Myasthenia gravis: what's going on?
Last reviewed: 23.04.2024
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Myasthenia gravis pathogenesis
Myasthenia gravis is a classic example of an autoimmune disease mediated by autoantibodies and dependent on the function of T cells. The main physiological and morphological changes in myasthenia gravis are localized in the neuromuscular junction and primarily depend on antibodies to acetylcholinesterase, which reduce the number of acetylcholinesterase on the muscular postsynaptic membrane. According to immunoelectron microscopy, with myasthenia, IgG and complement are deposited in the neuromuscular junction.
In muscle extracts with myasthenia, IgG are found in combination with acetylcholinesterase. At the same time, the number of acetylcholinesterase decreases, the architectonics of the postsynaptic membrane significantly simplifies and the ability of the membrane to build new AXRs decreases. These changes can be caused either by conformation changes (internalization) and by degradation of receptors, by the action of antibodies (antigenic modulation), or by damage to the structure of the postsynaptic membrane under the influence of antibodies and complement. The obtained data show that the cause of the neuromuscular transmission can be both processes. With myasthenia in the neuromuscular junction, a membrane-attack complement complex is found, with vesicles containing the membrane-attack complex located in the enlarged synaptic cleft. As a result of this permanent process, the number of acetylcholinesterase decreases and the structure of the neuromuscular junction is degraded. Decrease in the number of acetylcholinesterase can also be associated with the formation of cross-linking between acetylcholinesterase under the influence of antibodies, followed by their internalization and degradation. Thus, the cause of neuromuscular transmission disorders in myasthenia gravis can be a combination of antigenic modulation and complement mediated damage. The possibility of passive transfer of myasthenia from human to mice demonstrates the important role of humoral mechanisms in the pathogenesis of myasthenia, showing that antibodies alone can disrupt the functioning of the neuromuscular junction.
The factors that trigger the production of antibodies to AXR remain unknown. The identification of common epitopes in human acetylcholinesterase and a number of bacterial and viral antigens testifies to the possible role of molecular mimicry. However, myasthenia gravis detected polyclonal antibodies, and attempts to isolate the virus or to reveal the specificity of antibodies in relation to certain bacterial antigens were unsuccessful. Thus, the assumption of molecular mimicry with a single epitope is not able to explain the features of the immunological changes in myasthenia gravis. It is known that the production of antibodies to ACh requires the presence of both CD4 + lymphocytes (T-helpers) and B-lymphocytes. The experimental models of myasthenia gravis indicate that the pathological immune process is initiated by the presentation of acetylcholinesterase to T lymphocytes. There is no doubt that involvement of the thymus in the pathogenesis of myasthenia gravis. In 70% of patients with myasthenia, thymic hyperplasia with germinal centers in the gland is found, and in 15% at the time of diagnosis or later thymoma is detected. Thus, it can be assumed that the first processes leading to the development of myasthenia gravis occur in the altered thymus microenvironment. However, further studies are needed to determine how the acetylcholinesterase antigens are in the thymus (perhaps, thymus myoid cells serve as their source), and also how the thymus promotes the interaction of T and B cells, leading to the production of antibodies to AXR. Myasthenia has not been detected of one single dominant epitope of ACh, against which an immune response is triggered, as well as the corresponding type of T cells. This fact, as well as the ability of AChT epitopes to stimulate T cells, both in norm and in myasthenia gravis, indicate the possible role of an immunosuppression defect in the initiation of immunopathological processes in myasthenia gravis.
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