Myasthenia gravis - What's going on?

Pathogenesis of myasthenia gravis

Myasthenia is a classic example of an autoimmune disease mediated by autoantibodies and dependent on T-cell function. The main physiological and morphological changes in myasthenia are localized in the neuromuscular junction and primarily depend on antibodies to acetylcholinesterase, which reduce the amount of acetylcholinesterase on the muscle postsynaptic membrane. According to immunoelectron microscopy, IgG and complement are deposited in the neuromuscular junction in myasthenia.

In muscle extracts in myasthenia, IgG is found in a complex with acetylcholinesterase. In this case, the amount of acetylcholinesterase decreases, the architecture of the postsynaptic membrane is significantly simplified and the ability of the membrane to incorporate new AChRs decreases. These changes can be caused either by a change in conformation (internalization) and degradation of receptors under the influence of antibodies (antigenic modulation) or by damage to the structure of the postsynaptic membrane under the influence of antibodies and complement. The data obtained show that both processes can cause the disorder of neuromuscular transmission. In myasthenia, a membrane attack complex of complement is found in the area of the neuromuscular junction, and vesicles containing the membrane attack complex are located in the expanded synaptic cleft. As a result of this permanent process, the amount of acetylcholinesterase decreases and the structure of the neuromuscular junction area degrades. The decrease in acetylcholinesterase may also be due to the formation of cross-links between acetylcholinesterase under the influence of antibodies, followed by their internalization and degradation. Thus, the cause of the disturbance of neuromuscular transmission in myasthenia may be a combination of antigen modulation and damage mediated by complement. The possibility of passive transfer of myasthenia from humans to mice indicates the important role of humoral mechanisms in the pathogenesis of myasthenia, showing that antibodies themselves can disrupt the functioning of the neuromuscular junction.

Factors triggering the production of antibodies to AChR remain unknown. The detection of common epitopes in human acetylcholinesterase and a number of bacterial and viral antigens suggests a possible role of molecular mimicry. However, polyclonal antibodies are detected in myasthenia, and attempts to isolate the virus or identify the specificity of antibodies to certain bacterial antigens have been unsuccessful. Thus, the assumption of molecular mimicry with a single epitope cannot explain the features of immunological changes in myasthenia. It is known that the production of antibodies to AChR requires the presence of both CD4+ lymphocytes (T-helpers) and B-lymphocytes. Experimental models of myasthenia indicate that the pathological immune process is initiated by the presentation of acetylcholinesterase to T-lymphocytes. There is no doubt that the thymus is involved in the pathogenesis of myasthenia. In 70% of patients with myasthenia, thymus hyperplasia with the presence of germinal centers in the gland is detected, and in 15%, thymoma is detected at the time of diagnosis or later. Thus, it can be assumed that the first processes leading to the development of myasthenia occur in the altered microenvironment of the thymus. However, additional studies are needed to determine how acetylcholinesterase antigens end up in the thymus (possibly, their source is the myoid cells of the thymus), and how the thymus promotes the interaction of T and B cells, leading to the production of antibodies to AChR. In myasthenia, no single dominant AChR epitope against which the immune reaction is triggered has been identified, nor has the corresponding type of T cell. This fact, as well as the ability of AChR epitopes to stimulate T cells, both in normal conditions and in myasthenia, indicate a possible role for the immunosuppression defect in the initiation of immunopathological processes in myasthenia.

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