Multiple Sclerosis Cell Bio

Multiple Sclerosis Overview

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system.[1][2] The disease typically presents between the ages of 20 and 40 and impacts approximately 35,000 individuals in the United States alone. [1][2] MS can lead to substantial disability with deficits seen in sensory, motor, autonomic, and neurocognitive function.[1] The greatest incidence of the disease tends to be at the extreme latitudes of the northern and southern hemispheres and has been more commonly seen in Western European ancestry.[2] In the general population, MS impacts approximately 60-200 per 100,000 people in North America and Northern Europe (high risk areas) and 6-20 per 100,000 people in low risk areas.[1]

Figure 1. Prevalence of Multiple Sclerosis Around the World.

Trifecta Cause of Multiple Sclerosis

Genetic Factors

Genetic factors play an important role in susceptibility to MS. First-degree relatives of affected individuals have an approximately 2%–5% higher risk to develop MS, and rates in monozygotic twins vary between 20% and 35% in different studies, with the most recent studies placing it at 25%.[1] The prevalence of MS is seen 1.6-2 times more in females than in males therefore indicating possible hormonal variables as risk factors. [1] This hypothesis is supported by (a) lower relapse rates during, and disease rebound after, pregnancy (b) the worsening of MS during menstruation; (c) the correlation of high estradiol and low progesterone with increased MRI disease activity; (d) gender differences in EAE susceptibility related to the protective effect of testosterone; and (e) the therapeutic effects of estriol in Relapsing Remitting-MS. [1]

The data for the strongest susceptibility is the genes on the 6p21 chromosome in the major histocompatibility complex (human leukocyte antigen-HLA) which is thought to account for 10%-60% of the genetic risk.[1][3] The specific genes that provide the risk for MS are the HLA-DR and-DQ genes; the HLA-DR15 haplotype in caucasians (DRB1*1501, DRB5*0101, DQA1*0102, DQB1*0602).[1][3] The exact mechanism(s) by which the DRB1 gene influences susceptibility to MS remains undefined, but are likely related to the physiological function of HLA molecules in immune responses, including antigen binding and presentation, and T cell repertoire determination by negative selection of high-avidity autoreactive T cells within the embryonic microenvironment.[3]

Environmental Factors

There is a north to south gradient in MS disease prevalence on the Northern hemisphere and the opposite for the southern hemisphere. [1] Migration studies have suggested that exposure to the presumed environment occurs during early adolescence.[4] People who migrate from one area of the globe to another before adolescence are exposed to the environmental factors of the location to which they migrate.[1][4] In contrast, those who migrate sometime after adolescence carry with them the MS incidence of the location they migrated from.[1][4]

High levels of vitamin D decrease the risk for MS.[4] Vitamin D and sunlight exposure has been recognized as the possible geographical/latitude link for the incidence of MS.[2][4] Sunlight exposure has direct effects on serum levels of Vitamin D and the immunomodulatory effects of vitamin D on T-cell homeostasis.[2] Vitamin D status may play a role in a prenatal period and therefore may depend on the vitamin D status of the mother.[2][4]

Smoking has been identified as a significant risk factor for the development of MS.[4] There is also evidence to suggest that smoking can negatively impact disease progression in MS.[5]

Viral and Bacterial Factors

Evidence suggests exposure to an infectious agent may contribute to the development of MS. Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have been most strongly implicated as both have been shown to be present at a high rate in people with MS, at 80% and 90% respectively.[1] HHV-6 demonstrates features similar to MS as it tends to induce repeated infections. HHV-6 has also been found in oligodendrocytes in plaques associated with MS. EBV has been shown to strongly predict MS and 100% of patients with MS are reportedly seropositive for the virus. Furthermore, those who were infected with mononucleosis at a young age have a higher chance of developing MS. Chlamydia pneumoniae (Cpn) has also been studied in triggering MS, but evidence for this is unclear.[1]

Molecular mimicry is one mechanism proposed to explain how this occurs. During thymic selection, the T cells recognize the self-antigens, are positively selected, and are moved to the periphery. If these potentially self-reactive T cells come into contact with an antigen they may activate, cross the blood-brain barrier, and if antigens are then recognized, an autoimmune disease like MS may be triggered.[1]

Bystander activation is a second mechanism that may explain the infectious agent’s role in MS. During infection, proinflammatory cytokines and chemokines are produced and may activate CD8+ T cells. Activated CD8+ T cells have been shown to specifically recognize viral antigens.[1] However, without the cooperation of several mechanisms autoimmunity is not induced, indicating the role of multiple factors to produce an autoimmune response as in MS. It is unclear exactly how this process is involved in MS. Another mechanism of bystander activation is the reaction of T cells to viral tissue damage, where the viral cells are recognized and killed. This results in destruction of self-tissue and autoantigen release. When autoantigens and the infectious agent are present together, it may cause activation of the autoreactive T cells and thus initiate the autoimmune response.[1]



The cascade of cellular events involved with MS differs between individuals. However, the initial important event in MS occurs when autoreactive CD4+ T helper cells are activated in the periphery. CD4+ T cells are activated in genetically inclined individuals due to a variety of causes detailed in the Viral and Bacterial Triggers and Environmental Factors section. While in the periphery activated CD4+ T cells increase the immune response by recruiting additional immune cells including: CD8+ cells, B cells, granulocytes, monocytes, and mast cells. Activated CD4+ T and proinflammatory cells adhere to and then cross the blood brain barrier endothelium. In order to do so, activated cells produce proinflammatory cytokines (tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)), which activate adhesion molecules (LFA-1 and VLA-4) on the blood-brain endothelium.[6]

Following entry into the CNS, CD4+ T cells are reactivated by antigen-presenting cells. Following reactivation, CD4+ T cells release proinflammatory cytokines (IFN-gamma, TNF-alpha) and a variety of chemokines. These cytokines can amplify local inflammation by activating microglia and astrocytes, which can induce myelin phagocytosis and cause increased reactivation of CD4+ cells. Damage to CNS (myelin, oligodendrocytes, axons) occurs as a result of the following additional processes:
-B cells, auto-antibodies, and complement factors enter the CNS once the inflammation process has started. Upon entering the CNS, B cells and auto-antibodies produce a variety of responses to cause additional CNS damage. B cells provide co-stimulation to autoreactive T cells and can act as antigen presenting cells that present antigen to autoreactive T cells. B cells and auto-antibodies also bind to CNS tissues, which leads to increased autoreactive T cells recruitment, and thus increased T cells, monocytes, and eosinophils at the site of inflammation. B cells also produce myelin-specific antibodies that cause myelin destruction.[6]

  • Activated complement products also induce antibody opsonization of myelin and Macrophage uptake.
  • Activated CD8+ T cells lead to oligodendrocyte apoptosis and neural cell death by destroying specific receptors on oligodendrocytes.
  • Activated complement products also result in oligodendrocyte lysis and additional attraction of macrophages
  • The activity of phagocytes produces large amounts of toxic reactive oxygen and nitrogen intermediates, including the free radical nitric oxide. Dyemyelinated axons are susceptible to further degradation via nitric oxide activity.
  • γδ T cells have been shown to lyse oligodendrocytes, via the perforin pathway.
  • Glutamate production is increased while destruction and re-uptake is decreased leading to oligodendrocyte excitotoxicity.

Figure 2. Inflammatory Phase of Multiple Sclerosis

This inflammation process can last from a few days to two weeks. Following the response, stretches of axons are left demyelinated, oligodendrocytes are left damaged, and in some areas axon transsection is present. Oligodendrocytes surviving the procress begin to re-myelinate damaged areas, however the original myelin thickness is not achieved again. The combination of these events results in decreased axonal conduction.[6]


Normal mitochondrial function is described in detail on the mitochondria page. Disease can alter the function of the mitochondria and therefore alter the energy production of the tissue involved. Specifically, oxidative phosphorylation is affected, which can impair tissues that are dependent on high ATP supply such as the brain and nervous system.[7] The trademark of MS is damage to myelin sheaths and oligodentrocytes, which slows saltatory nerve conduction by increasing the size of the area where the axon continuously depolarizes. This process increases mitochondrial energy (ATP) production, decreases impulse velocity, and increases cellular demand for energy. The reduced supply of energy at damaged tissue has been shown to be associated with further tissue degeneration. This is due to the fact that in de-energized axonal areas sodium channels produce ectopic electrical potentials across the neuron, resulting in altered nerve communication. Limited ATP supply also alters ATP-dependent membrane channels and enzymes leading to increased intra-axonal Na+ and Ca2+. The accumulation of these processes further increases the cellular demand of mitochondrial energy production.[8]

Increased mitochondrial activity also correlates with increased reactive oxygen species (ROS) production. ROS has shown to have a significant role in the degenerative alterations seen in MS. ROS-induced lipid peroxidation can affect membrane utility and structure. Oligodendrocytes and myelin contain higher lipid content than most cells in the CNS, making them susceptible to ROS-induced damage and death. Additional, antioxidants that delay or suppress adverse effects of ROS have been found to be deficient in MS, as a result of chronic inflammation and oxidative stress.[8]

Increased oxidative and nitrative stress in MS also results in production of reactive nitrogen species (RNS). Stressed mitochondria increase production of nitric oxide (NO), which reacts with superoxide to form RNS peroxynitrite. This structure causes extensive damage to myelin sheaths, oxidative damage to mitochondria, and mtDNA damage.[8]

Another trademark of MS is impaired apoptosis of auto-reactive T cells, B cells, and marcophages in the periphery, which eventually cross the blood brain barrier into the CNS. While the exact cellular mechanisms are not fully understood, it is believed that damaged and stressed mitochondria demonstrate a poor ability to regulate this process in MS.[8]

Multiple Sclerosis Cellular Component Chart

The following chart explains in detail the cellular components involved in the Multiple Sclerosis cascade, as briefly described above. The components are in order according to the cascade.

