Elevated titers of serum antibodies against GM1-ganglioside have been associated to a variety of autoimmune neuropathies. Although there is cumulative evidence that the antibodies have a primary rol in the disease, it is not known the mechanism why they appear. Low affinity (binding labile to 1 M KSCN) anti-GM1 antibodies of the IgM isotype are part of the normal human repertoire of antibodies. In contrast, in neuropathy patients we found that in addition to the normal anti-GM1 antibodies, the plasma contains IgM-antibodies that recognize GM1 with higher affinity. By using HPTLC-immunostaining of GM1 and related glycolipids, soluble antigen binding inhibition and GM1 affinity columns we studied the fine specificity of both, normal and disease associated antibodies. Normal anti-GM1 antibodies cross-react with GA1 and GD1b. In the patients, different populations of antibodies, defined by their affinity and cross-reactivity, were detected. Although one population is frequently found (high affinity, not cross-reacting with GA1 and GD1b) is a remarkable fact that there are only few plasmas with the same set of populations. The results could indicate that the apparition of the new populations of antibodies is a random process as somatic mutation of previously existing antibodies and is consistent with the idea that disease associated antibodies could be originated from normal antibodies. This idea is supported by results obtained when the different antibody populations are analyzed in relation to the tridimensional structure of GM1. A small area of GM1 (the terminal Galß1-3GalNAc) is involved in the binding of normal anti-GM1 antibodies. In contrast patient antibodies recognize higher areas involving additional regions of the GM1 molecule as the NeuNAc residue