Trends in Immunology
Volume 25, Issue 2, February 2004, Pages 61-66
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The Guillain–Barré syndrome: a true case of molecular mimicry

https://doi.org/10.1016/j.it.2003.12.004Get rights and content

Abstract

Molecular mimicry between microbial antigens and host tissue forms an attractive hypothetical mechanism for the triggering of autoimmune disease by preceding infections. Recent crucial reviews state that molecular mimicry, as the causative mechanism, remains unproven for any human autoimmune disease. However, the peripheral neuropathy Guillain–Barré syndrome (GBS) is largely overseen in this debate. Based on recent evidence, we argue that GBS should be considered as an excellent paradigm and an attractive model for elucidation of both host and microbial aspects of molecular mimicry.

Section snippets

The Guillain–Barré syndrome

GBS is an immune-mediated disease of the peripheral nerves, involving both the myelin sheath and the axons, and is named after G. Guillain and J.A. Barré, two French neurologists who described the syndrome in 1916, together with A. Strohl [10]. The immunological attack consists of deposits of immunoglobulins and complement on the axon and Schwann cell surface accompanied by macrophage and T-cell infiltration of the nerve [11]. Patients suffer from generalised weakness, areflexia and a varying

Definition of molecular mimicry

The discussion as to whether molecular mimicry is a mechanism for the induction of autoimmune disease is hampered by loose definitions of molecular mimicry and the inconsistent use of previously defined criteria for a disease to be deemed due to this mechanism. The term molecular mimicry is both used to simply indicate the sharing of antigens between hosts and microorganisms and to cover the immunological process of cross-reactivity. We operationally define molecular mimicry as dual recognition

Criterion #1: establishment of an epidemiological association between an infectious agent and the immune-mediated disease

Defining the infectious agent(s) associated with the autoimmune disease is crucial in directing the search for the target antigen in the triggering microbe(s). This can be achieved with case-control studies using culture, serological and nucleic acid amplification techniques. In chronic autoimmune diseases it can be difficult to define the precipitating pathogen owing to the time lag between the precipitating infection and the occurrence of immune-mediated pathology. It is important to note

Criterion #2: identification of T cells or antibodies directed against host target antigens in patients

This is the demonstration of autoreactive T cells or antibodies in patients. The T cells or antibodies must have a pathogenic effect, demonstrated in vivo or in vitro. Ideally, the observed effect in the experimental situation directly reflects the symptoms observed in the human disease. It is a challenge to satisfy this criterion because in many instances the experimental limitations do not enable sufficient matching with the clinical situation.

Criterion #3: identification of microbial mimic of target antigen

This comprises demonstration of cross-reactivity of autoreactive T cells or antibodies with a microbial antigen, derived from an organism that has been epidemiologically linked to the disease. Subsequently, the microbial mimic must be purified and chemically characterised. This is essential for the design of further experiments, such as establishing the extent of cross-reactivity of antibodies or T cells and determining the influence of microbial strain differences on the development of

Criterion #4: reproduction of the disease in an animal model

Reproduction of the disease can be achieved either by infection or by immunisation with the precipitating microbe or purified antigens. On infection or immunisation, the animal develops a cross-reactive immune response, with similar specificity as seen in patients. In addition, the clinical symptoms and pathological features must closely resemble the human disease. When available, the animal model can also be used to investigate other aspects of mimicry, using genetically engineered microbes

Concluding remarks

The reasons for the relative obscurity of GBS among immunologists are unknown although the evidence discussed here convincingly implicates molecular mimicry as the causative mechanism in the development of GBS. We argue that GBS is a model disease with an enormous potential for studying many aspects of post-infectious immune-mediated disease.

GBS occurs worldwide and is the most frequent cause of flaccid paralysis in the Western world, making it relatively easy to obtain samples from human

Acknowledgements

We thank P.A. van Doorn for his crucial contributions to the experimental and clinical studies on the Guillain–Barré syndrome in the Erasmus MC and C. Zonneveld and A.F. de Vos for discussions on the concept of mimicry This work was supported by grants from the Netherlands Organization for Scientific Research (NWO 940–37–012, NWO 940–38–009), the Prinses Beatrix fonds (95–0518) and the Human Frontier Science Program (RG 38/203).

References (53)

  • D. Rowley et al.

    Antigenic cross-reaction between host and parasite as a possible cause of pathogenicity

    Nature

    (1962)
  • Lawrence, E. (ed.) (1995) Henderson's Dictionary of Biological Terms (11th edn), pp. 130, Longman Group,...
  • L.J. Albert et al.

    Molecular mimicry and autoimmunity

    N. Engl. J. Med.

    (1999)
  • C. Benoist et al.

    Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry?

    Nat. Immunol.

    (2001)
  • N.R. Rose et al.

    Molecular mimicry: a critical look at exemplary instances in human diseases

    Cell. Mol. Life Sci.

    (2000)
  • G. Guillain

    Sur un syndrome de radiculoneurite avec hyperalbuminose du liquide cephalo-rachidien sans reaction cellulaire

    Bull. Mem. Soc. Med. Hop. Paris

    (1916)
  • T.W. Ho

    Human autoimmune neuropathies

    Annu. Rev. Neurosci.

    (1998)
  • R.A. Hughes et al.

    Clinical and epidemiologic features of Guillain–Barre syndrome

    J. Infect. Dis.

    (1997)
  • F.G.A. Van der Meché et al.

    Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy: immune mechanisms and update on current therapies

    Ann. Neurol.

    (1995)
  • R.S. Fujinami et al.

    Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity

    Science

    (1985)
  • D.L. Kaufman

    Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes

    Nature

    (1993)
  • H.L. Lang

    A functional and structural basis for TCR cross-reactivity in multiple sclerosis

    Nat. Immunol.

    (2002)
  • T. Feizi et al.

    Carbohydrate recognition by Mycoplasma pneumoniae and pathologic consequences

    Am. J. Respir. Crit. Care Med.

    (1996)
  • Y.J. Jang et al.

    Anti-DNA antibodies: aspects of structure and pathogenicity

    Cell. Mol. Life Sci.

    (2003)
  • T. Kieber-Emmons

    Peptide mimotopes of carbohydrate antigens

    Immunol. Res.

    (1998)
  • M.W. Cunningham

    Pathogenesis of group A streptococcal infections

    Clin. Microbiol. Rev.

    (2000)
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