Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy

Nazem Ghasemi, Shahnaz Razavi, Elham Nikzad, Nazem Ghasemi, Shahnaz Razavi, Elham Nikzad

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) lesions that can lead to severe physical or cognitive disability as well as neurological defects. Although the etiology and pathogenesis of MS remains unclear, the present documents illustrate that the cause of MS is multifactorial and include genetic predisposition together with environmental factors such as exposure to infectious agents, vitamin deficiencies, and smoking. These agents are able to trigger a cascade of events in the immune system which lead to neuronal cell death accompanied by nerve demyelination and neuronal dysfunction. Conventional therapies for MS are based on the use of anti-inflammatory and immunomodulatory drugs, but these treatments are not able to stop the destruction of nerve tissue. Thus, other strategies such as stem cell transplantation have been proposed for the treatment of MS. Overall, it is important that neurologists be aware of current information regarding the pathogenesis, etiology, diagnostic criteria, and treatment of MS. Thus, this issue has been discussed according to recent available information.

Keywords: Cell Therapy; Demyelination; Etiology; Multiple Sclerosis.

Figures

Fig.1
Fig.1
Immune cells and their cytokines which involved in the pathogenesis of multiple sclerosis (MS).

References

    1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–1517.
    1. Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011;9(3):409–416.
    1. Weiner HL. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol. 2008;255(Suppl 1):3–11.
    1. Gadoth N. Multiple sclerosis in children. Brain Dev. 2003;25(4):229–232.
    1. Boiko A, Vorobeychicle G, Paty D, Devonshire V, Sondovnick D. University of British Columbia MS Clinic Neurologists.Early onset multiple sclerosis: a long longitudinal study. Neurology. 2002;59(7):1006–1010.
    1. Khan F, Turner-Stokes L, Ng L, Kilpatrick T. Multidisciplinary rehabilitation for adults with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2008;79(2):114–114.
    1. Holloman JP, Ho CC, Hukki A, Huntley JL, Gallicano GI. The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis. Am J Stem Cells. 2013;2(2):95–107.
    1. Hatch MN, Schaumburg CS, Lane TE, Keirstead HS. Endogenous remyelination is induced by transplant rejection in a viral model of multiple sclerosis. J Neuroimmunol. 2009;212(1-2):74–81.
    1. de Andrés C, Aristimuño C, de Las Heras V, Martínez-Ginés ML, Bartolomé M, Arroyo R, et al. Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis. J Neuroimmunol. 2007;182(1-2):204–211.
    1. Haas J, Korporal M, Balint B, Fritzsching B, Schwarz A, Wildemann B. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4 (+)CD25(+) FOXP3(+)CD31(+) T-cells in patients with multiple sclerosis. J Neuroimmunol. 2009;216(1-2):113–117.
    1. Ghasemi N, Razavi S, Mardani M, Esfandiari E, Salehi H, ZarkeshEsfahani SH. Transplantation of human adiposederived stem cells enhances remyelination in lysolecithininduced focal demyelination of rat spinal cord. Mol Biotechnol. 2014;56(5):470–478.
    1. Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E, et al. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells. 2009;27(10):2624–2635.
    1. Sadan O, Shemesh N, Cohen Y, Melamed E, Offen D. Adult neurotrophic factor-secreting stem cells: a potential novel therapy for neurodegenerative diseases. Isr Med Assoc J. 2009;11(4):201–204.
    1. Mohyeddin Bonab M, Mohajeri M, Sahraian MA, Yazdanifar M, Aghsaie A, Farazmand A, et al. Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells. Arch Med Res. 2013;44(4):266–272.
    1. Gandhi R, Laroni A, Weiner HL. Role of the innate immune system in the pathogenesis of multiple sclerosis. J Neuroimmunol. 2009;221(1-2):7–14.
    1. Kasper LH, Shoemaker J. Multiple sclerosis immunology: the healthy immune system vs the MS immune system. Neurology. 2010;74(Suppl 1):S2–8.
