to replace damaged myelin. This process is known as remyelination. Although the new myelin can work effectively, it tends to be thinner than unaffected myelin and so messages through the affected nerves may not be as fast as before the attack.

Remyelination tends to occur in the earlier stages of MS but, with repeated relapses or attacks, oligodendrocytes become damaged and destroyed. Eventually, they may not be able to produce more myelin. If an axon is left without the protection of myelin it will be more vulnerable to damage and may die.

Your central nervous system is able to overcome small areas of nerve damage by rerouting messages using undamaged nerve cells. This ability to adapt to avoid damaged areas is called plasticity. Messages may take longer to get through but your symptoms will improve to some extent.

Should the area of damage become too large, this rerouting process is no longer able to compensate. Messages to or from that part of the central nervous system are permanently blocked, resulting in symptoms that do not improve for you.

Remyelination and neuroprotection are potential areas where new treatments could be developed. Some research is looking into drugs that protect nerves from damage and so halt or slow down the progression of MS. Some research is investigating drugs that promote myelin repair, which would mean that damage could be reversed and function improved.


Abstract

Multiple sclerosis is a common cause of neurological disability in young adults. The disease is complex — its aetiology is multifactorial and largely unknown its pathology is heterogeneous and, clinically, it is difficult to diagnose, manage and treat. However, perhaps its most frustrating aspect is the inadequacy of the healing response of remyelination. This regenerative process generally occurs with great efficiency in experimental models, and sometimes proceeds to completion in multiple sclerosis. But as the disease progresses, the numbers of lesions in which demyelination persists increases, significantly contributing to clinical deterioration. Understanding why remyelination fails is crucial for devising effective methods by which to enhance it.


Abstract

Remyelination involves reinvesting demyelinated axons with new myelin sheaths. In stark contrast to the situation that follows loss of neurons or axonal damage, remyelination in the CNS can be a highly effective regenerative process. It is mediated by a population of precursor cells called oligodendrocyte precursor cells (OPCs), which are widely distributed throughout the adult CNS. However, despite its efficiency in experimental models and in some clinical diseases, remyelination is often inadequate in demyelinating diseases such as multiple sclerosis (MS), the most common demyelinating disease and a cause of neurological disability in young adults. The failure of remyelination has profound consequences for the health of axons, the progressive and irreversible loss of which accounts for the progressive nature of these diseases. The mechanisms of remyelination therefore provide critical clues for regeneration biologists that help them to determine why remyelination fails in MS and in other demyelinating diseases and how it might be enhanced therapeutically.


Multiple Sclerosis

Multiple Sclerosis: A Mechanistic View provides a unique view of the pathophysiology of multiple sclerosis (MS) and related disorders. As the only book on the market to focus on the mechanisms of MS rather than focusing on the clinical features and treatment of the disease, it describes the role of genetic and environmental factors in the pathogenesis of MS, the role of specific cells in the pathophysiology of the disease, and the pathophysiology of inflammatory and neurodegenerative disorders related to MS.

The book provides discussion of neurodegeneration and neuroregeneration, two critical emerging areas of research, as well as detailed discussion of the mechanisms of action of the approved and investigational drugs for treatment of MS and the emerging role of magnetic resonance spectroscopy (MRI) in investigations into MS.

It is the only book on the market to offer comprehensive coverage of the known mechanisms of MS and related diseases, and contains contributions from physicians and researchers who are worldwide experts in the field of study.

Multiple Sclerosis: A Mechanistic View provides a unique view of the pathophysiology of multiple sclerosis (MS) and related disorders. As the only book on the market to focus on the mechanisms of MS rather than focusing on the clinical features and treatment of the disease, it describes the role of genetic and environmental factors in the pathogenesis of MS, the role of specific cells in the pathophysiology of the disease, and the pathophysiology of inflammatory and neurodegenerative disorders related to MS.

The book provides discussion of neurodegeneration and neuroregeneration, two critical emerging areas of research, as well as detailed discussion of the mechanisms of action of the approved and investigational drugs for treatment of MS and the emerging role of magnetic resonance spectroscopy (MRI) in investigations into MS.

It is the only book on the market to offer comprehensive coverage of the known mechanisms of MS and related diseases, and contains contributions from physicians and researchers who are worldwide experts in the field of study.


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Principal Cause is Unknown

MS is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS) that affects the brain and spinal cord. It's the most common chronic neurologic disease in young people and adults in Europe and affects approximately 2.5 million people throughout the world. The study was published in the journal Archives of Neurology (66(2):173-9) and was carried out by the team of Dr. Pablo Villoslada at the University of Navarre. Last December, these researchers joined Hospital Clínic, Barcelona-IDIBAPS. Until now, it was thought that the atrophy seen in the brains of patients with MS was caused by the plaque in the white matter. The new results show that these plaques explain only 30% of the lesions.

Until now it was assumed that MS predominantly affected myelin, a fat that sheaths the nerves. It was thought that the plaques that form in the myelin were directly responsible for the atrophy of the grey matter. This study was designed to determine whether the loss of volume–atrophy–in the brain’s structures was related to the presence of lesions or cuts in the nerves connected to them.

The researchers analyzed the brains of 81 people (61 with MS and 20 healthy people) using magnetic resonance imaging (MRI) and a morphometric method (volumetry). The study focused on the optical pathway, starting with the hypothesis that lesions in this part of the brain, and in no other, correlate with atrophy of the occipital cortex and the lateral geniculate nucleus (LGN), the main centers for processing visual information. The results indicate that the lesions in the white matter of the nerves originating in the LGN explain up to 28% of the variation in volume. Atrophy of the occipital cortex did not correspond to the presence of lesions in the optical pathway, probably because it is associated with many other pathways.

