This area of investigation began with the demonstration of monoclonal anti-MAG antibodies in patients with mixed sensory-motor polyneuropathies occurring in association with IgM gammopathy (paraproteinemia). It was subsequently demonstrated that these anti-MAG antibodies were all directed toward carbohydrate epitopes in MAG and cross-reacted with other glycoproteins of PNS myelin, including P0 and PMP-22, as well as with the sphingoglycolipid, sulfate-3-glucuronyl paragloboside (SGPG). Monoclonal antibodies that are MAG/SGPG-negative in patients with gammopathy and neuropathy frequently react with ganglioside antigens in nerve. In the current year, we have demonstrated that a patient with a monoclonal IgA lambda antibody and neuropathy is more complex than originally thought. Although, the patient has reactivity to LM1 ganglioside that is restricted to the IgA class, the reactivity is present in both IgA lambda and kappa light chains suggesting that it is polyclonal. Furthermore, the patient also has IgM reactivity of the MAG/SGPG type. Little is known about the molecular mechanisms by which antibodies to acidic glycolipids (SGPG or gangliosides) in patients with demyelinating neuropathy exert their pathogenic effects. In order to elucidate the functions of acidic glycolipids in Schwann cell differentiation and myelination, as well as to understand the mechanisms by which the human antiglycolipid antibodies may perturb function, we are investigating gangliosides in cultured Schwann cells. We have extended our previous results showing that culturing primary Schwann cells on a basement membrane substratum (Matrigel) resulted in greater synthesis of gangliosides (primarily GM3) and complex neutral sphingoglycolipids in association with increased cellular proliferation. Purified laminin and collagen type IV have effects comparable to matrigel, suggesting that these components may be the ones signaling the Schwann cell response. Furthermore, PDMP, an inhibitor of UDPglucose:ceramide glucosyl transferase, inhibited both the basement membrane-induced proliferation of Schwann cells and the synthesis of glycolipids, suggesting that this synthesis may be functionally involved in the proliferative response. Finally, an investigation of the effects Brefeldin A on glycolipids synthesis in an immortalized Schwann cell line suggests that the synthesis of sulfatide and hydroxy fatty acid-containing galactosylceramide occurs in the late Golgi, and that there may be different pathways for the synthesis galactosylceramides containing hydroxy and nonhydroxy fatty acids, respectively.
