Brain Advance Access originally published online on February 11, 2004
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Brain, Vol. 127, No. 3, 680-691, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh083
Synthetic disialylgalactose immunoadsorbents deplete anti-GQ1b antibodies from autoimmune neuropathy sera
1 Clinical Neurosciences Division, University of Glasgow Department of Neurology, Southern General Hospital, and 2 Department of Chemistry, University of Glasgow, Glasgow, Scotland, and 3 Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada
Correspondence to: Professor Hugh J. Willison, University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, G51 4TF, UKE-mail: h.j.willison{at}clinmed.gla.ac.uk
Acute and chronic autoimmune neuropathies, including Guillain-Barré syndromes (GBS) are often characterized by the presence of autoantibodies that react with neural gangliosides. Evidence from human and animal studies indicates that anti-ganglioside antibodies play a primary neuropathogenic role, and their rapid elimination from the circulation through specific immunoadsorption therapy thus has the potential to ameliorate the course of the disease. Here we have tested this therapeutic principle in the Miller Fisher variant of GBS that is associated serologically with acute phase anti-GQ1b ganglioside immunoglobulin G (IgG) antibodies, and in chronic ataxic neuropathies associated with persistently elevated immunoglobulin M (IgM) antibodies that react with GQ1b, GD3 and other disialylated gangliosides. Human and mouse anti-GQ1b IgG and IgM antibodies may also react with GD3, suggesting the shared terminal disialoside epitope could be involved in antibody binding. We thus synthesized the terminal trisaccharide, NeuAc(
2–8)NeuAc(2–3)Gal common to GQ1b and GD3, and conjugated it to bovine serum albumin (BSA). This disialylgalactose glycoconjugate (DSG-BSA) binds anti-GQ1b antibodies in 32/58 (55%) human sera containing IgG or IgM anti-GQ1b antibodies at titres up to 1/130 000; it also binds a wide range of mouse monoclonal anti-GQ1b and -GD3 antibodies. When conjugated to Sepharose as mock therapeutic immmunoaffinity columns, the immobilized trisaccharide (DSG-Sepharose) eliminates anti-GQ1b antibodies from positive sera in proportion to their level of binding to DSG-BSA. Oligosaccharide-specific immunoadsorption therapy thus provides a new therapeutic approach to anti-GQ1b antibody-associated syndromes that could be applied to clinical practice. Furthermore, modification of the immobilized oligosaccharide epitopes to incorporate other glycan structures may allow this approach to be adapted to other forms of autoimmune neuropathy associated with uniform anti-glycolipid antibody profiles.
Key Words: peripheral neuropathy; gangliosides; autoantibodies; immunoadsorption; therapy
Abbreviations: AMAN= acute motor axonal neuropathy; BSA = bovine serum albumin; DSG = disialylgalactose; DSL = disialyllactose; DS = disialic acid; ELISA = enzyme-linked immunoaborbent assay; GBS = Guillain-Barré syndrome; IgG = immunoglobulin G; IgM = immunoglobulin M; IVIg = intravenous immunoglobulin; MFS = Miller Fisher syndrome; mAb = monoclonal antibody; PBS = phosphate-buffered saline; OND = other neurological disease; TGM2 = terminal trisaccharide of GM2.
Received September 24, 2003. Revised November 11, 2003. Accepted November 13, 2003.
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