Symptoms of MS
Types of MS
Myelin Sheaths and Saltatory Conduction
Causes of Immune Response
Multiple Sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system (CNS). This disease destroys the myelin sheath, a lipid-rich membrane that insulates axons. Oligodendrocytes, specialized glial cells of the brain and spinal cord, produce the myelin sheath. Demyelination slows down action potentials, which are electrical impulses by which neurons communicate (Waxman, 2000). This alteration impairs neuronal function. An estimated 300,000 individuals suffer from MS. This disease is most active in individuals between 20-45 years of age, and occurs twice as often in women than in men (The National Multiple Sclerosis Society, 2000). For a detailed outline of MS history from the 19th century to the present, click here.
The multifocal pathology of MS parallels a variable pattern of clinical manifestations (Waxman, 2000). Several systems are disturbed, and each patient suffers a different course. The visual system may be affected with double vision, loss of vision, uncontrollable rapid eye movement, and eye muscle spasms. Numbness, tingling, facial pain, lack of coordination, and dizziness disturb the motor system. A decline in memory, attention span, communication skills, and judgment are also observed (The National Multiple Sclerosis Society, 2000).
The time course of this disorder varies. Some patients remain healthy after their first episode, while others suffer from a chronic course of MS (Waxman, 2000). Individuals diagnosed with MS are distributed according to their specific symptoms into categories. Relapse-remitting (RR) is a recurrent pattern of MS episodes followed by near or total recovery. Primary progressive (PP) is an uninterrupted progression of the disease that involves little improvement. Secondary progressive initially meets the diagnosis of RR MS, but later changes to the PP form. Progressive-relapsing involves both a continuous decline, as seen in PP, and acute relapses from which individuals may recover (Wells, 1997).
Both myelinated and unmyelinated axons carry action potentials. An action potential propagated along an unmyelinated axon is regenerated at each point along the axon due to a relatively constant distribution of voltage sensitive Na and K channels. Transmission speed for unmyelinated axons varies from a slow velocity of 1 m/s for thin axons and a faster speed of 100 m/s for very thick axons. The myelin sheath increases the axon’s resistance to electrical transmission. The insulating myelin sheath increases propagation speeds to 120 m/s. Myelin sheaths, each a millimeter in length, are separated by nodes, which are one micrometer long. These short unmyelinated sections of the axon, nodes of Ranvier, contain a high concentration of sodium channels.
When an axon potential is generated at the axon hillock, it propagates along the axon until reaching the first segment of myelin. Sodium channels are only present at the nodes of Ranvier; therefore, sodium ions can cross only upon reaching these sections. At the node, sodium ions enter the axon and diffuse in both directions. Positive ions already present in the axon are repelled, and pushed towards the next node, at which point the action potential is regenerated. This jumping of potentials from node to node, saltatory conduction, speeds up action potentials and conserves energy. (Kalat, 1998; Waxman, 2000).
Although unmyelinated axons are a standard component of the CNS, demyelinated axons fail to function normally. Sodium channels only form at the nodes of myelinated axons (Waxman & Ritchie, 1985). After demyelination, the uncovered areas still lack sodium channels. Saltatory conduction does not occur without an insulating myelin sheath.
The blood brain barrier (BBB) separates the CNS from systemic circulation with tight junctions between its endothelial cells. Normally, this barrier effectively prevents cells and macromolecules from passing into the CNS. The CNS is immunologically unique, with low or undetectable expression of HLA molecules. An early sign of MS lesion development is the breakdown of the BBB. This degeneration was observed in gadolinium-enhanced magnetic resonance imaging scans of MS patients, which showed leakage of paramagnetic substances across the brain parenchyma (Harris, Frank, Patronas, McFarlin, & McFarland, 1991). With a defective BBB, white blood cells are able to leak into CNS tissue. Such permeability of the BBB in MS is not understood.
A macroscopic view of the demyelination process is identified in the MS plaque. This acute lesion consists of macrophages, lymphocytes, plasma cells, and demyelinated axons. Macrophages are a key component in the physical demyelination process. Coated pits (a type of vesicle) along the macrophage surface attach to superficial myelin lamellae (Martin, McFarland, & McFarlin, 1992). Through an unusual form of phagocytosis, the macrophage strips away the myelin lamellae. Macrophages also secrete proteasomes and complement that may also be involved.
An immune response can occur in the CNS without significant breaching of the BBB. Some resident cells of the CNS direct neural antigen (Ag)-directed immune responses. Becher, Prat, and Antel suggest that endogenous CNS cells direct or initiate an immune response (2000). Although systemic immune attack was previously considered to be a primary cause of MS, the cells may also be involved.
Although MS is not inherited, a higher concordance of MS has consistently been found in monozygotic twins (26%) than in dizygotic twins (2.3%) (Zamvil & Steinman, 1990). Therefore, several genes of moderate effect may predispose an individual to this disorder (Multiple Sclerosis Genetics Group, 1996). Specific genomic regions may harbor MS susceptibility genes. Major histocompatibility complex (MHC) and T cell receptor loci are both candidates for such genes. Linkage studies show that these candidate genes can produce significant genetic effects. For example, MS is much more common in people with the MHC class II allele HLA-DR2 (Martin et al., 1992). The involvement of these genes connects T cells to MS pathology.
Certain genes may make some individuals more susceptible to environmental factors. When around these factors, an autoimmune response results. Furthermore, certain environmental factors make individuals more susceptible to the disease. The risk of getting MS in latitudes between 40 degrees north and 40 degrees south is low (Waxman, 2000). Epidemiological studies show that people that move from a high risk area of world to a low one before 15 years of age will acquire the risk level associated with the new location. A virus may trigger MS. Etiological information suggests that this virus must be encountered before the age of 15 to cause MS (Waxman, 2000).