    1. Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007;96:41–101.
    1. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557–1569.
    1. Minty A, Chalon P, Derocq JM, Dumont X, Guillemot JC, Kaghad M, et al. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993;362(6417):248–250.
    1. Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21:425–456.
    1. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28(4):454–467.
    1. Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H, et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol. 2007;178(10):6092–6099.
    1. Kouchaki E, Salehi M, Reza Sharif M, Nikoueinejad H, Akbari H. Numerical status of CD4(+)CD25(+)FoxP3(+) and CD8(+)CD28(-) regulatory T cells in multiple sclerosis. Iran J Basic Med Sci. 2014;17(4):250–255.
    1. Li W, Maeda Y, Ming X, Cook S, Chapin J, Husar W, et al. Apoptotic death following Fas activation in human oligodendrocyte hybrid cultures. J Neurosci Res. 2002;69(2):189–196.
    1. Fujinami RS, von Herath MG, Christen U, Whitton JL. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev. 2006;19(1):80–94.
    1. O'Gorman C, Bukhari W, Todd A, Freeman S, Broadley SA. Smoking increases the risk of multiple sclerosis in Queensland, Australia. J Clin Neurosci. 2014;21(10):1730–1733.
    1. Speer G. Impact of vitamin D in neurological diseases and neurorehabilitation: from dementia to multiple sclerosis.Part I: the role of vitamin D in the prevention and treatment of multiple sclerosis. Ideggyogy Sz. 2013;66(9-10):293–303.
    1. Zhang SM, Willett WC, Hernán MA, Olek MJ, Ascherio A. Dietary fat in relation to risk of multiple sclerosis among two large cohorts of women. Am J Epidemiol. 2000;152(11):1056–1064.
    1. Bäärnhielm M, Olsson T, Alfredsson L. Fatty fish intake is associated with decreased occurrence of multiple sclerosis. Mult Scler. 2014;20(6):726–732.
    1. Sloka S, Silva C, Pryse-Phillips W, Patten S, Metz L, Yong VW. A quantitative analysis of suspected environmental causes of MS. Can J Neurol Sci. 2011;38(1):98–105.
    1. Dawson VL, Dawson TM, Bartley DA, Uhl GR, Snyder SH. Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J Neurosci. 1993;13(6):2651–2661.
    1. Merrill JE, Ignarro LJ, Sherman MP, Melinek J, Lane TE. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol. 1993;151(4):2132–2141.
    1. Mitrovic B, Ignarro LJ, Vinters HV, Akers MA, Schmid I, Uittenbogaart C, et al. Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes. Neuroscience. 1995;65(2):531–539.
    1. Somogyi E, Balogh I, Rubányi G, Sótonyi P, Szegedi L. New findings concerning the pathogenesis of acute carbon monoxide (CO) poisoning. Am J Forensic Med Pathol. 1981;2(1):31–39.
    1. Thom SR, Bhopale VM, Fisher D, Zhang J, Gimotty P. Delayed neuropathology after carbon monoxide poisoning is immune-mediated. Proc Natl Acad Sci USA. 2004;101(37):13660–13665.
    1. Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci. 2004;29(12):664–673.
    1. VanAmerongen BM, Dijkstra CD, Lips P, Polman CH. Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr. 2004;58(8):1095–1109.
    1. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B Cell differentiation. J Immunol. 2007;179(3):1634–1647.
    1. Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010;67(5):618–624.
    1. Banwell B, Bar-Or A, Arnold DL, Sadovnick D, Narayanan S, McGowan M, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lnacet Neurol. 2011;10(5):436–445.
    1. Disanto G, Morahan JM, Ramagopalan SV. Multiple sclerosis: risk factors and their interactions. CNS Neurol Disord Drug Targets. 2012;11(5):545–555.
    1. Wade DT, Young CA, Chaudhuri KR, Davidson DL. A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the "CariLoder regime") in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002;73(3):246–249.
    1. Bäärnhielm M, Hedström AK, Kockum I, Sundqvist E, Gustafsson SA, Hillert J, et al. Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1*15. Eur J Neurol. 2012;19(7):955–962.
