Pathogenesis of Multiple Sclerosis
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Pathogenesis of Multiple Sclerosis

MS (Multiple Sclerosis) is an inflammatory and demyelinating disease of the CNS (Central Nervous System). MS is classified according to its clinical course into several categories: benign, RR (Relapsing-Remitting, the most common variant), PR (Progressive-Relapsing), PP (Primary-Progressive) and SP (Secondary-Progressive). MS first manifests itself as a series of attacks followed by complete or partial remissions as symptoms mysteriously lessen, only to return later after a period of stability. Rarely, patients may have a PR course in which the disease takes a progressive path punctuated by acute attacks. PP, SP, and PR are sometimes lumped together and called Chronic Progressive MS (Ref.1). Initial and subsequent symptoms may dramatically vary in their expression and severity over the course of the disease that usually lasts for many years. Early symptoms may include numbness and/or paresthesia, mono- or paraparesis, double vision, optic neuritis, ataxia, and bladder control problems. Subsequent symptoms also include more prominent upper motor neuron signs, i.e., increased spasticity, increasing para- or quardriparesis. Vertigo, incoordination and other cerebellar problems, depression, emotional lability, abnormalities in gait, dysarthria, fatigue and pain are also commonly seen (Ref.2).

Susceptibility to MS is linked to genes in the MHC (Major Histocompatibility Complex) on chromosome 6. Other genes within the HLA (Human Leukocyte Antigen) complex are involved in the pathogenesis of MS, including TNF-Alpha (Tumor Necrosis Factor-Alpha), various components of the complement cascade, and myelin oligodendroglial glycoprotein (Ref.3). Predominantly, it is a disease of the "white matter" tissue. The white matter is made up of nerve fibers, which are responsible for transmitting communication signals both internally within the CNS and between the CNS and the nerves supplying rest of the body (Ref.4). Pathologically, MS is characterized by the presence of areas of demyelination and T-Cell predominant perivascular inflammation in the brain white matter. Disease begins most commonly with acute or subacute onset of neurologic abnormalities. During an MS attack, inflammation occurs in areas of the white matter of the CNS in random patches called plaques. Once immune cells have spread to the white matter of the CNS, the immune response is targeted to the entire supramolecular complex of myelin. This process is followed by destruction of myelin; the fatty covering that insulates nerve cell fibers in the brain and spinal cord. Myelin facilitates the smooth, high-speed transmission of electrochemical messages between the brain, the spinal cord, and the rest of the body; when it is damaged, neurological transmission of messages may be slowed or blocked completely, leading to diminished or lost function. The name "multiple sclerosis" signifies both the number (multiple) and condition (sclerosis, from the Greek term for scarring or hardening) of the demyelinated areas in the CNS (Ref.1). Another effect of the inflammation is to kill the maintenance glial cells. The most vulnerable of these are the oligodendrocytes, which are lost in great numbers. Almost no oligodendrocytes remain in the middle of chronic MS lesions. Additionally, the inflammation can also damage the underlying axonal membrane. This membrane is a sophisticated structure that enables the nerve transmission (the action potential) to travel along the nerve. As the disease progresses, axons are also destroyed though not necessarily by the inflammatory response. During the secondary progressive phase of the disease, inflammation becomes less and less common but still the axons continue to die. This degeneration of axons is known as Wallerian Degeneration (Ref.5). After axons have been demyelinated, the inflammation dies back. Neurons, which have not been damaged by the relapse, can resume their proper function and some recovery (remission) is usual, at least in the early stages of the RR form of the disease. Demyelinated axons can exhibit remarkable abilities to function despite losing their myelin. Recent work has shown that they produce greater numbers of sodium channels that contributes to remission in MS. The myelin maintenance cells in the CNS, the oligodendrocytes, can sponsor remyelination - a process whereby the myelin sheath around the axon is repaired (Ref.5).

T-Cells play a particularly important role in MS. They travel widely and continuously throughout the body patrolling for foreign invaders. In order to recognize and respond to each specific antigen, each T-Cells surface carries special receptor molecules for particular antigens. In autoimmune diseases such as MS, the detente between the immune system and the body is disrupted when the immune system seems to wrongly identify self as nonself and declares war on the part of the body (myelin) it no longer recognizes. The injected myelin probably stimulates the immune system to produce anti-myelin T-Cells that attack the animals own myelin (Ref.1). The T-Cells produce cytokines, notably lymphotoxin (LT-Alpha, also known as TNF-Beta) and TNF-Alpha, and then influence macrophages, as well as microglial cells and astrocytes, to produce nitric oxide and osteopontin (Ref.3). Chemokine receptors are also involved in MS. CC chemokines recruit the monocytes/macrophages and T-Cells in autoimmune diseases including MS. The neuronal damage that leads to paralysis in MS patients is initiated by an inflammatory phase in which T-Cells and monocytes are recruited across the blood-brain barrier. Activated T-Cells produce one of the chemokine receptors, CXCR3, which is responsible for the recruitment of auto-aggressive T-Cells. The ligands for CXCR3 include CXCL10, CXCL9 and CXCL11. Two CC chemokine receptors, CCR1 and CCR5 and their ligands CCL5, CCL3, CCL7 and CCL4 have also been observed in the pathogenesis of MS (Ref.6). These receptors are produced on T-Cells and monocytes/macrophages and the accumulation of these cells is directly correlated with lesions in which demyelination occurs, followed by axonal loss, which ultimately leads to paralysis.

Approximately half of all people with MS experience cognitive impairments but such symptoms are usually mild and are frequently overlooked (Ref.1). No two people get MS in exactly the same way and the expression of each individuals disease is as unique as their fingerprints. However, the different courses of the disease, both within an individual and within the whole population, principally differ in their timing, location and severity (Ref.4). Differential diagnosis for MS includes other demyelinating diseases of the nervous system, often of a viral or post infectious origin. Among them are encephalomyelitis, transverse myelitis, as well as other immune-mediated conditions, which affect CNS, such as sarcoidosis, systemic lupus erythematous, Vitamin-B12 deficiency, etc. There is no curative treatment available for the MS. However, a number of medications can be used to treat the disease symptomatically. Corticosteroids are medications of choice for treating exacerbations. IFN-Beta1B (Interferon-Beta-1B; Betaseron) as well as IFN-Beta1A (Avonex) is successfully used to reduce the frequency and severity of relapses. Specific medications are also available to treat fatigue, pain, spasticity, bladder control problems, etc. In the future, medications aimed at reducing specific autoimmune response, and, possibly, medications designed to assist in remyelination will help improve the quality of life of MS patients (Ref.2).