We studied a patient with an IgM M-protein and lower motor neuron disease to identify the antigens to which the M-protein bound. Gangliosides from peripheral nerve and spinal cord were separated by high-performance thin-layer chromatography and immunostained with the patient's serum. The serum IgM immunostained two gangliosides identified as GM1 and GD1b, and immunostaining was specific for the M-protein light chain type. IgM-binding to the two gangliosides was detectable by ELISA at serum dilutions of greater than 1:10,000, and the M-protein was selectively immunoabsorbed by liposomes containing GM1 or GD1b. The IgM M-protein also bound to asialo-GM1, indicating reactivity to the galactosyl(beta 1-3)N-acetylgalactosaminyl moiety shared by GM1, GD1b, and asialo-GM1.

Some patients with neuropathy have IgM M-proteins that bind to myelin and to myelin-associated glycoprotein (MAG). We compared the binding properties of a human anti-MAG M-protein with three mouse monoclonal anti-MAG antibodies (GEN-S1, GEN-S3, GEN-S8) and with a mouse monoclonal antibody (HNK-1) that binds to both MAG and to human natural killer cells. The antibodies GEN-S1, GEN-S3, and GEN-S8 bound to different epitopes in the polypeptide portion of MAG as shown by peptide mapping, deglycosylation and competitive binding studies. The M-protein and HNK-1 bound to both CNS and PNS MAG and to several additional protein bands of 70K, 30K, 26K, and 23K daltons in peripheral, but not in central myelin; they did not bind to deglycosylated MAG. The M-protein and HNK-1 immunostained myelin diffusely, whereas GEN-S8 immunostained only the periaxonal and outer regions of myelin sheath, and there was no staining with GEN-S1 or GEN-S3. The human M-proteins probably bind to a carbohydrate moiety in MAG that is also present in other PNS myelin proteins. This may explain the observed differences in immunostaining and the sparing of the CNS in patients with anti-MAG M-proteins.

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IgM lambda monoclonal antibodies in two patients with motor neuron disease showed the same unique antigenic specificity. They bound to gangliosides GM1 and GD1b and to lacto-N-tetraose-BSA. By immunofluorescence microscopy they bound to central and peripheral nerve tissue and to motor end-plates at the neuromuscular junction. Sera from control subjects did not contain antibodies of similar specificity. Monoclonal IgMs with the same unique specificity could be responsible for motor neuron disease in some patients with monoclonal gammopathies.

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