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.
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.
Bowes
Tyrone
T
University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland G51 4TF.
Wagner
Eric R
ER
Boffey
Judith
J
Nicholl
Dawn
D
Cochrane
Lynne
L
Benboubetra
Mustapha
M
Conner
Joe
J
Furukawa
Keiko
K
Furukawa
Koichi
K
Willison
Hugh J
HJ
D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis; D001323:Autoantibodies / Q000096:biosynthesis; D019013:CD40 Antigens / Q000378:metabolism; D002169:Campylobacter Infections / Q000150:complications / Q000276:immunology; D016123:Campylobacter jejuni / Q000276:immunology* / Q000472:pathogenicity*; D002240:Carbohydrate Sequence; D005260:Female; D005732:Gangliosides / Q000737:chemistry / Q000276:immunology; D020275:Guillain-Barre Syndrome / Q000209:etiology / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology*; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency / Q000235:genetics; D017634:Self Tolerance
D000907:Antibodies, Bacterial; D001323:Autoantibodies; D019013:CD40 Antigens; D005732:Gangliosides; D008070:Lipopolysaccharides; D008081:Liposomes; C023023:lipid-linked oligosaccharides; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase