The origin of anti-GM₁ antibodies in neuropathies: The "binding site drift" hypothesis

Elevated titers of serum antibodies against GM₁-ganglioside are associated with a variety of autoimmune neuropathies. The origin of these autoantibodies is still unknown, although there is evidence that they are produced by CD5⁺ B-lymphocytes and that antigen mimicry is involved. Anti-GM₁ IgM-antibodies in the normal human immunological repertoire are low affinity antibodies that cross-react with other glycoconjugates carrying Galβ1-3GalNAc and probably do not have GM₁-mediated biological activity. Other anti-GM₁ IgM-antibodies with higher affinity and/or different fine specificity are present in patients with motor syndromes. Based on our studies of structural requirement for binding, we hypothesize that disease-associated anti-GM₁ antibodies originate at random by mutations affecting the binding site of naturally-occurring ones. The hypothesis is conceptually similar to the established phenomenon of "genetic drift" in species evolutionary biology and is therefore termed "binding site drift".