Current Allergy and Asthma Reports

, Volume 11, Issue 3, pp 197–204 | Cite as

Guillain-Barré Syndrome: Modern Theories of Etiology

  • Todd A. Hardy
  • Stefan Blum
  • Pamela A. McCombe
  • Stephen W. Reddel


Guillain-Barré syndrome (GBS) is a classic failure of the immune system with a life-threatening attack upon a critical self-component. The active phase of the disease is short, concordant with the latency of a primary adaptive immune response. Triggers for GBS include infection and (rarely) vaccination; cross-reactivity between infectious and neural epitopes has been well demonstrated, particularly for Campylobacter jejuni and motor axonal forms of GBS in which non-protein gangliosides are antigenic. Most people are probably exposed to a GBS trigger, but only rarely does the disease develop. We propose that GBS illustrates competing determinants of the immune system’s decision about whether to mount a response, and that in unlucky affected individuals, co-presentation of cross-reactive antigens with danger signals activating pattern-recognition receptors overcomes normal self-recognition such that a primary response is initiated that attacks the nerve. Then, in most cases of GBS, the response rapidly turns off, and second attacks rarely occur. This suggests active restoration of tolerance, and specific privileged site attributes of nerve and declining danger signals as the trigger wanes may contribute to this restoration. Standard immunosuppression has not been effective in GBS. We suggest this is because immune tolerance is already being restored by the time such therapies are initiated. This in turn suggests that improvements in GBS outcomes are likely to come from better protection of the nerve cells under attack while normal resumption of tolerance is permitted to proceed rather than exploring more aggressive immunosuppressive approaches.


Guillain-Barré syndrome Acute inflammatory demyelinating polyradiculoneuropathy Acute motor axonal neuropathy Immune pathogenesis Autoimmune disease 



Dr. Blum has been funded by the Royal Brisbane and Women’s Hospital Research Scholarship.

Dr. Reddel has received honoraria, sponsorship, therapeutic trial payments, and/or grant funding from the National Health and Medical Research Council of Australia, the Muscular Dystrophy Association of the United States, and the Muscular Dystrophy Association of New South Wales. He also wishes to acknowledge helpful discussions with John Pollard, Judy Spies, and Hugh Willison.


