IMMUNE MECHANISMS IN THE INDUCTION OF MURINE MYASTHENIA

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Myasthenia gravis(MG) and its experimental models have become important diseases for the study of autoimmunity because the autoantigen, the nicotinic acetylcholine receptor(AChR), is a purified and well-characterized protein. This proposal addresses the problems of induction and propagation of autoimmunity in myasthenia; very little is known now about these topics in MG or any other autoimmune disease. There are two major thrusts, each dealing with a concept--the idiotype network and immunoregulation--central to the understanding of autoimmunity. The first deals with the initiation of anti-AChR autoimmunity and a unique, myasthenia-like disease in mice and rabbits via "internal images" within the idiotype network. Our use of monoclonal antibodies directed against AChR ligands, as well as synthetic peptides of the AChR-binding portion of snake toxins and rabies virus, will considerably facilitate extension of our preliminary work. The second thrust is the elucidation of the mechanisms by which immunoregulatory mechanisms are bypassed and clinical weakness propagated in the mouse model of myasthenia. Our preliminary work has shown that the disease we have induced using the anti-neurotoxin antiboides, network-induced myasthenic syndrome (NIMS), resembles experimental myasthenia in a number of ways: normal animals after immunization develop fatigable weakness reversed by Tensilon, anti-AChR antibodies appear, and electromyography using repetitive nerve stimulation reveals myasthenic features. Our generation of monoclonal antibodies directed against AChR ligands and their synthetic peptides will allow the use of a highly purified "internal image" as immunogens. As in our previous studies "internal image" -immunized animals will be analyzed clinically, serologically, electromyographically, and pharmacologically. This information will predict the nature of the "internal image" that is most likely to generate clinical disease, as well as providing information about the functional significance of various forms of "internal image". Finally, sera from patients with myasthenia gravis and Lambert-Eaton syndrome will be tested for their ability to interact with the various "internal images" of AChR. We have found that in both NIMS and murine experimental myasthenia (EAMG) only a minority of immunized mice manifest clinical weakness despite evidence for subclinical disease in all mice. Although the current dogma is that the reason for this is that mice have a high "safety factor" of neuromuscular transmission, we feel that the lack of clinical weakness may be due to highly efficient immunoregulation in these animals that may diminish the strength, i.e. pathogenicity, of the autoimmune response. We plan to investigate this question by interfering with immune suppression using irradiation, cyclophosphamide, contrasuppression, monoclonal antibodies against suppressor cells and their factors, mouse strains having putative suppressor cell defects, and estrogen. We will also assess by transfer experiments whether depletion of suppresor cells or amplification of the helper T cell population will increase the frequency and severity of disease.