Guillain-Barré syndrome: expanding the concept of molecular mimicry

Abstract

Guillain-Barré syndrome (GBS) is a rapidly progressive, monophasic, and potentially devastating immune-mediated neuropathy in humans. Preceding infections trigger the production of cross-reactive antibodies against gangliosides concentrated in human peripheral nerves. GBS is elicited by at least five distinct common bacterial and viral pathogens, speaking to the notion of polymicrobial disease causation. This opinion emphasizes that GBS is the best-supported example of true molecular mimicry at the B cell level. Moreover, we argue that mechanistically, single and multiplexed microbial carbohydrate epitopes induce IgM, IgA, and IgG subclasses in ways that challenge the classic concept of thymus-dependent (TD) versus thymus-independent (TI) antibody responses in GBS. Finally, we discuss how GBS can be exemplary for driving innovation in diagnostics and immunotherapy for other antibody-driven neurological diseases.

Key Figure, Figure 1.. Overview of the pathogenesis of Guillain-Barré syndrome (GBS)

GBS is an acute immune-mediated peripheral neuropathy usually triggered by a preceding infection, the predominant type being Campylobacter jejuni (~30%). Antibodies raised against C. jejuni lipo-oligosaccharide (LOS) during infection via carbohydrate mimicry may cross-react with various human nerve gangliosides, including GM1a. The specificity of the anti-ganglioside antibodies is associated with the type of clinical GBS variant, reflecting the distribution of the targeted gangliosides in peripheral nerves. GBS is caused by axonal degeneration and/or demyelination of the nerves. Antibody depositions are found in axonal GBS at the nerve axons, especially the nodes of Ranvier, and in demyelinating GBS, at the myelin sheaths. Serum antibodies are usually IgG1 of IgG3 (less frequently IgM or IgA) and the highest titers are found in patients upon hospital admission. Binding of these antibodies results in local deposition of complement factors (including C1q, C3b) and formation of membrane attack complex (MAC). Macrophages infiltrate the nerve at the site of damage and additional T cells may be found in nerves. GBS is a monophasic disorder reflecting transient immune-mediated damage; most patients begin to clinically improve with the disappearance of anti-ganglioside antibodies. Subsequent nerve regeneration is a slow process and is often incomplete, explaining the high proportion of patients with residual disability or complaints.

Figure 2.. Distinct symptom patterns of GBS variants that have been associated with elicited antibodies

The gangliosides indicated below the clinical variants represent the predominant targets of the antibodies found in the serum of these GBS patients. Antibodies against GM1 and GD1a are associated with the pure motor form of GBS, but also occur in other clinical variants, such as the paraparetic form in which only lower limbs are affected. The pharyngeal-cervical-brachial variant (affecting upper limbs), Miller Fisher syndrome and Bickerstaff brainstem encephalitis are associated with antibodies against GQ1b and GT1a. The figure is modified from [83].

Figure 3.. Molecular mimicry of LOS and gangliosides in GBS caused by Campylobacter jejuni

The upper part of the figure shows the oligosaccharide moiety of GM1a. The lipo-oligosaccharide (LOS) of C. jejuni mimics this structure. The terminal parts of the molecules are shared (common component) whereas LOS also contains a different component representing the inner core. The host ganglio-oligosaccharide has a glucose residue whereas the bacterial LOS has a heptose moiety at the same position. Furthermore, the heptose of LOS is linked to an inner core saccharide composed of additional heptose and ketodeoxyoctonic acid (KDO) moieties [25, 46].

Figure 4.. Chemoenzymatic diagnostics for monomeric and heteromeric-multiplexed antigens

Novel combinatorial diagnostics based on immunofluorescence detection are being developed to finely discriminate antibodies cross-reacting between host structures and pathogen mimetics. Panel a and b show examples of various oligosaccharides that have been synthesized [50]. Panel c shows examples of probed oligosaccharide arrays with a monoclonal antibody against GD1a, and the sera of two GBS patients (S005 and S010). Bound antibodies were visualized using fluorescently-conjugated anti-human IgG secondary antibodies and fluorescence intensities were quantified using a microarray scanner [50]. The numbers on the x-axis correspond to the structures displayed in a and b. These diagnostic systems can also be used to identify antibodies directed against epitopes being formed by heteromeric-multiplexed gangliosides. The figure is modified from [50].