Dr. Reddel has received honoraria, sponsorship, therapeutic trial payments, and/or grant funding from Bayer Schering Pharma and Genzyme Corp. Drs. Hardy, Blum, and McCombe reported no potential conflicts of interest relevant to this article.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Zinkernagel R. On observing and analyzing disease versus signals. Nat Immunol. 2007;8:8–10.PubMedCrossRefGoogle Scholar
  2. 2.
    Alshekhlee A, Hussain Z, Sultan B, Katirji B. Guillain-Barre syndrome: incidence and mortality rates in US hospitals. Neurology. 2008;70:1608–13.PubMedCrossRefGoogle Scholar
  3. 3.
    van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7:939–50.PubMedCrossRefGoogle Scholar
  4. 4.
    Hughes RAC, Cornblath DR. Guillain-Barre syndrome. Lancet. 2005;366:1653–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Ruts L, Drenthen J, Jacobs BC, Van Doorn PA. Distinguishing acute-onset CIDP from fluctuating Guillain-Barre syndrome: a prospective study. Neurology. 2010;74:1680–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. Am J Epidemiol. 1979;110:105–23.PubMedGoogle Scholar
  7. 7.
    Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre syndrome and the 1992–1993 and 1993–1994 influenza vaccines. N Engl J Med. 1998;339:1797–802.PubMedCrossRefGoogle Scholar
  8. 8.
    2009 H1N1 flu. Available at:
  9. 9.
    Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barre syndrome. Drug Saf. 2009;32:309–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis. Medicine. 1969;48:173–215.PubMedCrossRefGoogle Scholar
  11. 11.
    Kieseier BC, Kiefer R, Gold R, et al. Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system. Muscle Nerve. 2004;30:131–56.PubMedCrossRefGoogle Scholar
  12. 12.
    Csurhes PA, Sullivan AA, Green K, et al. T cell reactivity to P0, P2, PMP-22, and myelin basic protein in patients with Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Neurosurg Psychiatry. 2005;76:1431–9.PubMedCrossRefGoogle Scholar
  13. 13.
    McCombe PA, Csurhes PA. T cells from patients with Guillain-Barre syndrome produce interferon-gamma in response to stimulation with the ganglioside GM1. J Clin Neurosci. 2010;17:537–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Chi L-J, Wang H-B, Zhang Y, Wang W-Z. Abnormality of circulating CD4(+)CD25(+) regulatory T cell in patients with Guillain-Barre syndrome. J Neuroimmunol. 2007;192:206–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Harness J, McCombe PA. Increased levels of activated T-cells and reduced levels of CD4/CD25+ cells in peripheral blood of Guillain-Barré syndrome patients compared to controls. J Clin Neurosci. 2008;15:1031–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Hafer-Macko CE, Sheikh KA, Li CY, et al. Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy. Ann Neurol. 1996;39:625–35.PubMedCrossRefGoogle Scholar
  17. 17.
    Inglis HR, Csurhes PA, McCombe PA. Antibody responses to peptides of peripheral nerve myelin proteins P0 and P2 in patients with inflammatory demyelinating neuropathy. J Neurol Neurosurg Psychiatry. 2007;78:419–22.PubMedCrossRefGoogle Scholar
  18. 18.
    Feasby TE, Gilbert JJ, Brown WF, et al. An acute axonal form of Guillain-Barre polyneuropathy. Brain. 1986;109:1115–26.PubMedCrossRefGoogle Scholar
  19. 19.
    McKhann GM, Cornblath DR, Griffin JW, et al. Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in China. Ann Neurol. 1993;33:333–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Griffin JW, Li CY, Ho TW, et al. Pathology of the motor-sensory axonal Guillain-Barre syndrome. Ann Neurol. 1996;39:17–28.PubMedCrossRefGoogle Scholar
  21. 21.
    Ang CW, Yuki N, Jacobs BC, et al. Rapidly progressive, predominantly motor Guillain-Barre syndrome with anti-GalNAc-GD1a antibodies. Neurology. 1999;53:2122–7.PubMedGoogle Scholar
  22. 22.
    Ho TW, Willison HJ, Nachamkin I, et al. Anti-GD1a antibody is associated with axonal but not demyelinating forms of Guillain-Barre syndrome. Ann Neurol. 1999;45:168–73.PubMedCrossRefGoogle Scholar
  23. 23.
    Yuki N, Yamada M, Koga M, et al. Animal model of axonal Guillain-Barre syndrome induced by sensitization with GM1 ganglioside. Ann Neurol. 2001;49:712–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Lopez PHH, Zhang G, Bianchet MA, et al. Structural requirements of anti-GD1a antibodies determine their target specificity. Brain. 2008;131:1926–39.PubMedCrossRefGoogle Scholar
  25. 25.
    Kaida K, Kusunoki S. Antibodies to gangliosides and ganglioside complexes in Guillain-Barre syndrome and Fisher syndrome: Mini-review. J Neuroimmunol. 2010;223:5–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Rinaldi S, Willison HJ. Ganglioside antibodies and neuropathies. Curr Opin Neurol. 2008;21:540–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Hafer-Macko C, Hsieh ST, Li CY, et al. Acute motor axonal neuropathy: an antibody-mediated attack on axolemma. Ann Neurol. 1996;40:635–44.PubMedCrossRefGoogle Scholar
