Induction of experimental ataxic sensory neuronopathy in cats by immunization with purified SGPG

Abstract

SummaryIgM paraproteins in about 50% of the patients with neuropathy associated with IgM gammopathy react with carbohydrate moieties in myelin associated glycoprotein (MAG) and in sulfated glucuronic glycolipids (SGGLs) in human peripheral nerves. However, the role of anti-MAG/SGGL antibodies in the pathogenesis of neuropathy remains unclear. In order to induce an animal model of neuropathy associated with anti-MAG/SGGL antibodies, cats were immunized with sulfoglucuronyl paragloboside (SGPG). All four cats immunized with SGPG developed clinical signs of sensory neuronopathy within 11 months after initial immunization, characterized by unsteadiness, falling, hind limb weakness and ataxia. In two cats the ataxia and hind limb paralysis were so severe that the animals had to be euthanized. Pathological examination revealed sensory ganglionitis with inflammatory infiltrates in the dorsal root ganglia. No overt signs of pathology were noted in the examined roots or nerves. High titer anti-SGPG/MAG antibodies were detected in all 4 cats immunized with SGPG but not in 3 control cats. Our data demonstrate that immunization of cats with SGPG induced anti-SGPG antibodies and sensory neuronopathy clinically resembling the sensory ataxia of patients with monoclonal IgM anti-MAG/SGPG antibodies. This study suggests that these anti-MAG/SGPG antibodies play a role in the pathogenesis of this neuropathy.

An Update on Monoclonal Gammopathy and Neuropathy

“…Animal studies also support a direct causal link between anti-MAG antibodies and neuropathy: injecting anti-MAG IgM induces complement-mediated demyelination and neuropathy [37,38], and reducing titers of anti-MAG IgM improves the neuropathy [39,40].…”

Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity

“…IgM anti-MAG antibodies, which are consistently detectable in these patients, are very likely pathogenic, since their adoptive transfer to susceptible host animals induces peripheral demyelination and symptoms resembling those observed in patients with anti-MAG neuropathy (6)(7)(8)(9). Thus, anti-MAG neuropathy stands out among other human autoimmune diseases due to the known identity of the target antigen and a clear disease association with IgM autoantibodies.…”

Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy

“…Several animal models for anti-MAG neuropathy have been reported and are based on passive transfer of patients' IgM antibodies into healthy experimental animals, including cats (11,48) and chickens (12), and, more recently, on active immunization of cats with SGPG leading to a sensory ataxic neuropathy (13). Although these animal models partly mimic characteristics of the human myelin and nerve pathology of anti-MAG neuropathy, rodents do not display a clear neuropathic phenotype after immunization with SGPG (49,50).…”

“…Animals. Immunization was performed based on the protocol of Ilyas et al (13). Groups of four to six male BALB/c wild-type mice at the age of 6-8 wk were injected s.c. at multiple sites on the lower back with a total of 100 μg of purified SGPG/SGLPG (in PBS) mixed with KLH (1.4 mg/mL final concentration) and emulsified with an equal volume of TiterMax Gold.…”

“…Strong evidence for the pathogenic role of anti-MAG antibodies is provided by the damage of peripheral nerve myelin observed in experimental animals after the passive transfer of patients' anti-MAG antibodies (11,12). Additionally, active immunization of cats with the HNK-1-containing glycolipid sulfoglucuronyl paragloboside (SGPG) induced autoantibodies against the HNK-1 epitope and caused an ataxic sensory neuropathy resembling the human disease (13).…”