Abstract
Autoantibodies are infrequently detected in the sera of patients with the demyelinating form of Guillain-Barré syndrome most commonly encountered in the Western world, despite abundant circumstantial evidence suggesting their existence. We hypothesised that antibody specificities reliant on the cis interactions of neighbouring membrane glycolipids could explain this discrepancy, and would not have been detected by traditional serological assays using highly purified preparations of single gangliosides. To assess the frequency of glycolipid complex antibodies in a Western European cohort of patients GBS we used a newly developed combinatorial glycoarray methodology to screen against large range of antigens (11 gangliosides, 8 other single glycolipids and 162 heterodimeric glycolipid complexes). Serum samples of 181 patients from a geographically defined, Western European cohort of GBS cases were analysed, along with 161 control sera. Serum IgG binding to single gangliosides was observed in 80.0% of axonal GBS cases, but in only 11.8% of cases with demyelinating electrophysiology. The inclusion of glycolipid complexes increased the positivity rate in demyelinating disease to 62.4%. There were 40 antigens with statistically significantly increased binding intensities in GBS as compared to healthy control sera. Of these, 7 complex antigens and 1 single ganglioside also produced statistically significantly increased binding intensities in GBS versus neurological disease controls. The detection of antibodies against specific complexes was associated with particular clinical features including disease severity, requirement for mechanical ventilation, and axonal electrophysiology. This study demonstrates that while antibodies against single gangliosides are often found in cases with axonal-type electrophysiology, antibodies against glycolipid complexes predominate in cases with demyelinating electrophysiology, providing a more robust serum biomarker than has ever been previously available for such cases. This work confirms the activation of the humoral immune system in the dysimmune disease process in GBS, and correlates patterns of antigen recognition with different clinical features.
Highlights
Current evidence suggests that Guillain-Barré syndrome (GBS) is caused in some cases by autoantibodies arising via microbial molecular mimicry [1,2,3,4]
Since screening serum samples for anti-ganglioside complexes (GSC) reactivity is confounded by technical constraints, we developed a combinatorial glycoarray whereby very small quantities of glycolipid are sprayed onto polyvinylidene difluoride (PVDF) membranes and probed with serum [17], allowing us to screen a large cohort of sera from GBS patients against a large number of single and complex glycolipid antigens
The combinatorial glycoarray technique has substantially increased the number of glycolipid antibody specificities significantly associated with GBS
Summary
Current evidence suggests that Guillain-Barré syndrome (GBS) is caused in some cases by autoantibodies arising via microbial molecular mimicry [1,2,3,4]. GSC antibodies react with mixtures of two different gangliosides, whilst failing to recognise either component ganglioside alone, [12,13]. This concept builds on the long standing hypotheses of a lectin-binding “clustered saccharide patch” [14]. Following on from these serological studies, the pathological importance of GM1-complex antibodies [15,16] and the modulatory effects of GSCs on other lectin-carbohydrate interactions [17,18] have both been demonstrated. Biophysical studies show that cis (i.e. side-to-side) interactions between neighbouring glycolipids in artificial and living membranes do occur [19,20], the term ‘glycolipid complex’ is here used to denote the mixture of two different glycolipids applied to a membrane
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