Cellular Component Normal Response Changes in MS
Genes (hereditary component) Cell markers are present on the surface of all cells known as Major histocompatibility complex (MHC) proteins. There are 6 specific markers commonly known as human leukocytic antigens (HLA’s); HLA-A, HLA-B, HLA-C, referred to as class I antigens, and HLA-DP, HLA-DQ, and HLA-DR, referred to as class II antigens. These allow immune cells to recognize and communicate with each other and determine which antigen and how strong an individual will respond to.[9] The data for the strongest susceptibility is the genes on the 6p21 chromosome in the major histocompatibility complex (human leukocyte antigen-HLA) which is thought to account for 10%-60% of the genetic risk.[1][3] The specific genes that provide the risk for MS are the HLA-DR and-DQ genes; the HLA-DR15 haplotype in caucasians (DRB1*1501, DRB5*0101, DQA1*0102, DQB1*0602)[1][3]
Major Histocompatibility Complex (MHC) A region of chromosome 6p21.31 that encodes histocompatability genes. This region is noted to contain the most genes in the human genome and encodes the most proteins known currently. This region is divided into subregions referred to as classes I, II, and III. Classes I and II contain genes that are implicated in immune function.[10] Classes I and II contain alleles that have been highly linked to autoimmune diseases.[10]
HPA axis Hypothalamo-pituitary-adrenal (HPA) axis: this neuroendocrine axis is controlled by the hypothalamus, which receives input from higher cortical areas and other brain regions, including the limbic system. Activation of the axis leads to a cascade of hormone releases. The hormones secreted by the HPA axis have potent effects on immune function and other target tissues. Among the main activators for the HPA axis are psychological or physiological stressors, including inflammatory cytokines.[11] Studies using the EAE model of MS have shown that the HPA hyporesponsiveness to inflammatory stimuli predicts a more severe disease course. However, most clinical studies indicate a hyperactive HPA axis in MS, particularly in the progressive stages of the disease. A hyperactive axis can be associated with neurological disability, cognitive impairment and brain atrophy. There is also some evidence that HPA hyperactivity might predict future development of disability.[12]
T- cells T-cells are the main component of the cell-mediated immune response. Their role is to help B cells augment the production of antibodies; activate macrophages and help to destroy bacteria; help other T-cells recognize and destroy virally infected cells; help Natural Killer cells kill infected cells. T-cells also are capable of turning the entire immune system off through the actions of the helper T4 cells and the cytotoxic T8 cells.[9] Macrophages take up an unknown foreign substance and present the antigen to T-cells in the blood or lymph nodes, and activation and expansion of the T-cells occur. The activated T-cells display adhesion molecules that allow attachment to and entry through the endothelial lining of the blood-brain barrier. The activated T-cells appear to be reactive against myelin and other antigens within the CNS.[9]
Antigens An antigen is any foreign substance in the body that is capable of triggering an immune response[9] The recognition of self-antigens at intermediate levels of affinity by T cells leads to positive selection and export of these T cells to the periphery. Crossreactivity of these potentially self-reactive T cells with foreign antigens can lead to activation during infection, migration across the blood-brain barrier, CNS infiltration, and, if they recognize antigens expressed in the brain, tissue damage and potentially an autoimmune disease such as MS. [1]
CD4+ cells CD4+ cells are helper T cells and are the main cell involved in the immune response. Normal mature T cells carry a surface protein called CD4+ and act to defend against pathogenic infections. There are multiple subsets based on specific cytokine production (T1, T2, T17). These cells recognize class II MHC molecules.[13] Activated CD4+ cells can transfer EAE in vitro and arguments have been made for its occurrence in vivo. MS is considered a CD4+ T cell mediated disease; however the exact role of CD4+ cells is much more complex and not fully understood. In MS, CD4+ cells contribute to CNS- and CSF-infiltrating inflammatory cells and are present at higher frequencies than normal. Autoreactive CD4+ cells have been shown to target various proteins, including MBP, PLP, MOBP, and MOG,[1] which are explained below.
Cellular Component Normal Response Changes in MS
Th1 TH1 cells are a type of CD4+ T cell that produce interferon gamma (IF-γ) and IL-2 to maintain an effective immune response. They are associated with protection against intracellular bacterial and viral infections.[13] Dysregulation of TH1 levels has been associated with autoimmune inflammation,[14] such as with MS. Studies have shown that TH1 cells can induce EAE, however its specific role in MS is not clear.[14]
Th2 TH2 cells are a subset of T-helper cells that produce cytokines IL-4, IL-10, and TGF-β. These cells produce an anti-inflammatory response to tissue damage.[1] TH2 cells and its cytokines increase B cell proliferation, differentiation, and antibody production. TH2 cells and its cytokines have also been shown to proliferate following disease exacerbations and are important for disease resolution/prevention. [1]
Th17 TH17 cells are CD4+ T-cells that aid in defense against pathogens. They are mostly associated with protection against extracellular bacterial and fungal infections.[13] Dysregulation of T17 levels has been associated with autoimmune inflammation,[14] such as in MS. As with TH1 cells, TH17 cells have also been shown to be involved in inducing EAE but their exact role in MS is not clear.[14]
Eicosanoids Group of signaling molecules that mediate the inflammatory process in humans. Eicosanoids are composed from 20-carbon polyunsaturated fatty acids. Examples include: prostaglandins, thromboxanes, leukotrienes and epoxyeicosatrienoic acids.[15] During the inflammation process, macrophages enable myelin damage through a variety of cellular processes, including increasing eicosanioid production and release in order to proliferate inflammation.[16]
Cytokines Cytokines are cell-signaling polypeptides that are responsible for inter and intra-cellular communication. The term cytokine encompasses a broad family of immunomodulating agents including interferons and interleukins.[17] These cell modulators are major components of the inflammatory response.[18] In general, cytokines have been found to have a role in oligodendrocyte apoptosis and degeneration of axons in patients with MS.[18]
Cellular Component Normal Response Changes in MS
Chemokines A type of cytokine that chemically attracts inflammatory cells to the site of lesion[2] Increased activation in MS, chemokines have been considered a main activator of virus-specific CD8+ T cells and activator of the autoimmune response[1]
CD8+ cells A cytotoxic T cell that displays glycoprotein CD8. CD8 cells are part of the immune response, responding to specific antigens. They express T cell receptors (TCR) that associate with Class I MHC cells.[19] CD8+ cells have been seen in EAE with increased presence in plaques, CSF, and blood of mice with EAE.[19] CD8+ cells are more prevalent than CD4+ cells in brain tissue of patients with MS, however their role in the disease is less understood.[1][19]
B cells B cells are the main component in the humoral immune response. They are able to produce immunoglobulins (Ig), also known as antibodies. Recent studies show the cytokines produced by B cells are important in determining the nature of the immune response.[20] Increased levels of B cells have been identified in the CSF and CNS lesions in patients with MS. Clonal expansion has also been observed in the CSF of MS patients, along with the presence of oligoclonal Ig.[20] This data suggests there is an antigen-driven response in the CNS that leads to B cells producing a specific set of antibodies that produce oligoclonal banding. The presence of unique Ig banding in individuals with MS has shown antibody specificities against components of myelin.[20]This includes MOG, MBP, and oligodendrocyte proteins. While this data does suggest B cell involvement in MS, not all studies are in agreement in Ig’s specific role in the pathogenesis of MS.[20]
Monocytes/Macrophages Immune cell that migrate to inflamed tissue and differentiate into macrophage cells. These cells can produce cytokines, including TNF-alpha. Macrophages also induce phagocytosis.[6] Monocytes enter the CNS through the blood brain barrier and differentiate to macrophages, which produce TNF-a at the inflamed site. Macrophages also induce phagocytosis of myelin and oligodendrocytes within the CNS. Monocytes and macrophages are found in abundance in active MS lesions.[6]
Mast Cells Mast cells are effector cells of the immune system. They express cytokines including: TNF-alpha, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, and IL-16. Mast cells and its mediators are crucial components of the inflammatory response in humans. Normally found in low quantity within the CNS.[21] Mast cells contain TNF-α, which can increase adhesion molecule production. This process increases the blood brain barrier infiltration process. Within the CNS mast cells and its mediators cause direct damage to CNS by causing damage to oligodendrocytes and neurons.[1]
