Abstract
Guillain–Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness, is often preceded by Campylobacter jejuni infection. Molecular mimicry exists between the bacterial lipo-oligosaccharide and human ganglioside. Such C. jejuni infection induces production of immunoglobulin G1 (IgG1) autoantibodies against GM1 and causes complement-mediated motor nerve injury. For elucidating the molecular mechanisms linking autoantigen recognition and complement activation, we characterized the dynamic interactions of anti-GM1 IgG autoantibodies on ganglioside-incorporated membranes. Using high-speed atomic force microscopy, we found that the IgG molecules assemble into a hexameric ring structure on the membranes depending on their specific interactions with GM1. Complement component C1q was specifically recruited onto these IgG rings. The ring formation was inhibited by an IgG-binding domain of staphylococcal protein A bound at the cleft between the CH2 and CH3 domains. These data indicate that the IgG assembly is mediated through Fc–Fc interactions, which are promoted under on-membrane conditions due to restricted translational diffusion of IgG molecules. Reduction and alkylation of the hinge disulfide impaired IgG ring formation, presumably because of an increase in conformational entropic penalty. Our findings provide mechanistic insights into the molecular processes involved in Guillain–Barré syndrome and, more generally, into antigen-dependent interplay between antibodies and complement components on membranes.
Highlights
Immunoglobulin G (IgG) is a crucial mediator of the defensive mechanisms for eliminating infectious microorganisms [1]
We demonstrated that high-speed atomic force microscopy (HS-AFM) is a powerful tool for real-time observation of interactions of IgG molecules with the Fcγ receptor [9]
Previous studies revealed that GB2, directed against C. jejuni, was cross-reactive with GM1 but not with the other ganglioside components in the bovine brain, e.g., GD1a, GD1b, and GT1b [6], nor synthesized gangliosidic oligosaccharides derived from GM3, GD3, GM2, GD1a, and GT1a [10]
Summary
Immunoglobulin G (IgG) is a crucial mediator of the defensive mechanisms for eliminating infectious microorganisms [1]. Some Gram-positive bacteria possess cell wall proteins capable of binding to IgG molecules independent of their antigen-binding sites. Examples of such proteins are protein A from Staphylococcus aureus and protein G from streptococcus groups C and G, which can disturb host immune mechanisms [2,3]. Some Gram-negative bacteria can express outer membrane glycolipids that share common glycan structures with mammalian glycosphingolipids, enabling them to escape the immune surveillance [4,5]. Such bacterial glycolipids occasionally elicit the production of antibodies that are cross-reactive with host molecules [6]. The molecular mimicry between components of infectious bacteria and the host has been postulated as the mechanism underlying the onset and development of autoimmune diseases
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