Monoclonal antibodies raised against Guillain-Barré syndrome–associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle-nerve preparations
Carl S. Goodyear, … , Joe Conner, Hugh J. Willison
Carl S. Goodyear, … , Joe Conner, Hugh J. Willison
Published September 15, 1999
Citation Information: J Clin Invest. 1999;104(6):697-708. https://doi.org/10.1172/JCI6837.
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Article

Monoclonal antibodies raised against Guillain-Barré syndrome–associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle-nerve preparations

Abstract

Guillain-Barré syndrome and its variant, Miller-Fisher syndrome, are acute, postinfectious, autoimmune neuropathies that frequently follow Campylobacter jejuni enteritis. The pathogenesis is believed to involve molecular mimicry between sialylated epitopes on C. jejuni LPSs and neural gangliosides. More than 90% of Miller-Fisher syndrome cases have serum anti-GQ1b and anti-GT1a ganglioside antibodies that may also react with other disialylated gangliosides including GD3 and GD1b. Structural studies on LPS from neuropathy-associated C. jejuni strains have revealed GT1a-like and GD3-like core oligosaccharides. To determine whether this structural mimicry results in pathogenic autoantibodies, we immunized mice with GT1a/GD3-like C. jejuni LPS and then cloned mAb’s that reacted with both the immunizing LPS and GQ1b/GT1a/GD3 gangliosides. Immunohistology demonstrated antibody binding to ganglioside-rich sites including motor nerve terminals. In ex vivo electrophysiological studies of nerve terminal function, application of antibodies either ex vivo or in vivo via passive immunization induced massive quantal release of acetylcholine, followed by neurotransmission block. This effect was complement-dependent and associated with extensive deposits of IgM and C3c at nerve terminals. These data provide strong support for the molecular mimicry hypothesis as a mechanism for the induction of cross-reactive pathogenic anti-ganglioside/LPS antibodies in postinfectious neuropathies.

Authors

Carl S. Goodyear, Graham M. O’Hanlon, Jaap J. Plomp, Eric R. Wagner, Ian Morrison, Jean Veitch, Lynne Cochrane, Roland W. M. Bullens, Peter C. Molenaar, Joe Conner, Hugh J. Willison

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Figure 5

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Effects of CGM3-5 mAb’s on spontaneous quantal transmitter release at th...
Effects of CGM3-5 mAb’s on spontaneous quantal transmitter release at the mouse NMJ. (a) MEPP frequencies were measured in left diaphragm muscle-nerve preparations that were incubated with either CGM3 (48 μg/mL), CGM4 (67 μg/mL), CGM5 (29–39 μg/mL), or control IgM (67 μg/mL) (open bars) and then with normal human serum as a source of complement (filled bars). In contralateral right hemidiaphragms, control MEPP frequencies were measured in Ringer’s medium (shaded bars). Mean values ± SEM (n = 2 muscles; 7–15 NMJs sampled per muscle). (b) Typical examples of 1-second traces recorded in an untreated preparation and in CGM5-pretreated preparations with or without the addition of normal human serum as a source of complement.