Cellular Component Normal Response Changes in MS
IL-4 An anti-inflammatory cytokine that is produced by CD4+ cells and Th2 cells. It induces differentiation of CD4 helper T-cells and stimulates growth and differentiation of B cells. It’s role is to inhibit the activation of Th1 pro-inflammatory cells IL-1 and TNF-alpha and amplify the Th2 anti-inflammatory response.[18][22] In one study, patients with multiple sclerosis, the level of IL-4 producing T-cells is significantly lower than in controls.[22] Some studies have found that IL-4 deficient mice develop more severe form of EAE than controls.[18][22]. However, a review by Imitola et al.[18] concluded that a deficiency of IL-4 does not necessarily alter the disease course of EAE, but its’ upregulation may help reduce EAE severity. This may mean that other Th2 cytokines can substitute for the lack of IL-4. The review by Imitola et al. states that studies of IL-4 and MS are limited and its’ role in unclear.
IL-10 An anti-inflammatory cytokine that is produced by Macrophages, Monocytes, B cells and Th2 cells. Its’ role is to inhibit the proinflammatory Cytokines (IL-1 and TNF-alpha) produced by macrophages.[18] In EAE models, mice with IL-10 deficiency developed more severe EAE compared to controls and even to IL-4 deficient mice, suggesting IL-10 has a unique role that can't be substituted by other Th2 cytokines.[18] Treatment with IL-10 has also been shown to prevent EAE in mice.[23] In general there is decreased expression of IL-10 in patients with MS. Also, treatment with interferon beta induces an increased production of IL-10 and has lead to decreases in Th1 responses and clinical benefits.[23]
Endothelial cells Activated by Cytokines which then produce pro-inflammatory cytokines, such as IL-1 and TNF-alpha.[2] In MS, T cells present adhesion molecules and are able to attach to endothelial cells and enter blood brain barrier.[9]
Cellular Component Normal Response Changes in MS
Adhesion molecules Adhesion molecules are up-regulated by pro-inflammatory cytokines, such as IL-1 and TNF-alpha, and aid chemokines in attracting inflammatory cells to the site of lesion.[2] In MS, activated T cells display adhesion molecules in order to cross the blood brain barrier.[9] Natalizumab, a monoclonal antibody approved for treatment in the U.S. and Europe, is an antagonist of VLA4, thus blocking it from binding to adhesion molecues and preventing inflammatory cells from migrating to the area.[2]
Interferon-gamma (IFN-gamma) A cytokine that provides immunity against intracellular pathogens and controls tumor formation. IFN-gamma either upregulates or downregulates Major Histocompatibility Complex (MHC) classes I and II. It also initiates the production of pro-inflammatory cytokines to increase macrophage activity. IFN-gamma controls differentiation of the CD4+ cells into Th1 effectors which are vital in adjusting immunity against viral and bacterial infections, essentially acting to clear infectious antigens.[13] Found to be increased in the CSF and CNS of patients with MS. Administration of IFN-gamma also was seen to exacerbate MS. However, recent evidence has contradicted these findings and leads to questioning of IFN-gamma’s role in MS. Most notable are studies showing exacerbation of EAE in mice deficient in IL-2, TNF, and IFN-gamma.[24]
TNF-alpha Tumor necrosis factor-alpha (TNF-A) is an inflammatory cytokine with similar functions as IL-1. It is produced by several types of cells, but especially by macrophages. It affects most organs in the body and serves a variety of functions based on its locations. The primary role of TNF is in the regulation of immune cells. TNF-alpha is a key intermediary during local inflammation processes. TNF is able to induce apoptotic cell death and inflammation, and it possesses both growth stimulating and growth inhibitory abilities. TNF-alpha causes necrosis of some tumors while promoting the growth of other types of tumor cells.[25] The expression of TNF-alpha is elevated in active demyelinating lesions compared with inactive/remyelinating lesions.[1] There are different theories of mechanisms for this demyelination: TNF-alpha and IFN-gamma may be toxic for oligodendrocytes; or cytokines may activate macrophages and microglia, which then phagocytosize myelin; or proinflammatory cytokines may be involved in apoptosis induction/execution and subsequent demyelination.[1] Elevated numbers of blood cells expressing TNF-alpha mRNA, serum TNF-alpha concentrations, and peripheral blood mononuclear cells secreting TNF-alpha have been reported in MS patients.[1]
Cellular Component Normal Response Changes in MS
IL-1 A cytokine with similar functions as tumor necrosis factor (TNF). IL1 has a number of local actions that promote the inflammatory reaction. It also has some systemic actions that induce metabolic, hemodynamic, and hematologic alterations. IL1 causes a fever by raising the production of prostaglandins in the hypothalamus; it causes characteristic changes in blood chemistry; and it increases the number of neutrophils and decreases the number of lymphocytes in the circulation.[9] Proinflammatory cytokines can participate in the pathogenesis of MS at different points. They are thought to play a role in the pathogenesis of MS via immune system activation in the periphery and perhaps also by directly damaging the oligodendrocyte and myelin unit within the CSF and brain.[1] Proinflammatory cytokines have also been found in active MS lesions.[1]
Auto-antibodies Auto-antibodies are antibodies produced by the body after the immune systems fails to recognize the body’s cells and tissues. Through a cascade of events the auto-antibodies are synthesized to attack “self” proteins, leading to increased inflammation and cell death. [26] Auto-antibodies can contribute to the disease process through a variety of ways. Research has shown that auto-antibodies attached to neural tissues can elicit additional cell damage by increasing T-cells, monocytes, and eosinophils activity at the inflammation site.[27] Antibodies can also induce demyelination by increasing macrophage phagocytosis. Research has shown increased serum antimyelin antibodies is present in MS.[28]
Microglia Part of small immune cell presence normally in CNS, along with astrocytes and other immune cells that get through the tight blood brain barrier.[9] Activated by cytokines which then produce pro-inflammatory cytokines, such as IL-1 and TNF-alpha.[2] Post-mortem studies have proposed widespread microglial activation with associated axonal injury is characteristic of the global inflammatory response affecting the CNS in the MS disease process.[2][29] One study went further to say microglia activation was more profound in new symptomatic lesions in myelinated tissue that contains few or no lymphocytes or myelin phagocytes when compared to older lesions, thus raising speculation about the presumed pathogenesis and aetiology of MS.[2][30]
Cellular Component Normal Response Changes in MS
Astrocytes These are the main source of CNS complement, an auxiliary line of defense.[1] Normally, a minimal presence of astrocytes along with microglia and other immune cells get through the tight blood brain barrier.[9] Proliferate in damaged parts of the CNS, activated by cytokines which then produce pro-inflammatory cytokines, such as IL-1 and TNF-alpha.[2] Plaques, common in MS, are characterized by increased numbers of astrocytes and scar deposition.[1]
Eosinophils Eosinophils are granulocytes cells produced in bone marrow that circulate to damaged tissue in response to inflammation. These cells have the ability to create specific cytokines, such as IL-1, IL-3, IL-4, IL-5, IL-8, and TNF-α.[31] Eosinophil activity and attraction is increased in MS. Following lesion creation eosinophils pass into the CNS and increase the inflammatory response.[6]
Excitotoxic factors There are several types of excitotoxic factors but glutamate is one of the most important in cellular function. Glutamate is an excitatory neurotransmitter found throughout the central nervous system. Most commonly, glutmate is packaged in vesicles in pre-synaptic axons and released into the synaptic cleft following input from a nerve impulse. Once released into the cleft, glutamate binds to post-synaptic receptors, including NMDA receptors. In a normal functioning cell, glutamate is rapidly removed by glutamate transporters following action potential signaling.[32] Glutamate-mediated excitotoxicity of oligodendrocytes occurs due to an increased production and decreased breakdown/re-uptake of glutamate by astrocytes. This process leads to additional calcium influx through NMDA receptors and eventual oligodendrocyte and axonal damage.[33]
Myelin The outgrowth of a neuroglial cell (i.e. oligodendrocytes). It forms a protien-like, fatty, insulating sheath around the axon of a neuron that helps increase the speed at which nerve impulses propagate.[9] MS is considered to be an autoimmune disorder with an end result of the immune attack causing toxicity and destruction of the myelin sheath.[9]
Cellular Component Normal Response Changes in MS
Glial cells Glial cells are non neural cells found in the CNS that provide support, structure, and maintain homeostasis. Glial cells are important in the formation and maintenance of myelin. Astrocytes are one type of glial cell.[9] Glial cells, particularly astrocytes become activated during the acute inflammatory process.[1]
