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 associated with a variety of autoimmune neuropathies. Although much evidence indicates that these autoantibodies play a primary role in the disease processes, the mechanism of their appearance is unclear. Low-affinity anti-GM(1) antibodies of the IgM isotype are part of the normal human immunological repertoire. In patients with motor syndromes, we found that in addition to the usual 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 fine specificity of both normal and motor disease-associated antibodies using HPTLC-immunostaining of GM(1) and structurally related glycolipids, soluble antigen binding inhibition, and GM(1) affinity columns. Normal low-affinity anti-GM(1) antibodies cross-react with GA(1) and/or GD(1b). In the motor syndrome patients, different populations of antibodies characterized by their 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 results suggest that the appearance of the new antibody populations is a random process. When the different antibody populations were analyzed in relation to the three-dimensional structure of GM(1), a restricted area of the GM(1) oligosaccharide (the terminal Galbeta1-3GalNAc) was found to be involved in binding of normal anti-GM(1) antibodies. Patient antibodies recognize slightly different areas, including additional regions of the GM(1) molecule such as the NeuNAc residue. We hypothesize that disease-associated antibodies may originate by spontaneous mutation of normal occurring antibodies.
Lopez
P H
PH
Departamento de Química Biológica "Dr. Ranwel Caputto"-CIQUIBIC, CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, 5000, Córdoba, Argentina.
Lardone
R D
RD
Irazoqui
F J
FJ
Villa
A M
AM
Di Egidio
M
M
Saizar
R D
RD
Sica
R E
RE
Nores
G A
GA
D000906:Antibodies / Q000032:analysis* / Q000276:immunology; D001212:Asialoglycoproteins / Q000276:immunology; D001667:Binding, Competitive; D003429:Cross Reactions; D005677:G(M1) Ganglioside / Q000276:immunology*; D005732:Gangliosides / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000032:analysis* / Q000276:immunology; D009069:Movement Disorders / Q000276:immunology*; D012016:Reference Values
D000906:Antibodies; D001212:Asialoglycoproteins; D005732:Gangliosides; D007075:Immunoglobulin M; C033851:ganglioside, GD1b; D005677:G(M1) Ganglioside