Variable patterns of anti-GM(1) IgM-antibody populations defined by affinity and fine specificity in patients with motor syndromes: evidence for their random origin

Elevated titers of serum antibodies against GM(1)-ganglioside are associate d with a variety of autoimmune neuropathies. Although much evidence indicat es that these autoantibodies play a primary role in the disease processes, the mechanism of their appearance is unclear. Low-affinity anti-GM(1) antib odies of the I-M isotype are part of the normal human immunological reperto ire. In patients with motor syndromes, we found that in addition to the usu al anti-GM(1) antibodies. the sera contain IgM-antibodies that recognize GM (1) with higher affinity and/or different specificity. This latter type of antibodies was not detected in other autoimmune diseases. We studied the fi ne specificity of both normal and motor disease-associated antibodies using HPTLC-immunostaining of GM(1) and structurally related glycolipids, solubl e antigen binding inhibition, and GM(1) affinity columns. Normal low-affini ty anti-GM(1) antibodies cross-react with GA(1) and/or GD(1b). In the motor syndrome patients, different populations of antibodies characterized by th eir affinity and cross-reactivity were detected. Although one population is relatively common (low affinity, not cross-reacting with GA(1) and GD(1b)) , there are remarkably few sera having the same set of populations. These r esults suggest that the appearance of the new antibody populations is a ran dom process, When the different antibody populations were analyzed in relat ion to the three-dimensional structure of GM(1), a restricted area of the G M(1) oligosaccharide (the terminal Gal beta1-3GalNAc) was found to be invol ved in binding of normal anti-GM(1) antibodies. Patient antibodies recogniz e slightly different areas, including additional regions of the GM(1) molec ule such as the NeuNAc residue. We hypothesize that disease-associated anti bodies may originate by spontaneous mutation of normal occurring antibodies . (C) 2001 Elsevier Science B.V. All rights reserved.