Oligodendrocytes Type of glial cell. Role is to myelinate axons of the central nervous system.[9] Oligodendrocytes (OLG) are the targets of the inflammatory and immune attacks in MS and become deficient.[9] Oligodendrocyte death by apoptosis or necrosis causes the cell loss seen in MS plaques.[34] Following an acute inflammatory response, surviving olidogendrocytes remyelinate the damaged axons. They are not able to myelinate the axons to their original thickness, resulting in a slower signal transduction.[1]
Natural killer cells (NK cells) NK cells are a main component of innate immunity through both effector and regulatory functions by means of their cytotoxic activity against tumor cells and virally infected cells. NK cells are able to initiate their cytotoxic activity with their ability to secrete different cytokines.[35] Through EAE models it has been showed that NK cells can have both pathologic and protective effects in MS.[35][36] In vitro NK cells have demonstrated cytotoxic activity toward oligodendrocytes, astrocytes, and microglial cells during inflammation.[35] NK cells can also play a protective role in the CNS as they have the ability to produce neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3).[35]
Proteolipid protein The most abundant protein in CNS myelin.[1] PLP has been shown to have more significant encephalogenic properties than MBP in some EAE models and is considered to be the main target of activated T cells. PLP has also been shown to be immunodominant in humans and is elevated in people with MS. Its specific role in the pathophysiology of MS is not yet clear.[1]
Myelin basic protein (MBP) MBP is the second most abundant protein in myelin, found on the intracellular surface of the membrane. Its role is to maintain adhesion of the cytoplasmic surfaces to and allow efficient signal transfer.[1][37] MBP has been extensively studied in EAE models, showing ability to induce EAE in mouse, rat, and nonhuman primates. A significant overlap of encephalogenic epitopes of MBP have been identified between rodent and human models, supporting the suggestion that MBP is highly involved in the human version of EAE: MS. However, further research is necessary to confirm its role in MS.[1]
Myelin oligodendrocyte basic protein (MOBP) The third most abundant protein found in myelin in the CNS, possibly involved in its maintenance. Regulates the radical component of myelin and may also regulate axon diameter. MOBP is also important in stabilizing the multi-layer structure of myelin.[38] MOBP is encephalitogenic and can induce EAE in rodent models. Recent studies using EAE have shown MOBP may be a primary target of autoimmune T cells in MS. Attack on this important protein may result in destabilization of the multi-layer myelin and lead to its breakdown. This has not been confirmed with evidence, but is proposed to be highly likely based on animal study results and cellular properties of the protein.[38]
Cellular Component Normal Response Changes in MS
Myelin oligodendrocyte glycoprotein (MOG) A large glycoprotein found on the outer surface of the oligodendrocyte membrane in the CNS. [1] Due to its location, MOG is highly accessible to antibodies and has been thought to be a target of immune responses in MS. In certain EAE models, MOG has induced a chronic, nonrelapsing form of EAE. This protein’s role in MS has not been studied as extensively as PLP or MBP; however it has been seen in activated T cells in patients with the disease. More research is necessary to identify MOG’s specific role in MS.[1]
Reactive oxygen species (ROS) Reactive oxygen species (ROS) is a collective term that includes chemically-reactive molecules containing oxygen such as oxygen radicals, such as superoxide (O2), hydroxyl (OH ), peroxyl (RO2 ), and hydroperoxyl (HO2) radicals, and certain nonradical oxidizing agents, such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and ozone (O3), that can be converted easily to radicals.[39][40] The signature unpaired electrons make these species highly reactive. While they are a natural byproduct of typical metabolism, they do have the potential to cause cellular damage to DNA, RNA, and proteins.[39] ROS can have negative effects on cell metabolism such as apoptosis, though it is also able to function to signal mobilization of ion transport and oxidative signaling. They are released by platelets during wound healing to recruit additional platelets to the site of the injury. They are involved in enzymatic reactions, mitochondrial electron transport, signal transduction, activation of nuclear transcription factors, gene expression, and the antimicrobial action of neutrophils and macrophages.[39] Oxygen and nitrogen free radicals may be important in the pathogenesis of EAE and MS. Numerous studies of patients with MS have shown increased free radical activity. They have been implicated as mediators of demyelination and axonal injury in both EAE and MS. Free radicals can activate certain transcription factors, such as nuclear transcription factor-kappa B (NF-κB), which upregulate the expression of many genes involved in EAE and MS, including tumor necrosis factor-α (TNF-α).[1] Studies have demonstrated that activated mononuclear cells of MS patients produce high amounts of ROS and nitric oxide and that oxidative damage to DNA, including mitochondrial DNA develops in association with inflammation in chronic active plaques.[41][42]
Reactive nitrogen species (RNS) Reactive nitrogen species (RNS) are a family of molecules derived from nitric oxide and superoxide. They are produced by neutrophils.[43] They work with reactive oxygen species and are harmful to cells particularly in the nervous system. RNS molecules participate as signaling molecules that regulate signaling pathways; they also modulate protein and lipid kinases and phosphatases, membrane receptors, ion channels, and transcription factors, including NF-κB. During the inflammatory response, it modulates phagocytosis, secretion, gene expression, and apoptosis.[43] NOS has been found in MS lesions, suggesting a role in MS pathology. [1] The actual role of NOS in CNS injury in MS is not clear. Results from blocking NOS in EAE are not conclusive, and additional data suggest that it may even have an antiapoptotic effect or modulate immune responses and be beneficial.[1] Indirect evidence that reactive nitrogen species play a role in MS lesions includes the findings that proinflammatory cytokines including TNF have been identified in MS lesions. IL-1 and TNF have also been found within peripheral mononuclear cells and cells within the cerebrospinal fluid.[44]
Cellular Component Normal Response Changes in MS
Proteases Protease refers to a group of enzymes that hydrolyze the peptide bonds that link amino acids together in proteins. They can break a specific peptide bond depending on the sequence of the amino acids, or break down a complete peptide chain. Involved in a multitude of physiological reactions including highly-regulated cascades such as apoptosis pathways.[45] There are six general classifications of proteases based on composition of active site: 1) Serine proteases 2) Threonine proteases 3)Cysteine proteases 4) Aspartate proteases 5) Matalloprotease 6) Glutamic acid proteases.[45] May be responsible for axonal degeneration as a result of axons undergoing changes to restore impulse conduction after demyelination via redistribution of sodium channels along the axons. Due to the redistribution, ATP consumption is greatly increased and axonal ion concentrations may result in axon degeneration. The energy imbalance impairs the function of ATP-dependent ion chanels which leads to an increase in intracellular sodium concentrations. This ultimately increases intracellular calcium and calcium dependent enzymes and damages the axon. This activates proteases as a mechanism of axon degeneration[46] Electron microscopic imaging has found that individuals with MS have significant pathological changes suggesting increased calcium activated proteases activity.[46]
Granzyme A series of serine proteases released from natural killer cells and cytotoxic T cells that induce apoptosis within a target cell.[47] Due to the breakdown of the blood brain barrier, granzyme cells are more likely to circulate into the CNS, where they cause oligodendrocyte and axonal damage.[48]
Perforin Perforin is a pore forming protein found in most natural killer cells and cytotoxic T-cells. This protein binds to a target cell membrane in order to form a pore in the cell membrane in order to allow entry for granzyme.[47] Perfornin activity increases in the inflamed state, allowing for additional perforin to be released and cause eventual cell damage due to the perforin⁄ granzyme pathway.[48]
TGF-beta Transforming Growth Factor-beta (TGF-beta) is a growth factor that is part of the tissue repair response and is responsible for regulating the number of cellular reactions involved in the inflammatory response. TGF-beta specifically inhibits growth of cells and causes macrophages to become inactive.[9] In EAE, when TGF-beta is administered peripherally, it has been shown to play a role in the down-regulation of the immune response. However, increases in TGF-beta in the central nervous system have been found to do the opposite, and is associated with enhanced EAE with earlier onset.[18] In humans, TGF-beta is typically under-expressed and patients undergoing therapies that increase TGF-beta levels have shown the potential for decreased inflammation.[18]

