Lewis rats immunized with GM1 ganglioside do not develop peripheral neuropathy

Abstract

Elevated levels of anti-GM1 antibodies are associated with motor nerve syndromes. Although there is a lot of circumstantial evidence that anti-GM1 antibodies may be causing the disease, their precise role remains unclear. In order to study the role of anti-GM1 antibodies in the pathogenesis of peripheral neuropathy, eight Lewis rats were injected with GM1 ganglioside mixed with keyhole limpet hemocyanin (KLH) and emulsified with Freund's adjuvant and three rats were immunized with GM1 in liposomes. Although IgM class anti-GM1 antibodies were detected in all animals immunized with GM1, none of the animals exhibited overt signs of neuropathy during 6 months after initial immunization. IgG antibody to GM1 was not produced in any of the animals. There was no pathological evidence of nerve damage. These studies suggest that elevated levels of IgM anti-GM1 antibodies by themselves do not cause nerve damage in rats.

Introduction

Elevated levels of autoantibodies to glycolipids including gangliosides are frequently found in peripheral neuropathies (Ilyas et al., 1984, Ilyas et al., 1988b, Ilyas., in press, Latov, 1995, Quarles and Weiss, 1999, Willison and Yuki, 2002). Monosialoganglioside GM1 is a major glycosphingolipid of both the central and peripheral nervous system. Elevated levels of anti-GM1 antibodies are often associated with motor nerve syndromes. IgG anti-GM1 antibodies are associated with acute motor neuropathy syndromes including acute motor axonal neuropathy variant of the Guillain–Barre´ syndrome (GBS) (Ilyas et al., 1992b, Ilyas et al., 2001, Nobile-Orazio et al., 1992, van den Berg et al., 1992, Kornberg et al., 1994) and monoclonal or polyclonal IgM anti-GM1 antibodies are associated with chronic motor neuropathy syndromes (Freddo et al., 1986, Ilyas et al., 1988a, Pestronk et al., 1988, Pestronk et al., 1990, Baba et al., 1989, Kinsella et al., 1994, Taylor et al., 1996).

The close association of anti-GM1 antibodies with motor neuropathy syndromes lends strong support to the notion that anti-GM1 antibodies play a crucial role in the pathogenesis of neuropathy. This notion is supported by the induction of neuropathy in Japanese white rabbits by immunization with GM1 (Yuki et al., 2001). However, the role of anti-GM1 antibodies in the pathogenesis of neuropathy is questioned because passive transfer studies fail to transfer the disease (Hadden et al., 2001, Sheikh et al., 2004, Yuki et al., 2004) and other studies failed to induce neuropathy by active immunization of rabbits with purified GM1 (Lopez et al., 2002; Dasgupta et al., 2004). In this study, we immunize Lewis rats with purified GM1 ganglioside. Our data show that although IgM anti-GM1 antibodies were induced in all rats immunized with GM1, none of the animals with elevated IgM anti-GM1 antibodies exhibited overt neurological signs of neuropathy and/or neuropathological changes in peripheral nerves.