Recognition Characteristics of Monoclonal Antibodies That Are Cross-Reactive with Gangliosides and Lipooligosaccharide from Campylobacter jejuni Strains Associated with Guillain-Barré and Fisher Syndromes

Abstract

The enteropathogen Campylobacter jejuni has the ability to synthesize glycan structures that are similar to mammalian gangliosides within the core component of its lipooligosaccharide (LOS). Exposure to ganglioside mimics in some individuals results in the production of autoantibodies that deleteriously attack nerve surface gangliosides, precipitating the onset of Guillain-Barré and Fisher syndromes (GBS and FS). We have characterized the interaction of four monoclonal antibodies (mAbs), established by sensitization of mice with LOS isolated from GBS- and FS-associated C. jejuni strains, with chemoenzymatically synthesized gangliooligosaccharides. Surface plasmon resonance (SPR) measurements demonstrate that three of the mAbs interact specifically with derivatives corresponding to their targeted gangliosides, with dissociation constants ranging from 10 to 20 microM. Antibody binding to the gangliooligosaccharides was probed by saturation transfer difference (STD) NMR spectroscopy. STD signals, resulting from antibody/oligosaccharide interaction, were observed for each of the four mAbs. In two cases, differential saturation transfer rates to oligosaccharide resonances enabled detailed epitope mapping. The binding of GD1a-S-Phe with GB1 is characterized by close association of the immunoglobulin with sites that are distributed over several residues of the oligosaccharide. This contrasts sharply with the profile observed for the binding of both GD3-S-Phe and GT1a-S-Phe with FS1. The close antigenic contacts in these ganglioside derivatives are confined to the N-acetylmannosaminyl portion of the terminal N-acetylneuraminic acid (NeuAc) residue of the disialosyl moiety. Our characterization of FS1 provides insight, at an atomic level, into how a single antigenic determinant presented by the LOS of C. jejuni can give rise to antibodies with binding promiscuity to [alphaNeuAc-(2-8)-alphaNeuAc]-bound epitopes and demonstrates why sera from FS patients have antibodies that are often reactive with more than one disialylated ganglioside.

Enhanced expression of unique gangliosides with GM2-determinant in human uterine cervical carcinoma-derived cell lines

“…GalNAc-GD1a was characterized as a target antigen as to antibodies generated by infection with enterocolitis-associated bacteria such as Campylobacter jejuni, and with cytomegalovirus as a trigger on the onset of autoimmune neuropathies, such as the Guillain-Barré and Tolosa-hunt syndromes [18,[25][26][27][28]. Since GM2 determinant was also detected in the lipooligosaccharides from C. jejuni [29], it was revealed to exhibit a strong immunogenicity in the gut-associated immune system to yield anti-GM2 antibodies, and the resulting antibodies were thought to react with GalNAc-GD1a more strongly than with GM2 in neural tissues to disturb the neural functions through antibody-induced inflammation, leading to neuropathies. Detection of antibodies against GalNAc-GD1a was useful as a diagnostic marker for autoimmune neuropathies [18,[26][27][28][29], and Boku, OMC-4 and HCA-1 cells would be applicable as sources for preparation of GalNAc-GD1a and as target cells for the detection of anti-GalNAc-GD1a antibodies in sera of patients with autoimmune neuropathies.…”

“…Since GM2 determinant was also detected in the lipooligosaccharides from C. jejuni [29], it was revealed to exhibit a strong immunogenicity in the gut-associated immune system to yield anti-GM2 antibodies, and the resulting antibodies were thought to react with GalNAc-GD1a more strongly than with GM2 in neural tissues to disturb the neural functions through antibody-induced inflammation, leading to neuropathies. Detection of antibodies against GalNAc-GD1a was useful as a diagnostic marker for autoimmune neuropathies [18,[26][27][28][29], and Boku, OMC-4 and HCA-1 cells would be applicable as sources for preparation of GalNAc-GD1a and as target cells for the detection of anti-GalNAc-GD1a antibodies in sera of patients with autoimmune neuropathies. In fact, in our preliminary experiment, anti-GalNAc-GD1a IgG antibodies could be detected on immunohistochemical staining of Boku cells with sera of patients suffering from chronic motor axonal neuropathy [30].…”

Excretion into feces of asialo GM1 in the murine digestive tract and Lactobacillus johnsonii exhibiting binding ability toward asialo GM1. A possible role of epithelial glycolipids in the discharge of intestinal bacteria

“…In this connection, the strong antigenicities of DG-type glycolipids in Gram-positive bacteria and lipooligosaccharides in Gram-negative bacteria have been well recognized to be useful for the serotyping of bacterial species [13,24], and to cause the production of natural antibodies related to blood group antigens in normal human sera [25], and of disease-related antibodies in patients suffering from multiple sclerosis [26] and Guillan-Barré syndrome [27,28]. In addition to DG-type glycolipids, structures mimicking the oligosaccharide of GA1 were found to be present in glycoprotein of LJ, and to generate antibodies against GA1 on immunization with LJ, as shown in Fig.…”

Fisher Syndrome

“…Campylobacter jejuni [22] and Haemophilus influenzae [23] have been reported as infectious agents prior to the onset of Fisher syndrome, and the molecular mimicry between the structures of the lipooligosaccharides of these bacteria and GQ1b has also been noted [24,25]. Protein levels in the cerebrospinal fluid, without pleocytosis, are usually elevated in patients with Fisher syndrome.…”