Multiple sclerosis: Difference between revisions
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[[Image:MSLesions.jpg|450px|right|thumb|Courtesy of Intermountain Medical Imaging, Boise, Idaho.<ref>[http://www.health.com/health/library/mdp/0,,zm6056,00.html] Poinier, A.C., Husney, A., and Chalk, C. "Magnetic resonance imaging (MRI) of multiple sclerosis." ''Health.com'' Updated: 2010 Feb 18.</ref>]] | [[Image:MSLesions.jpg|450px|right|thumb|Courtesy of Intermountain Medical Imaging, Boise, Idaho.<ref>[http://www.health.com/health/library/mdp/0,,zm6056,00.html] Poinier, A.C., Husney, A., and Chalk, C. "Magnetic resonance imaging (MRI) of multiple sclerosis." ''Health.com'' Updated: 2010 Feb 18.</ref>]] | ||
'''Multiple sclerosis (MS)''' is an autoimmune disease defined by Nylander and Hafler as "a multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual."<ref name ="MS Nylander & Hafler">PMID:22466660</ref> Inflammation is the primary cause of damage in MS, and though the effects of the disease are well known and various treatments exist for the disease, the exact identity of an antigen or infectious agent that causes the initiation of a myriad of symptoms is unknown.<ref name='MS:Pathogenesis and Treatment'>PMID:22379455</ref> | |||
'''Multiple sclerosis (MS)''' | |||
There are three categories of MS: relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS). In RRMS, the patient experiences periods of time in which the symptoms increase considerably, although the neurological function of the patient can return to normal after the episode. Those with SPMS have symptoms like RRMS, but do not return to normal neurological function after the episode, rather they sustain the neurological damage (such as permanently losing the use of an arm). In PPMS, the patient has an initial episode that never ends. That is, once the symptoms begin, there is no remission in the neurological degradation. A constant autoimmune attack on the patient's body causes increasingly severe symptoms, which can sometimes lead to death. | There are three categories of MS: relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS). In RRMS, the patient experiences periods of time in which the symptoms increase considerably, although the neurological function of the patient can return to normal after the episode. Those with SPMS have symptoms like RRMS, but do not return to normal neurological function after the episode, rather they sustain the neurological damage (such as permanently losing the use of an arm). In PPMS, the patient has an initial episode that never ends. That is, once the symptoms begin, there is no remission in the neurological degradation. A constant autoimmune attack on the patient's body causes increasingly severe symptoms, which can sometimes lead to death. | ||
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== Immunopathology== | == Immunopathology== | ||
Classical MS pathology has been characterized by white matter plaques, shown in the | Classical MS pathology has been characterized by white matter plaques, shown in the image above, which are typically located in the subcortical or periventricular white matter, optic nerve sheaths, brain stem, and spinal cord. The lesions that occur in these regions are generally identified by perivascular infiltrates that contain clonally expanded <scene name='Multiple_sclerosis/Cd8tcell/2'>CD8+ T cells</scene> (two ectodomains shown, [[3qzw]]), as well as a smaller amount of <scene name='Multiple_sclerosis/Cd4tcell/2'>CD4+ T cells</scene> ([[3t0e]]), <scene name='Multiple_sclerosis/Monocyte/2'>monocytes</scene> ([[2ra4]]), and rare <scene name='Multiple_sclerosis/B_cell/2'>B cells</scene> ([[4e96]]) and <scene name='Multiple_sclerosis/Plasma_cell/2'>plasma cells</scene> ([[2wq9]]). Pathologists disagree on whether there are different mechanisms for the inflammatory and degenerative components of MS, especially given that older patients have generally progressed further along with their degeneration. There are many proposed degeneration mechanisms including Wallerian degeneration secondary to demyelination, and axonal transection, damage from reactive oxygen species and nitric oxide, or energy failure from mitochondrial dysfunction.<ref name="MS Nylander & Hafler" /><ref>PMID:20477831</ref><ref>PMID:12849456</ref><ref>PMID:21446022</ref> Many antigens have been investigated to determine whether they are the cause of <scene name='Multiple_sclerosis/Xtracllulrtcell/2'>T cell</scene> autoreactivity (extracellular domain shown, [[1tcr]]) in the hopes to determine a single culprit including: <scene name='Multiple_sclerosis/Mbp/2'>myelin basic protein</scene> (MBP, [[1bx2]]) with a peptide shown; <scene name='Multiple_sclerosis/Plp/2'>proteolipid protein</scene> (PLP, [[2xpg]]) with peptide shown; <scene name='Multiple_sclerosis/Mog/2'>oligodendrocyte glycoprotein</scene> (MOG, [[3csp]]); oligodendroglia-specific enzyme transaldolase, and heat shock protein <scene name='Multiple_sclerosis/Alphabcrystallin/2'>alphaB crystallin</scene> ([[2y1z]]).<ref name="MS Nylander & Hafler" /> | ||