Clinical Manifestations


Figure 3. Classifications of Multiple Sclerosis

Classifications of MS

There are two main forms of MS; relapsing-remitting (RR)-MS and secondary-progressive (SP)-MS. RR-MS is the most common form, with 85-90% of cases presenting as this type.[1] Most of these people will go on to develop SP-MS, which is associated with gradual loss of neurological function and eventual paralysis.[2] A third form is present in 10-15% of patients and is characterized by a steady disease progression with no relapses. This type is called primary-progressive (PP)-MS.[1]

Disease Course

It is important to first understand that the disease course for an individual with MS is diverse and variable. Initially, patients typically experience the clinical onset of an acute or subacute episode of neurological disturbance of the CNS.[49] Clinically, this is known as clinically isolated syndrome and may present with optic neuritis, isolated brain stem, partial spinal cord syndrome, or hemispheric syndromes.[49] As the disease progresses into MS, diagnoses can be made in a variety of ways using the McDonald Criteria for MS.

As the disease progresses, no patterns are visible in the timing or location of the lesions.[49] Most patients with MS (up to 85%) experience a relapsing-remitting course of MS (RRMS) that is characterized by episodes of symptoms over several weeks followed by full recovery or lasting residual symptoms.[1] Relapse is defined by the presence of new signs or symptoms for at least 24 hours that are unrelated to fever or elevated body temperature.[1]

Approximately 20% of patients will display benign MS, which is categorized as clinically stable presentation with full functionality of all neurological systems for 20 years.[1] The other 80% of individuals with MS will develop secondary progressive phase (SP) of MS.[1][49] There are two subtypes of this classification relapsing-SP disease in which progression results from a failure to recover from relapses and non-relapsing-SP disedase in which disability is acquired in the absence of superimposed relapses.[1][49]

Another disease course, though highly uncommon, is progressing relapsing MS which is progressive in nature from onset with clear acute relapses that occur with or without recovery while the periods between relapses continue progression in severity.[1]

Once again, MS is an unpredictable disease. Good prognostic signs include, female sex, a younger age of onset, an initial presentation of either optic neuritis or sensory symptoms, full recovery from the first attack, a long period between the first and second attacks and a low baseline lesion load on MRI but these prognostic factors cannot predict the course of the disase.[2] At 15 years after the onset of MS approximately 30% of patients have benign MS; this figure drops to 15% at 25 years and 5% after 30 years disease duration.[2]

MS is typically not a fatal disease; survival in MS is only marginally shortened by 5–7 years compared with general population in Western countries. Malignant MS occurs very rarely which typically refers to subjects who have frequent and disabling attacks with poor recovery. As a result of this rapidly progressive course, severe disability or death can occur within two years.[2][49]

Disease Modifiers

Pregnancy is a disease modifying factor of MS but it does not have a negative effect on the course of MS. In fact, women with MS who have no children have a poorer long-term outcome than those with children.[2] Recent findings also confirm that the relapse rate decreases significantly during the second and third trimester of pregnancy and increases after birth.[1][2] Hormone levels during menstruation and gender differences in EAE susceptibility related to the effects of testosterone also impact the disease course.[1] Finally, increasing MS disease activity as demonstrated on an MRI correlates to high estradiol and low progesterone levels.[1]

