A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies

Abstract

Serum antibodies to different gangliosides have been identified in some Guillain-Barré (GBS) subtypes and variants. In the January issue of Experimental Neurology Susuki and colleagues (2012) showed that in experimental neuropathies associated with antibodies to GM1, GD1a and GD1b the common mechanism is a complement mediated dysfunction and disruption of the nodes of Ranvier which causes a pathophysiological continuum from early reversible conduction failure to axonal degeneration. These observations, correlated and integrated with electrophysiological and pathological findings in humans indicate that the GBS subtypes acute motor conduction block neuropathy, acute motor axonal neuropathy, acute motor and sensory neuropathy and acute sensory neuropathy and possibly also a chronic disorder as multifocal motor neuropathy represent a spectrum of the same immunopathologic process. Being the nodal axolemma and the paranode the focus of the nerve injury, these immune mediated neuropathies could be more properly classified as nodo-paranodopathies.

Introduction

Gangliosides, glycosphingolipids made of a ceramide attached to one or more sugars, are important components of the plasma membranes organized in clusters forming, together with cholesterol and glycosylphosphatidylinositol-anchored proteins, microdomains termed lipid rafts (Simons and Toomre, 2000). In the peripheral nervous system gangliosides are present in both axons and myelin, and biochemically there are no significant quantitative differences of the major gangliosides in human ventral and dorsal roots (reviewed in Ogawa-Goto and Abe, 1998). Gangliosides GM1, GD1a and GD1b are highly enriched at or near the nodes of Ranvier, a critical region for generation and propagation of action potentials, and contribute to stability of paranodal junctions and ion channel clusters (Kaida et al., 2009, Susuki et al., 2007a).

In the last two decades serum antibodies to different gangliosides have been identified in some Guillain-Barré (GBS) subtypes and variants. IgG autoantibodies to gangliosides GM1 and GD1a are associated with acute motor axonal neuropathy (AMAN), acute motor conduction block neuropathy (AMCBN) and acute motor-sensory axonal motor neuropathy (AMSAN) (Capasso et al., 2003, Ho et al., 1999, Lugaresi et al., 1997, Yuki et al., 1990, Yuki et al., 1993, Yuki et al., 1999). IgG anti-GQ1b antibodies are strongly associated with Fisher syndrome (Chiba et al., 1993), mono-specific IgG antibodies to GD1b are found in patients with ataxic GBS and acute ataxic neuropathy (ASAN) (Kaida et al., 2008, Kusunoki et al., 1996, Notturno et al., 2008; Pan et al., 2001), and patients with pharyngeal–cervical brachial weakness more often carry IgG anti-GT1a antibodies, which may cross-react with GQ1b, and less often IgG anti-GD1a antibodies (Nagashima et al., 2007).

Two issues trouble the topic of acute anti-ganglioside antibody-mediated neuropathies: 1) whether anti-ganglioside antibodies are associated with only axonal or also demyelinating GBS subtypes; 2) given the ubiquity of gangliosides how to explain the selective fiber injury caused by antibodies to specific gangliosides.

In the January issue of Experimental Neurology Susuki et al. (2012) furnished an important contribution to the solution of the first issue showing that in the animal models of AMAN with antibody to GM1 and ASAN with antibody to GD1b, the antibodies attack and disrupt the node of Ranvier via complement pathway. Regarding the second issue in the AMAN rabbit model with anti-GM1 antibodies sensory fibers occasionally showed complement deposition, nodal disruption and Wallerian like degeneration demonstrating that motor involvement is predominant but not exclusive.

These observations have important translational implications for the understanding of clinical and electrophysiological characteristics of GBS subtypes associated with antibodies to gangliosides. Following are some comments resulting from the correlation and integration of experimental and clinical data.