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Infection and Immunity, September 2002, p. 5008-5018, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5008-5018.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Tolerance to Self Gangliosides Is the Major Factor Restricting the Antibody Response to Lipopolysaccharide Core Oligosaccharides in Campylobacter jejuni Strains Associated with Guillain-Barré Syndrome

Tyrone Bowes,1,2 Eric R. Wagner,1 Judith Boffey,1 Dawn Nicholl,1 Lynne Cochrane,1 Mustapha Benboubetra,1 Joe Conner,2 Keiko Furukawa,3 Koichi Furukawa,3 and Hugh J. Willison1*

University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland G51 4TF,1 Department of Biological Sciences, Glasgow Caledonian University, Glasgow, Scotland G4 OBAUnited Kingdom,2 Department of Biochemistry II, Nagoya University School of Medicine, Nagoya, Japan3

Received 25 January 2002/ Returned for modification 21 March 2002/ Accepted 30 May 2002

Guillain-Barré syndrome following Campylobacter jejuni infection is frequently associated with anti-ganglioside autoantibodies mediated by molecular mimicry with ganglioside-like oligosaccharides on bacterial lipopolysaccharide (LPS). The regulation of antibody responses to these T-cell-independent antigens is poorly understood, and only a minority of Campylobacter-infected individuals develop anti-ganglioside antibodies. This study investigates the response to gangliosides and LPS in strains of mice by using a range of immunization strategies. In normal mice following intraperitoneal immunization, antibody responses to gangliosides and LPS are low level but can be enhanced by the antigen format or coadministration of protein to recruit T-cell help. Class switching from the predominant immunoglobulin M (IgM) response to IgG3 occurs at low levels, suggesting B1-cell involvement. Systemic immunization results in poor responses. In GalNAc transferase knockout mice that lack all complex gangliosides and instead express high levels of GM3 and GD3, generation of anti-ganglioside antibodies upon immunization with either complex gangliosides or ganglioside-mimicking LPS is greatly enhanced and exhibits class switching to T-cell-dependent IgG isotypes and immunological memory, indicating that tolerance to self gangliosides is a major regulatory factor. Responses to GD3 are suppressed in knockout mice compared with wild-type mice, in which responses to GD3 are induced specifically by GD3 and as a result of polyclonal B-cell activation by LPS. The anti-ganglioside response generated in response to LPS is also dependent on the epitope density of the ganglioside mimicked and can be further manipulated by providing secondary signals via lipid A and CD40 ligation.

* Corresponding author. Mailing address: University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, Scotland, United Kingdom. Phone: 44 141 201 2464. Fax: 44 141 201 2993. E-mail: h.j.willison{at}udcf.gla.ac.uk.

Editor: R. N. Moore

Infection and Immunity, September 2002, p. 5008-5018, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5008-5018.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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