In the immune system, there are two types of white blood cells, B-cells and T-cells. T-cells exist in three forms, all responsible for different immune system responses. Helper T-cells recognize foreign antigens (the substance the immune system aims to destroy), stimulate antibody production, and produce cytokines (chemicals which act as biological messengers) which activate other T-cells. These T-cells are able to recognize antigens through their receptors, made of protein molecules that selectively bind to certain other molecules. Suppressor T-cells perform a function converse to that of their helper counterparts, turning off the immune system response. Cytotoxic T-cells directly attack and destroy antigenic material (6). In MS, an unknown trigger activates helper T-cells whose antigen specific receptors recognize central nervous system myelin as an antigen. While what exactly activates these T-cells is unknown, but there is speculation that the trigger may be environmental or viral (7). Once triggered, the activated T-cells reproduce clones that have the same myelin-specific activation. All of the activated T-cells then release cytokines and adhesion molecules that enable the T-cells to adhere to and cross over the blood-brain barrier, which normally prohibits the flow of substances into the brain (8,9). The proteins in these T-cells bind to myelin fragments on microglial cells and undergo a secondary activation (10), after which they multiply and release more cytokines, further invading the nervous system (11) and inflaming and damaging the blood-brain barrier. The greatly weakened barrier becomes easily permeable, allowing additional immune system cells, such as B-cells and cytotoxic T-cells to cross over (12). Once through the barrier, B-cells produce antibodies which bind to the oligodendracytes (the cells of the CNS which create myelin) and the myelin itself. Associated macrophages procede to destroy the myelin and may also damage the oligodendracytes (13).
Myelin, found only in vertebrate nervous systems, is a fatty substance that surrounds the axons and long dendrites of nerves in the brain and spinal cord tissue (4). By lowering the rate at which the axonal membrane absorbs nerve impulses, myelin acts as an insulator, allowing NS potentials to travel rapidly through the nervous system and maintain communication between the brain and the rest of the body (2). This communication between the brain and the rest of the CNS and peripheral nerves is a central component of the proper functioning of the body's sensory and motor capabilities. As the myelin is destroyed, the CNS loses some of its ability to send signals throughout the body, causing the debilitating symptoms of MS. A recent study discovered that there is not only myelin damage found in MS patients, but also damage to the axons themselves in areas of MS lesions. Researchers at the Cleveland Clinic in Ohio reported that there were "damaged nerve fibers in all MS lesion areas they studied. In many cases, the nerve fibers were actually severed (14)."If a nerve is severed, there is no way for it to perform its function of transmitting potentials. These findings indicate that many of the long-term neurological symptoms of MS are caused by a combination of both myelin and axon destruction.
MS has its most striking effect on motor and sensory neurons, which generally have long axons carrying information between the brain, spinal cord, and the rest of the body. Because these axons are longer, they have a greater need for the insulation myelin provides and are therefore most strikingly affected by its destruction. The most common symptoms and effects of MS demonstrate sensory or motor neuron failure. One common symptom is a problem with gait or with motor reflexes. These indicate an abnormality in the pyramidal tracts, the main motor nerve tract in control of voluntary movement (15). MS commonly affects other areas of sensory and motor function as well, including vision, coordination, strength, sensation, speech and swallowing, bladder control, and sexual function (16: symptoms). Coordination, speech, and bladder control are adversely affected when there is a breakdown of the function of motor neurons that carry signals from the brain and spinal cord to the muscles, which normally perform these functions.
The common MS symptoms of altered sensations, such as numbness, tingling and other indefinable sensations are caused by a breakdown of the function of sensory neurons which carry information from the sense organs to the brain. Visual disturbances and sexual dysfunction can be caused by a breakdown in function of either sensory or motor neurons, or both. Vision can be adversely affected when either motor neurons that control eye movement and visual coordination or the sensory optic nerve is damaged or inflamed by MS (17). Sexual function can be impaired if either the motor neurons controlling physical arousal or sensory axons which transmit information about sexual sensation are damaged (18). Sexual function can also be adversely affected by other symptoms of MS, such as incontinence, spasticity, or weakness.
While damage to a combination of motor and sensory neurons in both the spinal cord and brain can be responsible for most symptoms of MS, there are certain symptoms that are primarily caused by lesions in the brain itself. Among these are those scientists believe are related to cerebellar and cognitive functions. Since the cerebellum is responsible for maintaining the body's sense of equilibrium, MS lesions and other damage can cause problems with balance and spatial perception (19). Cognitive impairment occurs in only about one half of all MS patients. Of those with cognitive function impairment, only twenty percent have moderate to severe impairments, the rest having only mild dysfunction (20). Memory loss (confined primarily to recent events), difficulty with abstract reasoning, decreased language function, and lowered speed of information processing are the abnormal cognitive-related manifestations of MS (21). Intellectual function, such as the abilities to learn, reason and make appropriate judgements are least affected by the disease (22). Because MS can bring on depression, which can also cause symptoms of cognitive difficulties, it is often not known whether a patients mental impairment is a direct result of demyelination and nerve damage, or a secondary effect of MS induced clinical depression (20).