Viral or bacterial infections can also trigger an MS attack. Inactive influenza and hepatitis B component vaccines have found to be safe.[1] No other data exists for other vaccines but researchers have assumed that other inactive or hepatitis B component vaccines would be equally safe.[1] Live attenuated viral vaccines have not yet been found to be safe. Administering a live vaccine to an individual with an MS diagnosis has the potential risk for triggering an MS attack so the risk must be weighed between an MS attack or the infection as a result of not receiving the vaccine.[1]

Cortical lesions

Post-mortem research has shown that increased cortical demyelination is most commonly associated with progressive MS. Cortical lesions and damage to adjacent white matter is evident by diffuse axonal injury relating to the whole brain and meninges. Currently, there are three types of cortical lesions: cortico-subcortical (affecting cortical and related white matter), intracortical, and subpial (affecting areas adjoined to the subarachnoid space). Grey matter lesions occur with less inflammation compared to white matter lesions, as evident by decreased macrophage and lymphocyte activity at the lesion sites. Despite this finding, critical axonal transection and neuronal damage is present within lesions. Subpial cortical lesions are associated with follicle-like structures within the meninges containing B-cells and dendrite cells. These structures have been found in a subgroup of secondary progressive MS. Within this subgroup patients experienced more severe symptoms, increased disability, and earlier death.[2]

Figure 4. Clinical Manifestations of Multiple Sclerosis


Most common symptoms: [50]
• Fatigue - one of the most common symptoms of MS, occurring in about 80% of people.
• Numbness
• Walking (gait), balance, and coordination problems
• Bladder dysfunction - occurs in at least 80% of people with MS
• Bowel dysfunction
• Vision problems
• Dizziness and vertigo
• Sexual dysfunction
• Pain - up to 55% of people with MS have “clinically significant pain” at some time; almost 50% have chronic pain
• Cognitive function - approximately 50% of people with MS will develop problems with cognition.
• Emotional changes
• Depression
• Spasticity

Less common symptoms:
• Speech disorders - Speech and voice problems occur in approximately 25-40% of people with MS, particularly during relapses or periods of extreme fatigue.
• Swallowing problems
• Headache
• Hearing loss - approximately 6% of people who have MS report impaired hearing
• Seizures - fairly uncommon in people with MS, approximately 2% to 5% incidence rate compared to 3% incidence rate in the general population
• Tremors
• Respiration/breathing problems
• Itching

Animal Model of Experimental Autoimmune Encephalomyelitis (EAE)


Figure 5. Animal Models of Multiple Sclerosis.


EAE is an animal model of brain inflammation used to study central nervous system (CNS) demyelinating disorders such as MS as well as general T cell-mediated autoimmune diseases. The disease is introduced to animals by injection of a myelin antigen, which is activated in the periphery by myelin-specific T cells. The components of the injection include proteins found in myelin (primarily MBP) along with Freund’s adjuvant.[19] The inflammatory process is triggered by the body identifying its own myelin as a pathogen and mounting an attack, acting to "activate" the myelin antigen. The blood-brain barrier is permeated by these activated myelin antigens and they are then reactivated once in the CNS by activated antigen-presenting cells. These cells display MHC class II-associated peptides, which initiate the inflammatory process. This inflammatory process within the CNS leads to demyelination and axonal damage, similar to MS. EAE can present in animals as acute, chronic, or relapsing-remitting, depending on the protocol used and the background of the animals used.[19] EAE is induced in animals to investigate the viral and bacterial infection model for triggers of MS and is the most widely used model for the study of this disease. However, there is conflicting evidence for EAE as the primary trigger of MS in humans and thus its ability to predict disease course and treatment responses in humans has been questioned. Researchers are now reaching a stage where the immunology of EAE and animals models is understood very well while the mechanisms in human MS are still poorly understood. Some researchers are now turning their attention towards the further characterization of cytokines, growth factors, and developmental pathways and their effects upon cells of the nervous system.[6] Despite this, it remains the primary model to study CNS inflammatory diseases.[1]


EAE has helped provide a better understanding of the inflammatory processes involved in the course of a disease similar to MS, also helping in the development of treatments for MS such as glatiramer acetate and natalizumab.[13] Utilizing EAE has helped identify which factors are present at certain stages of the disease, which factors are initiating the process, and is helping to clarify specific cells’ roles in the pathogenesis of MS. Specifically, the role of T cells in MS has been studied and their specific function in MS remains controversial.[13]

Pharmacologic Interventions

Disease Modifying Agents

Interferon beta (IFN beta)

Interferon beta is a drug that is approved for the treatment of MS.[18] Brand names of this drug include Betaferon®, Extavia®, Avonex® and Rebif®.[2] It is theorized to have a modifying effect on several aspects of the disease course of MS. It has the ability to alter the inflammatory response, improve self-regulation of the immune system, restore the balance of the blood brain barrier and help repair cell damage.[51]

  • Mechanisms of action:
    • Effects on Cytokines and T-cells
      • Increases Th2 anti-inflammatory cytokines (IL-4 and IL-10) while decreasing Th1 pro-inflammatory cytokines (IFN-gamma, IL-12, IL-23)[18][51]
      • Reduces the percentage of T cells that produce IL-17, an inflammatory cytokine[51]
      • Increases presence of IL-1R alpha and TNF-RII which are able to block cell responses to IL-1 and TNF (inflammatory cytokines) [51]
      • Causes apoptosis of activated T cells due to an increase in survivn levels, a modulator of apoptosis [18][51]
      • Restores function and causes expansion of regulatory T cells[51]
    • Effects on Chemokines and Adhesion molecules
      • VLA-4 and LFA-1 adhesion molecules on T cells are decreased. This may contribute to apoptosis of the activated T cells mentioned above[51]
      • Surpresses expression of CNS neutrophil chemokines and T cell chemokines[51]
      • Causes beneficial changes in Matrix metallo-proteases (MMPs) by increasing the levels of TIMP-1 which is an MMP inhibitor. MMP’s are important for the passage of immune cells through the blood brain barrier[51]
      • Increases adenosine levels which helps to prevent lymphocytes from crossing the blood brain barrier[51]
    • Other Effects
      • Decreases B-cell stimulatroy effects[51]
      • ReducesMHC II expression on a variety of cells[51]
      • Increases B7-H1 expression, which is found on dendritic cells and monocytes and supresses T-cell inflammatory responses[51]
      • Increases number of CD56(bright) natural killer cells[51]
      • Acts to turn cells towards a Th2 phenotype as opposed to Th1 phenotype [51]
  • Side Effects:
    • Hepatotoxicity, which is life-threatening, is very rare [51]
    • Hypothyroidism, fatigue, depression and myalgias common but managable [51]
    • Flu-like symptoms that usually reside after 2-3 months on the drug [2]
    • Possible liver abnormalities and mild lymphopaenia require regular blood testing [2]