Cell-Mediated Immune Response
If the BBB is breached, then T cells can enter the CNS. If T cells encounter antigen-presenting cells that present their specific antigen, then they are activated and stimulated to secrete cytokines. Perivascular infiltrates of lymphocytes and macrophages are associated with demyelination. The margin of the lesion contains CD4+ and CD8+ cells; only CD4 + Helper 1 T cells are found in the adjacent white matter (Zamvil & Steinman, 1990).
Chemokines with two adjacent cysteine residues (members of the CC family) (Janeway et al., 2000) are expressed in the cell-mediated immune response and induce the inflammation seen in MS (Woodroofe, Cross, Harkness, & Simpson, 1997). Macrophage chemoattractant protein-1 (MCP-1) induces monocytes to migrate from the bloodstream into the surrounding tissues to become macrophages. This chemokine is secreted by astrocytes and macrophages. RANTES induces T lymphocytes to enter the tissues and is secreted by macrophages.
For several decades, scientists have focused on myelin basic protein (MBP) and its involvement in MS. MBP, a component of myelin, is a hydrophilic protein that interacts with myelin lipids through electrostatic and hydrophobic interactions. It may support and maintain myelin’s structure. Trotter et al. have identified another protein that may trigger the immune system to attack myelin (1998). Proteolipid protein (PLP) accounts for half of the protein that composes myelin. It may trigger the immune system to attack myelin. Experimental allergic encephalomyelitis (EAE) is a disorder induced in genetically susceptible animals by injection of myelin proteins. EAE is an animal model of MS. Both MBP and PLP cause EAE in animals.
Trotter et al. constructed synthetic peptides of PLP (1998). The concentration of T cells that recognized an oligopeptide of PLP was 4 fold higher in the blood of MS patients than in controls. This amount of T cells can cause disease. MBP is not recognized with a higher frequency in MS individuals than controls. In future studies, this research group plans to isolate cells that respond to this peptide, and modify the peptide so that it will bind to T cells, but fail to stimulate differentiation. With such a treatment, T cells could no longer bind and destroy myelin.
Humoral Immune Response
Increased immunoglobulin (Ig) concentrations in the CSF of MS patients have been observed for the last 50 years (Martin et al., 1992). This increase may be due to a humoral response to an unidentified infectious agent or a defect in immune regulation. IgG, IgM, and IgA are all found in MS CSF.
No known cure for MS exists. Treatment is aimed at controlling symptoms and maintaining function to give the maximum quality of life. Many medications are available to reduce the symptoms of MS. Medications like baclofen, dantrolene, and diazepam reduce muscle spasticity. Corticosteroids suppress inflammation (Wells, 1997).
Transforming growth factor-beta 2 (TGF-beta2) normally inhibits both cell growth and inflammation. As a treatment for MS, TGF-beta2 decreases the function and infiltration of macrophages into the CNS, reduces chronic demyelination, and suppresses cytokine production (Wells, 1997).
Interferon-beta (IFN-beta) normally increases the expression
of MHC I and works as an antiviral agent.
Becher B, Prat A, Antel JP. 2000. Brain-immune connection: immuno-regulatory properties of CNS-resident cells. Glia 29 (4): 293-304.
Harris JO, Frank JA, Patronas N, McFarlin DE, McFarland HF. 1991. Serial gadolinium-enhanced magnetic resonance imaging scans in patients with early, relapsing-remitting multiple sclerosis: implications for clinical trials and natural history. Annals of Neurology 29 (5): 548-555.
Janeway CA, Travers P, Walport M, Capra JD. 1999. Immunobiology: The immune system in health and disease. New York, NY: Current Biology Publications. p. 380.
Kalat JW. 1998. Biological Psychology. Pacific Grove, CA: Brooks/Cole Publishing Company. p 42-43.
Martin R, McFarland HF, McFarlin DE. 1992. Immunological aspects of demyelinating diseases. Annual Review of Immunology 10: 153-187.
Multiple Sclerosis Genetics Group. 1996. A complete genomic screen for multiple sclerosis underscores a role for the major hisocompatibility complex. Nature Genetics 13: 469-471.
National Multiple Sclerosis Society. 2000. <http://www.nmss.org/index/html> Accessed 2000 April 18.
Trotter JL, Pelfrey CM, Trotter AL, Selvidge JA, Gushleff KC, Mohanakumar T, McFarland HF. 1998. T cell recognition of myelin proteolipid protein and myelin proteolipid protein peptides in the peripheral blood of multiple sclerosis and control subjects. Journal of Neuroimmunology 84 (2): 172-178.
Waxman SG. 1999. Correlative Neuroanatomy. New York, NY: Lange Medical Books. p 22-23; p 316-317.
Waxman SG, Ritchie JM. 1985. Organization of ion channels in the myelinated nerve fiber. Science 228: 1502-1507.
Wells, S. 1997. The Process and Medical Treatments. Multiple Sclerosis Association of America. <http://www.msaa.com/msaa/litpro.htm> Accessed 2000 April 18.
Whitaker, J. Immunology and Degradation of Myelin Basic Protein. <http://www.physiology.uab.edu/wyss/faculty/whitaker.htm> Accessed 2000 April 18.
Woodroofe N, Cross A, Harkness K, Simpson J. (1999). The Role of Chemokines in the Pathogenesis of Multiple Sclerosis. Advances in Experimental Medicine and Biology, 468, 135-150.
Zamvil SS, Steinman L. 1990. The T lymphocyte in experimental allergic encephalomyelitis. Annual Review of Immunology 8: 579-621.
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