Scientists researching treatments, forms of prevention and cures for MS are looking at two different areas: the possible causes of MS and ways to repair the damage to myelin and nerve cells. Determining the cause or trigger for MS will help to both better understand the disease and develop refined treatments and determine ways to avoid or prevent the disease before it occurs. Reversing or eliminating the diseases effects will, of course, help those who already suffer from MS. Those investigating possible reasons why a person is susceptible to or actually gets MS are primarily focusing on genetic susceptibility, environmental susceptibility and causes and possible viral triggers. The summary of observations show that even though MS is not hereditary, having a primary (parent or sibling) relative with MS appears to greatly increase one's chances of getting MS by up to seventy percent (23). Another indicator that genetics may increase susceptibility to MS is that monozygotic twins (twins with identical genetic blueprints) have a higher rate of concordant development of MS than dizygotic twins (twins having different genetic blueprints) (23). This "genetic susceptibility"could have many explanations. One possibility is that a person's genetic makeup may include a predisposition to abnormal myelin proteins, which may help trigger the disease (24). Another more likely possibility is that a person may be born with a genetic predisposition to certain environmental factors, which may then trigger the autoimmune response responsible for MS (7).
In addition to genetics, environmental factors are also being studied for their possible contributions to the onset of MS. Studies have shown that there are patterns that relate where a person lives to their chances for developing MS. Those born in an area of high risk and move to an area of lower risk acquire a lower risk if the move takes place before the subject is 15 years old (7). This data has lead some scientists to the conclusion that MS may be triggered by early exposure to some environmental agent. The risk of MS increases geographically as well, with a higher risk further away from the equator. Because most initial exposure to viruses takes place before the age of 15, and viruses are a recognized cause of demyelination and inflammatory responses, and because increased viral antibodies have been found in the sera and cerebrospinal fluid of MS patients during active disease episodes, many speculate that a virus triggers the disease (7, 24, 25). If this is the case, identification and isolation of the virus could lead to new treatments or prevention for the disease.
Research into ways to combat and repair damage done by the disease includes finding ways to restore and promote the regrowth of myelin and damaged axons as well as ways to combat or deactivate the T-cells which promote MS. In recent experiments on "shaking pups"(dogs with a mutation which are born with little or no myelin), transplanted glial cells from healthy animals were able to remyelinate nerves in the area of their implantation (26). A natural substance called insulin-like growth factor (IGF-1) as well as a protein found in the brain have both also been successful in promoting various degrees of remyelination in animals with experimental allergic encephalomyelitis (EAE), which is a animal dymelinating model for MS research (27, 28).
As far as combating the immune system response that causes the demyelination, many treatments are being studied which work to varying degrees. Currently, MS patients are treated with medications such as betaseron, interferon, and prednisone (28). These medications help reduce exacerbations and the volume of MS lesions (28, 29). Other current research includes investigating cytokines, such as interleukin 4, which reduce immune attacks and ways of promoting suppressor T-cell activity (28). Although the cause, trigger and solution to the demyelination and nerve damage the body's own immune system causes in Multiple Sclerosis are still unknown, what researchers do know provides for basic understanding and treatment of MS. Further research into the genetic, environmental, and other factors which may influence the occurrence of this disease, as well as chemical and biological ways to fight its onset and symptoms, will lead to even better understanding and control over this debilitating neurological disease.
4) Multiple Sclerosis: What is MS?
8) Activated T cells bind to the blood brain barrier
9) Activated T cells cross the blood brain barrier
10) Activated T cells bind to a myelin antigen
11) Super-activated T cells proliferate within the CNS
12) Inflammatory products damage the blood/brain barrier
13) Macrophages strip the myelin from the axons
14) NEW STUDY FINDS DAMAGE TO NERVE FIBERS IN MULTIPLE SCLEROSIS
16) What is Multiple Sclerosis (MS)?
20) Forgetfulness or Confusion
21) Assessing mental impairment
22) Cognitive and Perceptual Problems in MS.
24) FIRST RESULTS FROM NMSS STUDY ON MS GENETIC SUSCEPTIBILITY
26) Remyelination Progress Reported
27) EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS
29) Virtual Hospital, Chapter 14: Neurology: MS
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