Acetylcholine receptor (AChR) binding and AChR modulating
antibodies were found with approximately the same frequency (86%) in 349 patients with
myasthenia gravis (MG). However, the total yield of positive serological results was significantly improved (90%) by assaying AChR modulating
antibodies when AChR binding
antibodies were not detected, because in 27 patients (8%) only one of the two tests was positive. The immunoprecipitation test for AChR
blocking antibodies yielded fewer positive results (52%), but there was a significant correlation between the degree of AChR blockade and generalization of
muscle weakness. In no patient was this the only positive test, because the test for AChR modulating
antibodies in this study detected both AChR blocking and modulating
antibodies. Human muscle AChR was used as
antigen in all tests. False positive results were rare and were attributed to unexplained
antibodies to 125I-alpha-Bgt (AChR binding antibody assay) and recent
general anesthesia using muscle relaxants (AChR blocking and AChR modulating antibody assays). Unexplained positive results, documented previously in 5% of patients with the
Lambert-Eaton myasthenic syndrome and
amyotrophic lateral sclerosis (ALS), were found in this study in two of 22 patients with ALS, but in none of 427 patients with miscellaneous neurological diseases. Patients with severe generalized MG and/or
thymoma tended to have higher titers of AChR binding
antibodies and greater AChR modulating antibody activity. However, some patients with severe
muscle weakness had low titers of
antibodies, and some patients in remission or with only ocular manifestations had high titers. These seemingly paradoxical results reflect heterogeneity in the specificities, affinities, and isotypes of anti-AChR
antibodies. To effect pathogenicity,
antibodies must have access in vivo to extracellular antigenic sites on the AChR. One would anticipate that
antibodies with greatest pathophysiological potential would be of an
IgG with greatest pathophysiological potential would be of an
IgG subclass that activates
complement, or of a specificity that competes for
acetylcholine's binding site on the receptor or readily cross-links two AChR molecules to trigger receptor modulation (e.g., by binding to sites on the duplicated alpha-subunit). In patients with suspected MG who lack serological evidence of anti-AChR
antibodies, motor endplate biopsy is required for microelectrophysiological, immunochemical, and ultrastructural studies to establish with certainty whether or not the condition is acquired MG.