Multiple sclerosis

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

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."[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 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.

Immunopathology

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 CD8+ T cells (two ectodomains shown, 3qzw), as well as a smaller amount of CD4+ T cells (3t0e), monocytes (2ra4), and rare B cells (4e96) and plasma cells (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 T cell autoreactivity (extracellular domain shown, 1tcr) in the hopes to determine a single culprit including: myelin basic protein (MBP, 1bx2) with a peptide shown; proteolipid protein (PLP, 2xpg) with peptide shown; oligodendrocyte glycoprotein (MOG, 3csp); oligodendroglia-specific enzyme transaldolase, and heat shock protein alphaB crystallin (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 lingo-1 ectodomain 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

A protein growth factor that stimulates an antiviral defense interferon-beta is one of the only two known vertebrate structural genes that lacks introns.[8] Interferon-β is a relatively simple biological response modifier, with several identifiable regions. It consists of five alpha helices, as well as multiple interconnecting loop regions. Helices A, B and D run parallel to one another, and helices C and E run anti-parallel to the other three helices, but parallel 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-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 interferon-α 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-α has a 31% sequence homology to interferon-β. It too has many identifiable regions with two disulfide bonds: one between the N-terminus and Helix E, and the other between Loop AB and Helix G. It has seven alpha helices, as compared to the five of interferon-β, and therefore has more loop regions. The helices A, C, and F run parallel to one another, and anti-parallel to B, E, and G which run parallel to each other.Helix D 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 three domains: an N-domain, with two disulfide bonds, a C-domain, with one disulfide bond, and a linker region. The termini regions of the receptor have no secondary structure, allowing for some serious flexibility, leading to eight clashes amongst the domains, which are all illustrated on the N-terminus region.[12]

Interferon-α binds to an interferon receptor mainly with helices C and G. There are many residues, shown in ball-and-stick, within 4 angstroms of one another. These residues could form many different types of bonds, 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.[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]


Click on the green links to the left to observe the various proteins involved in MS immunopathology (PDB entry: 2hym)

Drag the structure with the mouse to rotate



Other Treatments

There are many other treatments for MS ranging from small polymers to monoclonal antibodies to cytotoxic agents. While all have their benefits, they also have their side effects. While clinical trials can out short-term effects, long-term effects are a continuous threat and worry to contend with. Treatment of women, who are more effected than males, is particularly dangerous when the woman is potentially pregnant. Another great concern is the safety of treating children.[3]

Glatiramer Acetate

Formerly known as copolymer 1, glatiramer acetate (GA) is a random polymer of glutamic acid, lysine, alanine, and tyrosine which are the most common amino acids in MBP. As with Interferon-β, the exact mechanism of glutarimer acetate is not yet known, although Racke et al. have shown that GA inhibits response of various antigen-specific murine T cell hybridomas in addition to blunting human MBP-specific T cell lines from lysing targets in the presence of three human leukocyte antigen-DR types associated with MS.[15] Additionally, studies have shown that GA increases cytokine levels, anti-inflammatory action, and acts upon CD8+D T cells by correcting their regulatory deficit. The only drug on the market is called Copaxone and it is approved for use of treatment of RRMS. It has shown effects on exacerbation rate and MRI clinical assessment. Copaxone is injected subcutaneously on a daily basis.[3]

Monoclonal Antibodies

Monoclonal antibodies have been studied since the 1980s and a great deal is known about them. There are three different types that are differentiated by their structural similarity to human antibody structure. Humanized antibodies have more than 90% human components with the rest being murine. These include natalizumab, alemtuzumab, and daclizumab. Rituximab is a chimeric antibody, which contain at least 66% human sequence and structure. Monoclonal antibodies have specific targets and as such have varying mechanisms of binding, blocking, or signaling.[3]

Cytotoxic and Other Agents

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.[3]

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

  1. ↑ [1] Poinier, A.C., Husney, A., and Chalk, C. "Magnetic resonance imaging (MRI) of multiple sclerosis." Health.com Updated: 2010 Feb 18.
  2. ↑ 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
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011 Sep;9(3):409-16. PMID:22379455 doi:10.2174/157015911796557911
  4. ↑ 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
  5. ↑ Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol. 2002 Aug;1(4):232-41. PMID:12849456
  6. ↑ 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
  7. ↑ 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
  8. ↑ Voet, D., Voet, J.G., and C. Pratt. Fundamentals of Biochemistry 3rd Edition. Hoboken, NJ: John Wiley and Sons, 2008. Print.
  9. ↑ 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
  10. ↑ http://www.uniprot.org/uniprot/P00784
  11. ↑ [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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 'MS:Pathogenesis and Treatment'
  15. ↑ Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010 Jan 5;74 Suppl 1:S25-30. PMID:20038760 doi:10.1212/WNL.0b013e3181c97e39

Relevant 3D Structures

Interferon Beta

1au1 - Homo sapiens

1ifa, 1wu3 - Mus musculus

Interferon Receptors

3s98, 3se3, 3se4, 1n6u, 1n6v, 2hym, 2kz1, 2lag, 3s8w, 3s9d - Homo sapiens

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