Thus, although the sclerotic plaques in the nerves contribute significantly to the atrophy of the grey matter, the remaining 72% must still be explained. The data suggest that other neurodegenerative processes are involved. Because atrophy of the grey matter is the main cause of the progressive form of the disease and its severe sequelae, it's important to gain a better understanding of the principal mechanism of the damage, apart from the classic plaques, in order to be able to apply this knowledge to treating the disease.

Cerebral Atrophy and Depression

A recent study reported on the UCLA Newsroom, looks at brain atrophy as a cause of depression for those with MS. Adding to all that ails people managing their MS is depression ― for which MS sufferers have a lifetime risk as high as 50%.

Yet despite its prevalence, the cause of this depression is not understood. It's not related to how severe one's MS is, and it can occur at any stage of the disease. That suggests it's not simply a psychological reaction that comes from dealing with the burden of a serious neurologic disorder.

Now, in the first such study in living humans, researchers at UCLA suggest a cause, and it's not psychological, but physical: atrophy of a specific region of the hippocampus, a critical part of the brain involved in mood and memory, among other functions.

Reporting in the early online edition of the journal Biological Psychiatry, senior study author Dr. Nancy Sicotte, a UCLA associate professor of neurology, Stefan Gold, lead author and a postdoctoral fellow in the UCLA Multiple Sclerosis Program, and colleagues used high-resolution magnetic resonance imaging (MRI) to identify three key sub-regions of the hippocampus that were found to be smaller in people with MS when compared with the brains of healthy individuals.

The researchers also found a relationship between this atrophy and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a complex set of interactions among three glands. The HPA axis is part of the neuroendocrine system that controls reactions to stress and regulates many physiological processes. It's thought that this dysregulation may play a role in the atrophy of the hippocampus and the development of depression.

"Depression is one of the most common symptoms in patients with multiple sclerosis," Gold said. "It impacts cognitive function, quality of life, work performance and treatment compliance. Worst of all, it's also one of the strongest predictors of suicide."

The researchers examined three sub-regions of the hippocampus. They imaged 29 patients with relapsing-remitting MS (RRMS) and compared them with 20 healthy control subjects who did not have MS. They also measured participants' cortisol level three times a day cortisol is a major stress hormone produced by the HPA axis that affects many tissues in the body, including the brain.

In addition to the difference between MS patients and healthy controls, the researchers found that the MS patients diagnosed with depression showed a smaller CA23DG sub-region of the hippocampus, along with excessive release of cortisol from the HPA axis.

"Interestingly, this idea of a link between excessive activity of the HPA axis and reduced brain volume in the hippocampus hasn't received a lot of attention, despite the fact that the most consistently reproduced findings in psychiatric patients with depression (but without MS) include hyperactivity of the HPA axis and smaller volumes of the hippocampus," Sicotte said.


Myelin Sheath Damage and Multiple Sclerosis (MS)

The central nervous system or CNS is the part of the nervous system made up of the brain and spinal cord.

  • The brain controls most bodily functions, such as voluntary movements, perception of sensations, memory, awareness, and thoughts.
    • The cerebrum controls voluntary actions, speech, thought, and memory. The cortex, also called gray matter, is the outer part of the cerebrum and is made of neurons (nerve cells). Most of the brain's information processing is done in the cortex.
    • The brain is divided into two halves: the right hemisphere and the left hemisphere. These hemispheres lie on a central structure called the thalamus, which relays information between the peripheral input from the senses and the brain. Other central structures include the hypothalamus, which regulates automatic functions such as appetite and thirst, and the pituitary gland, which is partially responsible for growth, metabolism, and stress response.
    • The brain is connected with the brainstem (midbrain, pons, and medulla). The cerebellum is located posteriorly to the brainstem and plays a role in maintaining equilibrium and muscle tone. It also participates in complex mathematical and musical skills.

    How Does the Myelin Sheath Work?

    Myelin is a fatty material that coats, protects, and insulates nerves, enabling them to quickly conduct impulses between the brain and different parts of the body. Myelin also contains proteins that can be targeted by the immune system. Myelin coats the nerves of both the central nervous system and the peripheral nervous system the destruction of the myelin in the central nervous system is what triggers many of the symptoms of multiple sclerosis (MS).

    Nerve cells are coated with sections of myelin, and the tiny spaces between the sections are called nodes. As the brain sends messages through the nerves of the spinal cord, the impulses jump from node to node. The myelin sheath prevents these impulses from escaping from the nerve at the wrong point.

    What Destroys the Myelin Sheath?

    In multiple sclerosis (MS), the body's immune system T cells attack the myelin sheath that protects the nerve fibers. The T cells either partially or completely strip the myelin off the fibers, leaving the nerves unprotected and uninsulated. The nerves are not as able to pass messages from the brain to the other body parts. The messages the nerves try to send are delayed or distorted and the messages the brain receives may be misinterpreted.

    Myelin is lost in multiple areas, leaving scar tissue that due to its hardened characteristics is called sclerosis. These damaged areas where the sheath has been destroyed and further disrupt the ability for the nerves to pass messages are also called plaques. These plaques can be identified by magnetic resonance imaging (MRI), a technique that helps doctors assess and monitor the progression of multiple sclerosis.



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