Multiple sclerosis

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Courtesy of Intermountain Medical Imaging, Boise, Idaho.^[1]

Multiple sclerosis (MS) - an autoimmune disease that effects every patient differently based on the neurologic lesions inflicted throughout the body. While some can go through their lives with relatively mild symptoms and short periods of relapse, others can become incapacitated within years or even months. Defined by Nylander and Hafler, MS is a "multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual."^[2] 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.^[3]

There are three ways in which MS is categorized: 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 usually returns 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.

Taking a biochemical look at the immunopathology and some of the various treatments that exist for MS helps in the understanding that MS is no longer a diagnosis which is hopeless, but is in fact full of hopeful and helpful treatments.

Click on the green links to the left to observe the various proteins involved in MS immunopathology (PDB entry: 1tcr)

Drag the structure with the mouse to rotate

Immunopathology

Classical MS pathology has been characterized by white matter plaques 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 (two ectodomains shown, 3qzw), as well as a smaller amount of (3t0e), (2ra4), and rare (4e96) and (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.^[2]^[4]^[5]^[6] Many antigens have been investigated to determine whether they are the cause of autoreactivity (extracellular domain shown, 1tcr) in the hopes to determine a single culprit including: (MBP, 1bx2) with a peptide shown; (PLP, 2xpg) with peptide shown; (MOG, 3csp); oligodendroglia-specific enzyme transaldolase, and heat shock protein (2y1z).^[2]

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 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.^[7]

Interferon-β

is a protein growth factor that stimulates an antiviral defense. Its encoding gene is one of only two known vertebrate structural genes that lacks introns.^[8]

Interferon-β is a relatively simple biological response modifier, with several . It consists of five , as well as multiple interconnecting . Helices A, B and D run , and helices C and E run to the other three helices, but 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.^[9]^[10]

Interferon Alpha, Interferon Beta, and Interferon Receptors 1 & 2

Since a PDB reference does not exist for interferon beta interacting with interferon receptors 1 or 2, and a multitude of files exist on 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.

Interferon alpha has a 31% sequence homology to interferon beta. It, too, has many with two : one between the , and the other between . It has seven , as compared to the five of interferon-β, and therefore has several more The helices A, C, and F run to one another, and to B, E, and G which run to each other.

does not run parallel or anti-parallel to either set, but rather runs at a 45-90 degree angle to them. Helix A consists of residues 10-12; Helix B of 40-43; Helix C of 53-68; Helix D of 70-75; Helix E of 78-100; Helix F of 109-132; and Helix G of 137-158.

Interferons -α and -β interact with a receptor at the cell surface.^[11] This receptor has : an

, with two disulfide bonds, a , with one disulfide bond, and a . The of the receptor have no secondary structure, allowing for some serious flexibility, leading to .^[12]

Interferon-α to an interferon receptor mainly with helices C and G. There are many within 4 angstroms of one another. These residues could form many , 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.^[13]

Interferon-β and MS

Interferon-β was first approved for the treatment of MS in 1993. The drug has shown to be extremely effective on RRMS and SPMS, though more so on RRMS, with a reduction in relapse rate, decrease in disability progression, and MRI evidence of disease activity. While the exact mechanism of effectiveness is not known, it is quite clear that when administered, interferon-β is extremely effective at slowing the progression of the two less severe types of MS. Two types of interferon-βs exist on the market: interferon-β 1a and interferon-β 1b. Interferon-β 1a products Avonex and Rebif are recombinant peptides that are produced in Chinese hamster ovary cells and are identical to natural human Interferon-β. Avonex is injected intramuscularly once a week, while Rebif is injected subcutaneously three times a week. Interferon-β 1b products Betaseron and Extavia are produced recombinantly in Escherichia coli bacteria and administered subcutaneous injection every other day. The sequence is only one residue off from that of human Interferon-β. Interferon-β 1b is titrated to a target dose over 6 weeks. All four of these major market drugs bind to the same human interferon receptor.^[14]

Other Treatments

Copaxone

References

↑ [1] Poinier, A.C., Husney, A., and Chalk, C. "Magnetic resonance imaging (MRI) of multiple sclerosis." Health.com Updated: 2010 Feb 18.
↑ ^2.0 ^2.1 ^2.2 Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012 Apr 2;122(4):1180-8. doi: 10.1172/JCI58649. Epub 2012 Apr 2. PMID:22466660 doi:10.1172/JCI58649
↑ Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011 Sep;9(3):409-16. PMID:22379455 doi:10.2174/157015911796557911
↑ Dziedzic T, Metz I, Dallenga T, Konig FB, Muller S, Stadelmann C, Bruck W. Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis. Brain Pathol. 2010 Sep;20(5):976-85. Epub 2010 Apr 14. PMID:20477831 doi:10.1111/j.1750-3639.2010.00401.x
↑ Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol. 2002 Aug;1(4):232-41. PMID:12849456
↑ Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM, Mahad DJ. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol. 2011 Mar;69(3):481-92. doi: 10.1002/ana.22109. Epub 2010 Nov 8. PMID:21446022 doi:10.1002/ana.22109
↑ Mosyak L, Wood A, Dwyer B, Buddha M, Johnson M, Aulabaugh A, Zhong X, Presman E, Benard S, Kelleher K, Wilhelm J, Stahl ML, Kriz R, Gao Y, Cao Z, Ling HP, Pangalos MN, Walsh FS, Somers WS. The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. J Biol Chem. 2006 Nov 24;281(47):36378-90. Epub 2006 Sep 27. PMID:17005555 doi:M607314200
↑ Voet, D., Voet, J.G., and C. Pratt. Fundamentals of Biochemistry 3rd Edition. Hoboken, NJ: John Wiley and Sons, 2008. Print.
↑ Kudo M. Management of hepatocellular carcinoma: from prevention to molecular targeted therapy. Oncology. 2010 Jul;78 Suppl 1:1-6. Epub 2010 Jul 8. PMID:20616576 doi:10.1159/000315222
↑ http://www.uniprot.org/uniprot/P00784
↑ [2] 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
↑ Chill JH, Quadt SR, Levy R, Schreiber G, Anglister J. The human type I interferon receptor: NMR structure reveals the molecular basis of ligand binding. Structure. 2003 Jul;11(7):791-802. PMID:12842042
↑ Quadt-Akabayov SR, Chill JH, Levy R, Kessler N, Anglister J. Determination of the human type I interferon receptor binding site on human interferon-alpha2 by cross saturation and an NMR-based model of the complex. Protein Sci. 2006 Nov;15(11):2656-68. Epub 2006 Sep 25. PMID:17001036 doi:10.1110/ps.062283006
↑ 'MS:Pathogenesis and Treatment'