  28. 28.
    • Halstead SK, Zitman FMP, Humphreys PD, et al: Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model. Brain 2008, 131:1197–1208. This study demonstrated a realistic therapy for possible trials in human GBS. PubMedCrossRefGoogle Scholar
  29. 29.
    Yuki N, Kuwabara S, Koga M, Hirata K. Acute motor axonal neuropathy and acute motor-sensory axonal neuropathy share a common immunological profile. J Neurol Sci. 1999;168:121–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Uncini A, Manzoli C, Notturno F, Capasso M. Pitfalls in electrodiagnosis of Guillain-Barré syndrome subtypes. J Neurol Neurosurg Psychiatry. 2010;81:1157–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Madrid RE, Wiśniewski HM. Axonal degeneration in demyelinating disorders. J Neurocytol. 1977;6:103–17.PubMedCrossRefGoogle Scholar
  32. 32.
    Sobottka B, Harrer MD, Ziegler U, et al. Collateral bystander damage by myelin-directed CD8+ T cells causes axonal loss. Am J Pathol. 2009;175:1160–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Chiba A, Kusunoki S, Shimizu T, Kanazawa I. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome. Ann Neurol. 1992;31:677–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Damian RT. Molecular mimicry: antigen sharing by parasite and host and its consequences. Am Nat. 1964;98:129–49.CrossRefGoogle Scholar
  35. 35.
    Yuki N, Kuwabara S. Axonal Guillain-Barre syndrome: carbohydrate mimicry and pathophysiology. J Peripher Nerv Syst. 2007;12:238–49.PubMedCrossRefGoogle Scholar
  36. 36.
    van Belkum A, van den Braak N, Godschalk P, et al. A Campylobacter jejuni gene associated with immune-mediated neuropathy. Nat Med. 2001;7:752–3.PubMedCrossRefGoogle Scholar
  37. 37.
    Koga M, Takahashi M, Masuda M, et al. Campylobacter gene polymorphism as a determinant of clinical features of Guillain-Barre syndrome. Neurology. 2005;65:1376–81.PubMedCrossRefGoogle Scholar
  38. 38.
    Halstead SK, O’Hanlon GM, Humphreys PD, et al. Anti-disialoside antibodies kill perisynaptic Schwann cells and damage motor nerve terminals via membrane attack complex in a murine model of neuropathy. Brain. 2004;127:2109–23.PubMedCrossRefGoogle Scholar
  39. 39.
    Illa I, Ortiz N, Gallard E, et al. Acute axonal Guillain-Barre syndrome with IgG antibodies against motor axons following parenteral gangliosides. Ann Neurol. 1995;38:218–24.PubMedCrossRefGoogle Scholar
  40. 40.
    Shamshiev A, Donda A, Prigozy TI, et al. The alphabeta T cell response to self-glycolipids shows a novel mechanism of CD1b loading and a requirement for complex oligosaccharides. Immunity. 2000;13:255–64.PubMedCrossRefGoogle Scholar
  41. 41.
    Shamshiev A, Donda A, Carena I, et al. Self glycolipids as T-cell autoantigens. Eur J Immunol. 1999;29:1667–75.PubMedCrossRefGoogle Scholar
  42. 42.
    Godfrey DI, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Investig. 2004;114:1379–88.PubMedGoogle Scholar
  43. 43.
    Spies JM, Westland KW, Bonner JG, Pollard JD. Intraneural activated T cells cause focal breakdown of the blood–nerve barrier. Brain. 1995;118:857–68.PubMedCrossRefGoogle Scholar
  44. 44.
    Pollard JD, Westland KW, Harvey GK, et al. Activated T cells of nonneural specificity open the blood–nerve barrier to circulating antibody. Ann Neurol. 1995;37:467–75.PubMedCrossRefGoogle Scholar
  45. 45.
    Ho TW, Mishu B, Li CY, et al. Guillain-Barre syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118:597–605.PubMedCrossRefGoogle Scholar
  46. 46.
    • Kuitwaard K, van Koningsveld R, Ruts L, et al: Recurrent Guillain Barre syndrome. Journal of Neurology, Neurosurgery & Psychiatry 2009, 80:56–59. This article confirmed the low rate of recurrent GBS and demonstrated that the few patients who do have recurrences have other features of autoimmunity, and that the standard on-off case does not. CrossRefGoogle Scholar
  47. 47.
    • Steiner I, Rosenberg G, Wirguin I: Transient immunosuppression: a bridge between infection and the atypical autoimmunity of Guillain-Barre syndrome? Clin Exp Immunol 2010. This article presents an interesting related hypothesis that suggests more of a role for transient immunosuppression as an initiating feature but also deals well with the reasons why GBS is not a typical autoimmune disease. Google Scholar
  48. 48.
    Matzinger P. Friendly and dangerous signals: is the tissue in control? Nat Immunol. 2007;8:11–3.PubMedCrossRefGoogle Scholar

Copyright information

© Her Majesty in Right of Australia 2011

Authors and Affiliations

  • Todd A. Hardy
    • 1
  • Stefan Blum
    • 2
  • Pamela A. McCombe
    • 2
  • Stephen W. Reddel
    • 3
  1. 1.Department of NeurologyConcord HospitalSydneyAustralia
  2. 2.Department of NeurologyRoyal Brisbane and Women’s HospitalBrisbaneAustralia
  3. 3.Departments of Neurology and Molecular MedicineUniversity of Sydney, Concord HospitalSydneyAustralia

Personalised recommendations