    1. Bates D, Cartlidge NE, French JM, Jackson MJ, Nightingale S, Shaw DA, et al. A double-blind controlled trial of long chain N-3 polyunsaturated fatty acids in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatr. 1989;52(1):18–22.
    1. Swank RL, Lerstad O, Strom A, Backer J. Multiple sclerosis in rural Norway its geographic and occupational incidence in relation to nutrition. N Engl J Med. 1952;246(19):722–728.
    1. Alter M, Yamoor M, Harshe M. Multiple sclerosis and nutrition. Arch Neurol. 1974;31(4):267–272.
    1. Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013;80(6):548–552.
    1. Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis.Canadian Collaborative Study Group. Nature. 1995;377(6545):150–151.
    1. Sadovnick AD, Ebers GC, Dyment DA, Risch NJ. Evidence for genetic basis of multiple sclerosis.The Canadian Collaborative Study Group. Lancet. 1996;347(9017):1728–1730.
    1. Sadovnick AD, Dircks A, Ebers GC. Genetic counselling in multiple sclerosis: risks to sibs and children of affected individuals. Clin Genet. 1999;56(2):118–122.
    1. Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet. 2008;9(7):516–526.
    1. Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC. Canadian Collaborative Study Group.Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci USA. 2003;100(22):12877–12882.
    1. Stewart GJ, McLeod JG, Basten A, Bashir HV. HLA family studies and multiple sclerosis: a common gene, dominantly expressed. Hum Immunol. 1981;3(1):13–29.
    1. Amirzargar A, Mytilineos J, Yousefipour A, Farjadian S, Scherer S, Opelz G, et al. HLA class II (DRB1, DQA1 and DQB1) associated genetic susceptibility in Iranian multiple sclerosis (MS) patients. Eur J Immunogenet. 1998;25(4):297–301.
    1. Masterman T, Ligers A, Olsson T, Andersson M, Olerup O, Hillert J. "HLA-DR15 is associated with lower age at onset in multiple sclerosis. Ann Neurol. 2000;48(2):211–219.
    1. Quelvennec E, Bera O, Cabre P, Alizadeh M, Smadja D, Jugde F, et al. Genetic and functional studies in multiple sclerosis patients from Martinique attest for a specific and direct role of the HLA-DR locus in the syndrome. Tissue Antigens. 2003;61(2):166–171.
    1. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet. 2007;39(9):1083–1091.
    1. Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269–290.
    1. Røsjø E, Myhr KM, Løken-Amsrud KI, Bakke SJ, Beiske AG, Bjerve KS, et al. Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis. J Neuroimmunol. 2014;271(1-2):60–65.
    1. Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54(9):11720–11725.
    1. Greene DN, Schmidt RL, Wilson AR, Freedman MS, Grenache DG. Cerebrospinal fluid myelin basic protein is frequently ordered but has little value: a test utilization study. Am J Clin Pathol. 2012;138(2):262–272.
    1. Shah I, James R, Barker J, Petroczi A, Naughton DP. Misleading measures in Vitamin D analysis: a novel LCMS/MS assay to account for epimers and isobars. Nutr J. 2011;10:46–46.
    1. Tenembaum SN, Segura MJ. Interferon beta-1a treatment in childhood and juvenile-onset multiple sclerosis. Neurology. 2006;67(3):511–513.
    1. Dhib-Jalbut S, Marks S. Interferon-beta mechanisms of action in multiple sclerosis. Neurology. 2010;74(Suppl 1):S17–24.
    1. Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010;74(Suppl 1):S25–30.
    1. Ciccone A, Beretta S, Brusaferri F, Galea I, Protti A, Spreafico C. Corticosteroids for the longterm treatment in multiple sclerosis. Cochrane Database Syst Rev. 2008;(1):CD006264–CD006264.
    1. Martinelli Boneschi F, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2005;(4):CD002127–CD002127.
    1. La Mantia L, Milanese C, Mascoli N, D'Amico R, WeinstockGuttman B. Cyclophosphamide for multiple sclerosis. Cochrane Database Syst Rev. 2007;(1):CD002819–CD002819.
    1. Vollmer T, Stewart T, Baxter N. Mitoxantrone and cytotoxic drugs’ mechanisms of action. Neurology. 2010;74(Suppl 1):S41–46.