Interesting discoveries have been made on possible inhibitors of myelin repair functions within the body, with an obvious application to MS treatment. The structure of the <scene name='Multiple_sclerosis/Lingo-1ectodomain/2'>lingo-1 ectodomain</scene> is a module implicated in central nervous system repair inhibition. The interactions of lingo-1 with receptors lead to neurite and axonal collapse. Lingo- 1 also regulates oligodendrocyte differentiation and myelination, thus leading to the suggestion that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies.<ref name='Lingo-1'>PMID:17005555</ref> | Interesting discoveries have been made on possible inhibitors of myelin repair functions within the body, with an obvious application to MS treatment. The structure of the <scene name='Multiple_sclerosis/Lingo-1ectodomain/2'>lingo-1 ectodomain</scene> is a module implicated in central nervous system repair inhibition. The interactions of lingo-1 with receptors lead to neurite and axonal collapse. Lingo- 1 also regulates oligodendrocyte differentiation and myelination, thus leading to the suggestion that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies.<ref name='Lingo-1'>PMID:17005555</ref> | ||
==Interferon-β== | ==Interferon-β== | ||
<scene name='Multiple_sclerosis/Interferon_beta/ | A protein growth factor that stimulates an antiviral defense <scene name='Multiple_sclerosis/Interferon_beta/9'>interferon-beta</scene> is one of the only two known vertebrate structural genes that lacks introns.<ref name="Biochem Text">Voet, D., Voet, J.G., and C. Pratt. ''Fundamentals of Biochemistry'' 3rd Edition. Hoboken, NJ: John Wiley and Sons, 2008. Print.</ref> Interferon-β is a relatively simple biological response modifier, with several <scene name='Multiple_sclerosis/Interferon_beta_labeled/2'>identifiable regions</scene>. It consists of five <scene name='Multiple_sclerosis/Ifnb_helices_in_color/2'>alpha helices</scene>, as well as multiple interconnecting <scene name='Multiple_sclerosis/Interferon_beta_loops/3'>loop regions</scene>. Helices A, B and D run <scene name='Multiple_sclerosis/Ifnb_parallel_abd/4'>parallel to one another</scene>, and helices C and E run <scene name='Multiple_sclerosis/Ifnb_antiparallel/3'>anti-parallel</scene> to the other three helices, but <scene name='Multiple_sclerosis/Ifnb_antiparallel_ce/4'>parallel</scene> to one another. Helix A consists of residues 6-23; Helix B consists of residues 49-65; Helix C consists of residues 77-91; Helix D consists of residues 112-131; and Helix E consists of residues 135-155.<ref name="Structure Ifn B">PMID:20616576</ref><ref name="UniProt">http://www.uniprot.org/uniprot/P00784</ref> | ||
===Interferon-α, Interferon-β, and Interferon Receptors=== | |||
===Interferon-α, Interferon-β, and Interferon Receptors | |||
Since a PDB reference does not exist for interferon-β interacting with interferon receptors 1 or 2, and a multitude of files exist on <scene name='Multiple_sclerosis/Ifna/5'>interferon-α</scene> interacting with the receptor, a comparison to interferon-α will be made prior to demonstrating the types of bonding that occur between the interferon and its receptor. To see more information regarding interferons, please visit the [[Interferons]] site. | Since a PDB reference does not exist for interferon-β interacting with interferon receptors 1 or 2, and a multitude of files exist on <scene name='Multiple_sclerosis/Ifna/5'>interferon-α</scene> interacting with the receptor, a comparison to interferon-α will be made prior to demonstrating the types of bonding that occur between the interferon and its receptor. To see more information regarding interferons, please visit the [[Interferons]] site. | ||
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Interferons-α and -β interact with a receptor at the cell surface.<ref>[http://www.jbc.org/content/282/28/20045.full?sid=cbf08059-44d4-4957-8ea7-0351cab9c2ac] Samuel, C.E. "Interferons, Interferon Receptors, Signal Transducer and Transcriptional Activators, and Inteferon Regulatory Factors." ''J Biol Chem'' 2007 282: 20045-20046. First Published on May 14, 2007, doi:10.1074/jbc.R700025200</ref> This receptor has <scene name='Multiple_sclerosis/Ifnr_domains_labeled/2'>three domains</scene>: an <scene name='Multiple_sclerosis/Ifnr_n_domain_labeled/2'>N-domain</scene>, with two disulfide bonds, a <scene name='Multiple_sclerosis/Ifnr_c_domain_labeled/2'>C-domain</scene>, with one disulfide bond, and a <scene name='Multiple_sclerosis/Ifnr_linker_region_labeled/2'>linker region</scene>. The <scene name='Multiple_sclerosis/Ifnr_termini_labeled/2'>termini regions</scene> of the receptor have no secondary structure, allowing for some serious flexibility, leading to <scene name='Multiple_sclerosis/Ifnr_clash_n-c/2'>eight clashes amongst the domains</scene>, which are all illustrated on the N-terminus region.