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Myasthenia gravis (MG) is an organ-specific autoimmune disease in which autoantibodies against nicotinic acetylcholine receptors (AChR) at the postsynaptic membrane cause loss of functional AChR and disturbed neuromuscular transmission. The immunopathogenic mechanisms responsible for loss of functional AChR include antigenic modulation by anti-AChR antibodies, complement-mediated focal lysis of the postsynaptic membrane, and direct interference with binding of acetylcholine to the AChR or with ion channel function. The loss of AChR and subsequent defective neuromuscular transmission is accompanied by increased expression of the different AChR subunit genes, suggesting a role for the target organ itself in determining susceptibility and severity of disease. Experimental autoimmune myasthenia gravis (EAMG) is an animal model for the disease MG, and is very suitable to study the immunopathogenic mechanisms leading to AChR loss and the response of the AChR to this attack. In this article the current concepts of the structure and function of the AChR and the immunopathological mechanisms in MG and EAMG are reviewed.

Myasthenia gravis (MG) is an organ-specific autoimmune disease caused by an antibody-mediated assault on the muscle nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. Binding of antibodies to the AChR leads to loss of functional AChRs and impairs the neuromuscular signal transmission, resulting in muscular weakness. Although a great deal of information on the immunopathological mechanisms involved in AChR destruction exists due to well-characterized animal models, it is not known which etiological factors determine the susceptibility for the disease. This review gives an overview of the literature on the AChR, MG and experimental models for this autoimmune disease.

The effect of target organ manipulation by means of denervation and treatment with anabolic steroids on the severity of disease in EAMG was assessed in inbred rats. Unilateral limb denervation, a procedure known to increase the AChR content of muscle, 'protected' the denervated leg against antibody-mediated AChr loss in acute EAMG induced by passive transfer of mAb 35 directed against the main immunogenic region. Also in chronic EAMG, brought about by immunizing rats with AChR in complete Freund's adjuvant, the AChR loss of the denervated leg was about one fourth (13.5 vs. 53%) of the control leg. In both acute and chronic EAMG the amount of AChR complexed with antibody was lower in the denervated leg. This lower AChR occupancy with antibody in the denervated leg occurred also in conditions of marked antibody excess and was therefore due to enhanced AChR synthesis. Next the effect of treatment with a weakly virilizing anabolic steroid nandrolone in chronic and acute EAMG was examined in order to examine whether a hypothesized enhanced synthesis of AChR would protect animals from disease. In the absence of an immunosuppressive effect, in terms of concentration of antibodies to AChR, nandrolone treatment protected the rats from severe disease in the chronic EAMG model as shown by the fact that of the 9 rats 6 showed mild (1+) disease and 3 no disease at all; conversely 6 out of 9 control rats showed severe (3+) disease. Rats treated with nandrolone showed a 48 +/- 1.7% loss of AChR compared to a loss of 58 +/- 3.6% in the control rats, suggesting enhanced AChR synthesis. When nandrolone-pretreated rats were given acute EAMG by passive transfer of mAb 35 a paradoxical effect was seen. In contrast to the controls all of the rats pretreated with nandrolone showed severe signs of EAMG; this was associated with a higher loss of AChR and increased consumption of complement C4 as suggested by decreased concentrations of C4 in the serum. Results show increased AChR synthesis to protect against chronic EAMG both in terms of clinical disease (nandrolone) as well as AChR loss (nandrolone, denervation). In addition it was shown that nandrolone increases serum C4 consumption which in the complement-dependent acute EAMG model causes enhancement of the severity of clinical disease and increased AChR loss.