    1. Gray O, McDonnell GV, Forbes RB. Methotrexate for multiple sclerosis. Cochrane Database Syst Rev. 2004;(2):CD003208–CD003208.
    1. Baxter AG. The origin and application of experimental autoimmune encephalomyelitis. Nat Rev Immunol. 2007;7(11):904–912.
    1. Di Ianni M, Del Papa B, De Ioanni M, Moretti L, Bonifacio E, Cecchini D, et al. Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol. 2008;36(3):309–318.
    1. Svobodova E, Krulova M, Zajicova A, Pokorna K, Prochazkova J, Trosan P, et al. The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or proinflammatory helper T-cell 17 population. Stem Cells Dev. 2012;21(6):901–910.
    1. Mikaeili Agah E, Parivar K, Joghataei MT. Therapeutic effect of transplanted human Wharton’s jelly stem cell-derived oligodendrocyte progenitor cells (hWJ-MSC-derived OPCs) in an animal model of multiple sclerosis. Mol Neurobiol. 2014;49(2):625–632.
    1. Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003;422(6933):688–694.
    1. Wang X, Kimbrel EA, Ijichi K, Paul D, Lazorchak AS, Chu J, et al. Human ESC-derived MSCs outperform bone marrow MSCs in the treatment of an EAE model of multiple sclerosis. Stem Cell Reports. 2014;3(1):115–130.
    1. Fisher-Shoval Y, Barhum Y, Sadan O, Yust-Katz S, BenZur T, Lev N, et al. Transplantation of placenta-derived mesenchymal stem cells in the EAE mouse model of MS. J Mol Neurosci. 2012;48(1):176–184.
    1. Trubiani O, Giacoppo S, Ballerini P, Diomede F, Piattelli A, Bramanti P, et al. Alternative source of stem cells derived from human periodontal ligament: a new treatment for experimental autoimmune encephalomyelitis. Stem Cell Res Ther. 2016;7:1–1.
    1. Azimi Alamouti M, Bakhtiyari M, Moradi F, Mokhtari T, Hedayatpour A, Zafari F, et al. Remyelination of the corpus callosum by olfactory ensheathing cell in an experimental model of multiple sclerosis. Acta Med Iran. 2015;53(9):533–539.
    1. Ravanidis S, Poulatsidou KN, Lagoudaki R, Touloumi O, Polyzoidou E, Lourbopoulos A, et al. Subcutaneous transplantation of neural precursor cells in experimental autoimmune encephalomyelitis reduces chemotactic signals in the central nervous system. Stem Cells Transl Med. 2015;4(12):1450–1462.
    1. Bai L, Lennon DP, Caplan AI, DeChant A, Hecker J, Kranso J, et al. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat Neurosci. 2012;15(6):862–870.
    1. Ghasemi N, Razavi Sh. Transdifferentiation potential of adipose-derived stem cells into neural lineage and their application. Journal of Histology & Histopathology. 2014;1(1):1–35.
    1. Razavi S, Mardani M, Kazemi M, Esfandiari E, Narimani M, Esmaeili A, et al. Effect of leukemia inhibitory factor on the myelinogenic ability of Schwann-like cells induced from human adipose-derived stem cells. Cell Mol Neurobiol. 2013;33(2):283–289.
    1. Razavi S, Razavi MR, Kheirollahi-Kouhestani M, Mardani M, Mostafavi FS. Co-culture with neurotrophic factor secreting cells induced from adipose-derived stem cells: promotes neurogenic differentiation. Biochem Biophys Res Commun. 2013;440(3):381–387.
    1. Zuk P. Adipose-derived stem cells in tissue regeneration: a review. ISRN Stem Cells. 2013 2013.
    1. Gronthos S, Franklin DM, Leddy HA, Robey PG, Storms RW, Gimble JM. Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol. 2001;189(1):54–63.
    1. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, TemmGrove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292–1298.
    1. González MA, Gonzalez-Rey E, Rico L, Büscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136(3):978–989.
    1. Ghasemi N, Razavi SH, Salehi H. Improvement of myelin ultrastructure after transplantation of human adipose tissue-derived stem cell in rat multiple sclerosis model. J Isfahan Med Sch. 2016;33(366):2333–2340.
    1. Shalaby SM, Sabbah NA, Saber T, Abdel Hamid RA. Adipose-derived mesenchymal stem cells modulate the immune response in chronic experimental autoimmune encephalomyelitis model. IUBMB Life. 2016;68(2):106–115.

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