<ref name="Interferon Receptor Structure">PMID:12842042</ref> | Interferons-α and -β interact with a receptor at the cell surface.<ref>[http://www.jbc.org/content/282/28/20045.full?sid=cbf08059-44d4-4957-8ea7-0351cab9c2ac] Samuel, C.E. "Interferons, Interferon Receptors, Signal Transducer and Transcriptional Activators, and Inteferon Regulatory Factors." ''J Biol Chem'' 2007 282: 20045-20046. First Published on May 14, 2007, doi:10.1074/jbc.R700025200</ref> This receptor has <scene name='Multiple_sclerosis/Ifnr_domains_labeled/2'>three domains</scene>: an <scene name='Multiple_sclerosis/Ifnr_n_domain_labeled/2'>N-domain</scene>, with two disulfide bonds, a <scene name='Multiple_sclerosis/Ifnr_c_domain_labeled/2'>C-domain</scene>, with one disulfide bond, and a <scene name='Multiple_sclerosis/Ifnr_linker_region_labeled/2'>linker region</scene>. The <scene name='Multiple_sclerosis/Ifnr_termini_labeled/2'>termini regions</scene> of the receptor have no secondary structure, allowing for some serious flexibility, leading to <scene name='Multiple_sclerosis/Ifnr_clash_n-c/2'>eight clashes amongst the domains</scene>, which are all illustrated on the N-terminus region.<ref name="Interferon Receptor Structure">PMID:12842042</ref> | ||
Interferon-α <scene name='Multiple_sclerosis/Ifnawithreceptorcolored/2'>binds</scene> to an interferon receptor mainly with helices C and G. There are many <scene name='Multiple_sclerosis/Ifnawithreceptorintrxns/6'>residues</scene>, shown in ball-and-stick, within 4 angstroms of one another. These residues could form many <scene name='Multiple_sclerosis/ | Interferon-α <scene name='Multiple_sclerosis/Ifnawithreceptorcolored/2'>binds</scene> to an interferon receptor mainly with helices C and G. There are many <scene name='Multiple_sclerosis/Ifnawithreceptorintrxns/6'>residues</scene>, shown in ball-and-stick, within 4 angstroms of one another. These residues could form many <scene name='Multiple_sclerosis/Ifnawithreceptorcolored/3'>different types of bonds</scene>, with hydrogen bonds illustrated in white dotted lines. Given that interferon-α does not undergo many structural changes upon binding to interferon receptor II, Quadt-Akabayov et al. have concluded that the binding mechanism is similar to that of a lock and key. While interferon-α and -β bind to the same receptors as one another, the affinities with which they bind to IFNAR1 and IFNAR2 differ. While the binding to IFNAR2 is stronger for both in comparison to IFNAR1, interferon-β has a much stronger affinity for IFNAR1 than interferon-α.<ref name="Interferon Receptor Interferon Alpha">PMID:17001036</ref> | ||
===Interferon-β and MS=== | ===Interferon-β and MS=== | ||
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Some clinicians will use cytotoxic agents to treat MS, although only mitoxantrone is FDA approved for the treatment of MS. Off label use of cytotoxic agents is based on small studies, and cyclophosphamide, azathioprine, methotexate, and mycophenolate mofetil are the most frequently used. Their mechanism of action appears to be a broad immunosurppressive action, and these agents have much more severe side effects, such as an increase of infections and neoplasia, than the other more traditional treatments. Immunomodulatory agents, such as intravenous immunoglobulin and corticosteroids, are also sometimes used.<ref name='MS:Pathogenesis and Treatment' /> | Some clinicians will use cytotoxic agents to treat MS, although only mitoxantrone is FDA approved for the treatment of MS. Off label use of cytotoxic agents is based on small studies, and cyclophosphamide, azathioprine, methotexate, and mycophenolate mofetil are the most frequently used. Their mechanism of action appears to be a broad immunosurppressive action, and these agents have much more severe side effects, such as an increase of infections and neoplasia, than the other more traditional treatments. Immunomodulatory agents, such as intravenous immunoglobulin and corticosteroids, are also sometimes used.<ref name='MS:Pathogenesis and Treatment' /> | ||
===Dalfampridine=== | |||
Approved in the U.S. in 2012, '''dalfampridine''', with the pharmaceutical name ampyra, has been shown in medical studies to help MS patients improve walking ability, and is the first drug in its class. The form of administration is an extended release oral tablet. Dalfampridine, a mixture of fampridine and 4-aminopyridine, is a potassium channel antagonist. Its mechanism of action prolongs the action potential and improves the conduction in demyelinated axons, as well as potentiation of synaptic and neuromuscular transmission. The potential of this drug is promising for a patient who has been robbed of their ability to walk. | |||
==References== | ==References== | ||