Glatiramer acetate (GA)

Glatiramer acetate (GA), also known as Copaxone®, is an approved treatment for MS.[18] It is composed of amino acids that are similar to the peptide fragments found in myelin basic protein.[2][51] It is theorized to work by modifying the inflammatory response, improving self-regulation of the immune system and helping to augment damage.[51] Compared to Interferon beta, GA is more specific to myelin antigen targeting cells.[51] In general, GA causes a long-term shift from the pro-inflammatory Th1 response, to an anti-inflammatory Th2 response in the central nervous system.[18][51]

  • Mecahnisms of Action:
    • Effects on Cytokines and T-cell populations
      • T-cells that respond specifically to GA have increased expression of brain-derived neurotrophic factor (BDNF) and the anti-inflammatory cytokines IL-10 and TGF-beta .[18][51]
      • Increased production of BDNF may be what helps repair myelin damage.
      • Causes decrease in Th1 cell expression of cytokines and chemokines, surpressing IL-12, IL-17, and INF-gamma.[18][51]
      • Surpresses lymphocyte proliferation.[51]
      • Causes apoptosis of CD4+ cells.[51]
    • Effects on Chemokines and Adhesion Molecules
      • Decreases expression of certian chemokines which results in a decrease in the ability of T-cells to cross the blood brain barrier.[51]
      • Reduces expression of RANTES, a cytokine that attracts T lymphocytes, in astroglial cells.[51]
    • Other Effects
      • Causes production of IgG4 which affects the humoral immune response so that patients with stronger antibody responses had fewer relapses. [51]
      • Competes with MBP epitpoes and can prevent responses of antigen presenting cells and T-cell receptors to myelin antigens.[51]
      • Can cause antigen presenting cells to secrete Th2 cytokines.[51]
      • Enhances dendritic cell migration from the periphery into the CNS and enhances survival of neural cells under oxidaitve stress.[51]
  • Side Effects:
    • Possible skin reactions at injection site [2][51]
    • No reported significant toxicities or systemic effects [2][51]


Mitotoxantrone works as a broad spectrum immunosuppresive cytotoxic drug.[2][51]
It is theorized to work mainly by modulating the inflammatory response of the immune system.[51] It induces apoptosis of active immune cells and inhibits activation of several pro-inflammatory cells and macrophages.[2][51]

  • Mechanisms of Action:
    • Effects on Cytokines and T-cell populations
      • Reduces active, circulating CD4+ and CD8+ T cell numbers[51]
      • Possibly decreases the level of IL-10 [51]
    • Effects on Chemokines and Adhesion Molecules
      • May reduce migration of CD4+, CD8+ and CD14+ monocytes across the endothelium
      • Inhibits CNS MMP -9 activity in EAE models.
    • Other Effects
      • In mice models, dendritic cells exposed to Mitoxantrone are less able to break down myelin .[51]
  • Side Effects:
    • Rare but significant is the possibility of treatment related leukemia. [2][51]
  • Dose-dependent cardiotoxicity is possible and therefore use of the drug must be limited.[51]


Natalizumab is theorized to work by modulating inflammation and restoring the integrity of the blood brain barrier.[51] It is a monoclonal antibody specific to VLA-4 that blocks VLA-4 from binding to VCAM, an immune cell ligand that is upregulated on the endothelium during inflammation [2][51] Overall, this leads to apoptosis of activated T-cells and decreased migration across the blood brain barrier.[51]

  • Mechanisms of Action:
    • Effects on Cytokines and T-cell populations
      • Decreases numbers of CD4+ and CD8+ lymphocytes in the cerebrospinal fluid
        • However, CD4+ and CD8+ cells producing IFN-gamma, TNF-alpha and IL-17 increase in peripheral circulation, possibly due to a decrease in migration across the blood brain barrier to the CNS[51]
          • This raises concern of a rebound effect of the disease once treatment with Natalizumab is stoppped.[51] The significance and consequences of this effect are currently unclear[51]
      • Decreases production of IFN-ϒ
      • Increases production of IL-10
    • Effects on Chemokines and Adhesion Molecules
      • Directly affects the α4 integrin adhesion molecule which is expressed on lymphocytes, monocytes, basophils and eosinophils and is part of the VLA-4 antigen that pairs with vascular cell adhesion molecule- 1, or VCAM-1. VLA-4 and VCAM interactions allow lymphocytes to cross the blood brain barrier and proliferate. This is thought to play an important role in contributing to lesions in MS.[51]
      • The rational then for treatment with Natalizumab is that it inhibits the relationship between VLA-4 and VCAM-1 and therefore decreases transmission across the blood brain barrier and decreases proliferation of lymphocytes.[51]
    • Other Effects:
      • Decreases number of B cells in the cerebrospinal fluid (also via inhibition of VLA-4 signaling).[51]
      • Reduces number of dendritic cells in perivascular spaces of the brain.[51]
  • Side Effects:
    • Rare but devastating possibility of progressive multifocal leukoencephalopathy, a viral disease that also causes white matter degeneration.[2][51]

* Also rare, but a few patients reported CNS lymphoma [51]

  • The effects on fertility and pregnancy for all of the above mentioned therapies is unknown.[51]

Symptomatic Therapies

Many patients use pharmacological therapies to treat the disease process, however, often, these medications do not resolve the associated symptoms of multiple sclerosis. In fact, some patients may forego disease-modifying therapies in exchange for symptom-based therapies if thought to be more beneficial. The most commonly reported MS-related symptoms include fatigue, spasticity, weakness, bladder/ bowel/ and sexual dysfunction, depression, cognitive problems, tremor, vertigo, nystagmus, and pain.[52]

The following chart was composed from information taken from a literature review, by Schwendimann 2006 [52], of current treatments of MS symptoms:

Symptomatic Therapies Chart


Clearly, many cellular factors are involved in the pathogenesis and perpetuation of Multiple Sclerosis. The multi-factorial cause of MS makes it challenging to isolate a definitive pathway for the development of the disease. Despite advanced understanding of the pathogenesis and perpetuation of CNS auto-immune inflammatory diseases through EAE models, a cure has not yet been developed. Further research in this area is necessary to fully understand this disease and develop a cure.

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