Localization of major gangliosides in the PNS: Implications for immune neuropathies

Antibodies targeting major gangliosides that are broadly distributed in the nervous system are sometimes associated with clinical symptoms that imply selective nerve damage. For example, anti-GD1a anti-bodies are associated with acute motor axonal neuropathy (AMAN), a form of Guillain-Barré syndrome that selectively affects motor nerves, despite reports that GD1a is present in human axons and myelin and is not expressed differentially in motor versus sensory roots. We used a series of high-affinity monoclonal antibodies (mAbs) against the major nervous system gangliosides GM1, GD1a, GD1b and GT1b to test whether any of them bind motor or sensory fibres differentially in rodent and human peripheral nerves. The following observations were made. (i) Some of the anti-GD1a antibodies preferentially stained motor fibres, supporting the association of human anti-GD1a antibodies with predominant motor neuropathies such as AMAN. (ii) A GD1b antibody preferentially stained the large dorsal root ganglion (DRG) neurones, in keeping with the proposed role of human anti-GD1b antibodies in sensory ataxic neuropathies. (iii) Two mAbs with broad structural cross-reactivity bound to both gangliosides and peripheral nerve proteins. (iv) Myelin was poorly stained; all clones stained axons nearly exclusively. Our findings suggest that anti-ganglioside antibody fine specificity as well as differences in ganglioside accessibility in axons and myelin influence the selectivity of injury to different fibre systems and cell types in human autoimmune neuropathies.