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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(a–c) Whole-mount diaphragm NMJ colabeled with BTx to identify the posts...
(a–c) Whole-mount diaphragm NMJ colabeled with BTx to identify the postsynaptic membrane (a) and the mAb CGM5 (b, overlaid in c). CGM5 gives punctate staining overlaying the postsynaptic membrane (×1,020). (d–f) Sciatic nerve node of Ranvier colabeled with CTB (d) and the mAb CGM3 (e, overlaid in f). CTB stains the paranodal myelin that lies either side of the nodal gap (arrow). CGM3 gives a bright signal directly overlying the nodal axolemma, with a weaker ribbon of axonal staining either side of the node (×790). (g–i) Mouse trigeminal nerve at the transition zone between the PNS (right) and the CNS (left), colabeled with anti-NF (h) and the mAb CGM3 (h, overlaid in i). CGM3 strongly and preferentially binds the peripheral portion of this nerve (×90). (j–l) Transverse section through 2 NMJs from an electrophysiological preparation of hemidiaphragm treated with the mAb CGM3 and a source of human complement. Postsynaptic regions labeled with BTx (j) are associated with human C3c deposits (k); however the BTx and human C3c deposits are slightly offset (l) in a pattern suggesting that the site of complement activation is pre- rather than postsynaptic. The domed structure (arrow) is a perinuclear halo from a capping Schwann cell, indicating that complement deposits are, at least in part, on the surface of these cells (×900). (m–o) Whole-mount stained NMJ from an electrophysiological preparation of hemidiaphragm treated with the mAb CGM3 and a source of human complement. The nerve terminal contains closely but not identically overlapping deposits of IgM (m) and C3c (n, overlaid in o). The tissue was permeabilized with detergent to expose cryptically located IgM (×960). (p–r) NMJ from the diaphragm of a mouse passively immunized with mAb CGM3, colabeled with BTx (p) and anti-mouse IgM (q, overlaid in r). IgM deposits were more extensive than the area delineated by BTx (×1,010).