We have shown that IgG from patients with AAG have inhibitory effects on the function of ganglionic AChRs in vitro. This IgG-mediated inhibition of AChR current did not require complement or any other immune mediators. Our studies provide some clues into the mechanism of action of the antibody effect. Ganglionic AChR IgG reduced the magnitude of the current but did not affect the whole-cell current desensitization time constant. The main effect was gradual in onset, was abolished at low temperature, and could not be readily reversed by removing antibody from the bath solution. These features suggest that the predominant action of IgG on the AChR is not due to interference with agonist binding or ion permeation but consistent with antigenic modulation (antibody-mediated internalization and depletion of cell surface AChR) as has been described for muscle AChR antibodies in myasthenia gravis. In previous MG studies, IgG-mediated blocking occurs rapidly (within 60 seconds) and is readily reversible.12
Antigenic modulation, on the other hand, develops more slowly. Although it is often studied after prolonged (overnight) exposure to IgG, our study and others indicate that considerable AChR modulation in vitro takes place within minutes.11
Other mechanisms of IgG-mediated inhibition may also contribute. In one case (Patient 6), IgG produced an immediate reduction in ganglionic AChR current as well as more gradual modulation. Fab fragments from this patient's IgG produced the immediate but not the gradual inhibition of current. In this case, binding of IgG (or Fab) to the receptor likely either interferes with agonist binding or allosterically modifies channel kinetics. This patient's serum did not block epibatidine binding to solubilized ganglionic AChR. Similarly, previous studies have shown that IgG from MG patients can rapidly block muscle AChR currents even when the IgG shows no binding or blocking of solubilized AChR.12
Either there are mechanisms of rapid antibody-mediated receptor inhibition that do not involve blocking of agonist or the immunoprecipitation blocking assay lacks the sensitivity to detect lower levels of blocking antibodies.
Antibodies from patients with MG inhibit the function of the muscle AChR by blocking and antigenic modulation.13
We have now shown that IgG from patients with AAG has similar effects on the ganglionic AChR. This effect on ganglionic AChR would be expected to produce a potent impairment in ganglionic cholinergic fast synaptic transmission. Indeed, we have observed that autonomic deficits in animal models of AAG are associated with impaired ganglionic neurotransmission.6,7
It remains to be seen whether long-term exposure to these antibodies has other effects on neurons or if chronic inhibition of synaptic transmission leads to irreversible changes in autonomic function. Our findings further confirm that AAG is an antibody-mediated neurologic disorder. As pathophysiologic effects are mediated by IgG, therapies that reduce levels of pathogenic antibodies, including plasma exchange, are rational treatment for AAG patients with serum ganglionic AChR antibodies.4