Multiple sclerosis

  • Jorge Correale
Part of the Progress in Inflammation Research book series (PIR)


Multiple sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System (CNS). Although its etiology remains unknown, several lines of evidence support autoimmunity as playing a major role in the development of the disease. MS incidence has significantly increased during the second half of the 20th century. This has been attributed to improved sanitation and reduced exposure to infection. The hygiene hypothesis is not new and is currently used to explain the increasing incidence of allergies and other autoimmune diseases. Because helminths are powerful modulators of the host immune system, it has also been suggested that reduced exposure to helminths due to improved hygiene conditions may favor MS development. In this chapter epidemiological, experimental and clinical data supporting the protective role of helminths in MS are reviewed. Better understanding of host-parasite interactions, as well as identification of specific parasite molecules causing immunomodulatory modulation will help combat allergies and autoimmune diseases without having to pay the price of undesired infectious side-effects.


Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Multiple Sclerosis Patient Experimental Allergic Encephalomyelitis Helminth Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 46: 907–911PubMedGoogle Scholar
  2. 2.
    Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747CrossRefPubMedGoogle Scholar
  3. 3.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L (1998) Axonal trasection in the lesions of multiple sclerosis. N Engl J Med 338: 278–285CrossRefPubMedGoogle Scholar
  4. 4.
    Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of newly forming lesions. Ann Neurol 55: 458–468CrossRefPubMedGoogle Scholar
  5. 5.
    Marrie RA (2004) Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol 3:709–718CrossRefPubMedGoogle Scholar
  6. 6.
    Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL (2008) The genetics of multiple sclerosis: SNP to pathways to pathogenesis. Nat Rev Genet 9: 516–526CrossRefPubMedGoogle Scholar
  7. 7.
    Dyment DA, Ebers GA, Sadovnick AD (2004) Genetics of multiple sclerosis. Lancet Neurol 3: 104–110CrossRefPubMedGoogle Scholar
  8. 8.
    The International Multiple Sclerosis Genetics Consortium, Hafler DA, Compstom A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ et al (2007) Risk alleles for multiple sclerosis identified by a genome wide study. N Engl J Med 357: 851–862CrossRefPubMedGoogle Scholar
  9. 9.
    Sadovnick AD, Armstrong H, Rice GPA, Bulman D, Hashimoto L, Paty DW, Hashimoto SA, Warren S, Hader W, Murray TJ et al (1993) A population-based study of multiple sclerosis in twins: update. Ann Neurol 33: 281–285CrossRefPubMedGoogle Scholar
  10. 10.
    Rosati G (2001) The prevalence of multiple sclerosis in the world: an update. Neurol Sci 22: 117–139CrossRefPubMedGoogle Scholar
  11. 11.
    Kurtzke JF (1997) The epidemiology of multiple sclerosis. In: Raine CS, McFarland HF, Tourtellotte WW (eds): Multiple Sclerosis Clinical and Pathogenic Basis. Chapman & Hall Medical, London, 91–140Google Scholar
  12. 12.
    Elian M, Nigthingale S, Dean G (1990) Multiple Sclerosis among United Kingdom-born children of immigrants from the Indian subcontinent, Africa and the West Indies. J Neurol Neurosurg Psychiatry 53: 906–911CrossRefPubMedGoogle Scholar
  13. 13.
    Kahana E, Zilber N, Abramson JH, Biton V, Libowitz Y, Abramsky O (1994) Multiple Sclerosis: genetic versus environmental aetiology: epidemiology in Israel updated. J Neurol 241: 341–346CrossRefPubMedGoogle Scholar
  14. 14.
    Ascherio A, Munger KL (2007) Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann Neurol 61: 288–299CrossRefPubMedGoogle Scholar
  15. 15.
    Ascherio A, Munger KL (2007) Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 61: 504–513CrossRefPubMedGoogle Scholar
  16. 16.
    Gilden DH (2005) Infectious causes of multiple sclerosis. Lancet Neurol 4: 195–202PubMedGoogle Scholar
  17. 17.
    Christen U, von Herrath MG (2005) Infections and autoimmunity — Good or bad? J Immunol 174: 7481–7486PubMedGoogle Scholar
  18. 18.
    Poskanzer DC, Walker AM, Yonkondy J, Sheridan JL (1976) Studies in the epidemiology of multiple sclerosis in the Okney and Shetland Islands. Neurology 26: 14–17PubMedGoogle Scholar
  19. 19.
