Trends in Immunology
The Guillain–Barré syndrome: a true case 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)
Analysis of the relationship between viral infection and autoimmune disease
Immunity
(2001)Ablation of ‘tolerance’ and induction of diabetes by virus infection in viral antigen transgenic mice
Cell
(1991)A very high level of crossreactivity is an essential feature of the T-cell receptor
Immunol. Today
(1998)- et al.
Presentation of self and microbial lipids by CD1 molecules
Curr. Opin. Immunol.
(2001) - et al.
Defining criteria for autoimmune diseases (Witebsky's postulates revisited)
Immunol. Today
(1993) Pathogenesis of Guillain–Barré syndrome
J. Neuroimmunol.
(1999)A case of Guillain–Barré syndrome following a family outbreak of Campylobacter jejuni enteritis
J. Neuroimmunol.
(2000)- et al.
Chagas disease etiology: autoimmunity or parasite persistence?
Parasitol. Today
(1999) - et al.
Mechanisms of autoimmune disease induction. The role of the immune response to microbial pathogens
Arthritis Rheum.
(1995) Molecular mimicry: antigen sharing by parasite and host and its consequences
Am. Nat.
(1964)
Antigenic cross-reaction between host and parasite as a possible cause of pathogenicity
Nature
Molecular mimicry and autoimmunity
N. Engl. J. Med.
Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry?
Nat. Immunol.
Molecular mimicry: a critical look at exemplary instances in human diseases
Cell. Mol. Life Sci.
Sur un syndrome de radiculoneurite avec hyperalbuminose du liquide cephalo-rachidien sans reaction cellulaire
Bull. Mem. Soc. Med. Hop. Paris
Human autoimmune neuropathies
Annu. Rev. Neurosci.
Clinical and epidemiologic features of Guillain–Barre syndrome
J. Infect. Dis.
Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy: immune mechanisms and update on current therapies
Ann. Neurol.
Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity
Science
Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes
Nature
A functional and structural basis for TCR cross-reactivity in multiple sclerosis
Nat. Immunol.
Carbohydrate recognition by Mycoplasma pneumoniae and pathologic consequences
Am. J. Respir. Crit. Care Med.
Anti-DNA antibodies: aspects of structure and pathogenicity
Cell. Mol. Life Sci.
Peptide mimotopes of carbohydrate antigens
Immunol. Res.
Pathogenesis of group A streptococcal infections
Clin. Microbiol. Rev.
Cited by (290)
Microbes as triggers and boosters of Type 1 Diabetes – Mediation by molecular mimicry
2023, Diabetes Research and Clinical PracticeRheumatic diseases: From bench to bedside
2023, Translational Autoimmunity: Volume 6: Advances in Autoimmune Rheumatic DiseasesGuillain-Barré syndrome: expanding the concept of molecular mimicry
2022, Trends in ImmunologyRole of real-time DNA analyses, biomarkers, resistance measurement, and ecosystem management in Campylobacter risk analysis
2022, Present Knowledge in Food Safety: A Risk-Based Approach through the Food Chain