    Kurtzke JF (1993) Epidemiological evidence for multiple sclerosis as an infection. Clin Microbiol Rev 6: 382–427PubMedGoogle Scholar
  20. 20.
    Rickinson AB, Kieff E (1996) Epstein-Barr virus. In. Fields BN, Knipe DM, Howley PM (eds) Fields virology, 3rd edition. Lippincott-Raven Publishers, Philadelphia, 2397–2446Google Scholar
  21. 21.
    Kasunoki Y, Huang H, Fukuda Y, Ozaki K, Saito M, Hirai Y, Akiyama M (1993) A positive correlation between the precursors frequency of cytotoxic lymphocytes to autologous Epstein-Barr virus-transformed B cells and antibody titer level against Epstein-Barr virus-associated nuclear antigen in healthy seropositive individuals. Microbiol Immunol 37: 461–469Google Scholar
  22. 22.
    Henle W, Henle G, Niederman JC, Klemola E, Haltia K (1971) Antibodies to early antigens induced by Epstein-Barr virus in infectious mononucleosis. J Infect Dis 124: 58–67PubMedGoogle Scholar
  23. 23.
    Lunemann JD, Edwards N, Muraro PA, Hayashi S, Cohen JI, Münz C, Martin R (2006) Increased frequency and broadened specificity of latent EBV nuclear antigen-1 specific T cells in multiple sclerosis. Brain 129: 1493–1506CrossRefPubMedGoogle Scholar
  24. 24.
    von Herrath MG, Fujinami RS, Whitton JL (2003) Microorganisms and autoimmunity: making the barren field fertile? Nature Rev Microbiol 1: 151–157CrossRefGoogle Scholar
  25. 25.
    Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347: 911–920CrossRefPubMedGoogle Scholar
  26. 26.
    Starchan DP (1989) Hay fever, hygiene and household size. Br Med J 299: 1259–1260CrossRefGoogle Scholar
  27. 27.
    Leibowitz U, Atanovsky A, Medalie JM, Smith HA, Halpern L, Alter M (1966) Epidemiological study of multiple sclerosis in Israel. II. Multiple Sclerosis and level of sanitation. J Neurol Neurosurg Psychiatry 29: 60–68CrossRefPubMedGoogle Scholar
  28. 28.
    Poser S, Stickel B, Krsch U, Burckhardt D, Nordman B (1989) Increasing incidence of multiple sclerosis in South Lower Saxony, Germany. Neuroepidemiology 8: 207–213CrossRefPubMedGoogle Scholar
  29. 29.
    Gonzalez O, Sotelo J (1995) Is the frequency of multiple sclerosis increasing in México? J Neurol Neurosurg Psychiatry 59: 528–530CrossRefPubMedGoogle Scholar
  30. 30.
    Pugliatti M, Riise T, Sotgiu MA, Sotgiu S, Satta WM, Mannu L, Sanna G, Rosati G (2005) Increasing incidence of multiple sclerosis in the province of Sassari, northern Sardinia. Neuroepidemiology 25: 129–134CrossRefPubMedGoogle Scholar
  31. 31.
    Sotgiu S, Pugliatti M, Sotgiu A, Sanna A, Rosati G (2003) Does the “hygiene hypothesis” provide an explanation for the high prevalence of multiple sclerosis in Sardinia? Autoimmunity 36: 257–260CrossRefPubMedGoogle Scholar
  32. 32.
    Fleming JO, Cook TD (2006) Multiple sclerosis and the hygiene hypothesis. Neurology 67: 2085–2086CrossRefPubMedGoogle Scholar
  33. 33.
    Cabre P, Signate A, Olindo S, Merle H, Caparros-Lefebvre D, Bera O, Smadja D (2005) Role of return migration in the emergence of multiple sclerosis in the French West Indies. Brain 128: 2899–2910CrossRefPubMedGoogle Scholar
  34. 34.
    Sewell D, Qing Z, Reinke E, Elliot D, Weinstock J, Sandor M, Fabry Z (2003) Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization. Int Immunol 15: 59–69CrossRefPubMedGoogle Scholar
  35. 35.
    La Flamme AC, Ruddenklau K, Bäckstrom BT (2003) Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect Immun 71: 4996–5004CrossRefPubMedGoogle Scholar
  36. 36.
    Correale J, Farez M (2007) Association between parasite infection and immune responses in Multiple Sclerosis. Ann Neurol 61: 97–108CrossRefPubMedGoogle Scholar
  37. 37.
    Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE (2004) Helminth parasites-masters of regulation. Immunol Rev 201: 89–116CrossRefPubMedGoogle Scholar
  38. 38.
    Correale J, Farez M, Razzitte G (2008) Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol 64: 187–199CrossRefPubMedGoogle Scholar
  39. 39.
    Mauri C, Gray D, Mushtaq N, Londei M (2003) Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 197: 489–501CrossRefPubMedGoogle Scholar
  40. 40.
    Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhank AK (2002) Chronic intestinal inflammatory conditions generate IL-10 producing regulatory B cells characterized by CD1d upregulation. Immunity 16: 219–230CrossRefPubMedGoogle Scholar
  41. 41.
    Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3: 944–950CrossRefPubMedGoogle Scholar
  42. 42.
    Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Artkins H, Kim HJ, Bar-Or A (2007) Distinct effector cytokine profiles of memory and naïve human B cell subsets and implication in multiple sclerosis. J Immunol 178: 6092–6099PubMedGoogle Scholar
  43. 43.
    Jankovic D, Steinfleder S, Kullberg MC, Sher A (2006) Mechanisms underlying helminth-induced Th2 polarization: default, negative or positive pathways. Chem Immunol Allergy 90: 65–81CrossRefPubMedGoogle Scholar
  44. 44.
    Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114: 1379–1388PubMedGoogle Scholar
  45. 45.
    Colgan SP, Hersberg RM, Furuta GT, Blumberg RS (1999) Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of cytoplasmic tail in autocrine signaling. Proc Natl Acad Sci USA 96: 13938–13943CrossRefPubMedGoogle Scholar
  46. 46.
    Kane CM, Cervi L, Sun J, McKee AS, Masek KS, Shapira S, Hunter CA, Pearce EJ. Helminth antigens modulate TLR-initiated dendritic cell activation (2004) J Immunol 173: 7454–7461PubMedGoogle Scholar
  47. 47.
    Fillatreau S, Gray D, Anderton SM (2008) Not always the bad guys: B cells as regulators of autoimmune pathology. Nat Rev Immunol 8: 391–397CrossRefPubMedGoogle Scholar
  48. 48.
    Correale J, Farez M (2008) Toll-like receptors induce regulatory B cells during helminth infections associated with multiple sclerosis. J Neuroimmunol 203: 132–133Google Scholar
  49. 49.
    Summers RW, Elliot DE, Urban JF Jr, Thompson R, Weinstock JV (2005) Trichuris suis therapy for active ulcerative colitis: a randomized trial. Gastroenterology 128: 825–832CrossRefPubMedGoogle Scholar
  50. 50.
    Croese J, O’Neil J, Masson J, Cooke S, Melrose W, Pritchard D, Spare R (2006) A proof of concept study establishing Necator americanus in Crohn’s patients and reservoir donors. Gut 55: 136–137CrossRefPubMedGoogle Scholar
  51. 51.
    Fleming JO (2007) The hygiene hypothesis and multiple sclerosis. Ann Neurol 61: 85–89CrossRefPubMedGoogle Scholar
  52. 52.
    Constantinescu C. Immunoregulation by controlled parasite exposure in Multiple Sclerosis. Available at: http: // (accessed 10 November 2008)Google Scholar
  53. 53.
    van Shayck CP, Knottnerus JA (2004) No clinical evidence base to support the hygiene hypothesis. Prim Care Respir J 13: 76–79CrossRefGoogle Scholar
  54. 54.
    Sadovnick AD, Yee IM, Ebers GC, Canadian Collaborative Study Group (2005) Multiple sclerosis and birth order: a longitudinal cohort study. Lancet Neurol 4: 611–617CrossRefPubMedGoogle Scholar
  55. 55.
    Goverman J, Woods A, Larson L, Weiner L, Hood L, Zaller DM (1993) Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72: 551–560CrossRefPubMedGoogle Scholar
  56. 56.
    Yokote H, Miyake S, Croxford JL, Oki S, Mizusawa H, Yamamura T (2008) NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora. Am J Pathol 173: 1–10CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Jorge Correale
    • 1
    • 2
  1. 1.Dr. Raúl Carrea Institute for Neurological ResearchFLENIBuenos AiresArgentina
  2. 2.School of Biomedical SciencesAustral UniversityBuenos AiresArgentina

Personalised recommendations