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Myasthenia gravis (MG) is the most common disorder affecting the neuromuscular junction (NMJ) of the skeletal musclesIt usually involves muscles of the eyes, throat, and extremities. The reduced transmission of electrical impulses across the neuromuscular junction due to the formation of autoantibodies against the specific postsynaptic membrane proteins consequently causes muscle weakness. A wide variety of conditions can precipitate MG, such as infections, immunization, surgeries, and drugs. Myasthenia gravis causes a significant number of complications. These include myasthenic crisis, an acute respiratory paralysis that requires intensive care, as well as adverse events due to long term medication treatment like opportunistic infections and lymphoproliferative malignancies.Pathophysiology
The pathophysiologic mechanisms in MG are dependent on the type of antibodies present.
In n-AChR MG, the antibodies are of the IgG1 and IgG3 subtype. They bind to the n-ACh receptor present in the postsynaptic membrane of the skeletal muscles and activate the complement system leading to the formation of the membrane attack complex (MAC). MAC brings about the final degradation of the receptors. They may also act by functionally blocking the binding of ACh to its receptor or by enhancing the endocytosis of the antibody-bound n-ACh receptor.
In MusK MG and LPR4 MG, the antibodies are of the IgG4 subtype and do not have the complement activating property. They bind to the Agrin–LRP4–MuSK protein complex in the NMJ, whose primary function is the maintenance of the NMJ, including the n-ACh receptor distribution and clustering. The inhibition of the complex leads to a reduced number of n-ACh receptors.[6][7] The ACh released at the nerve terminal, in turn, is unable to generate the postsynaptic potential required to generate an action potential in muscle due to a reduced number of n-ACh receptors leading to the symptoms of muscle weakness. The weakness is more pronounced with the repeated use of a muscle group since it causes depletion of the ACh store in the NMJ.Histopathology
The histopathological findings in MG differ by the type of antibodies present.
Muscle: In n-AChR MG, the muscles show significant atrophic changes, whereas, in MuSK MG, there are minimal muscle atrophic changes and significant mitochondrial abnormalities (giant, swollen, and degenerative features). The differences suggest different pathophysiologic mechanisms of the two subtypes of MG. Neurogenic atrophy seems to be prominent in n-AchR MG, whereas mitochondrial abnormalities in MuSK MG.[8]
Thymus: In n-AChR MG, thymus shows epithelial hyperplasia and extra-parenchymal involvement with T-cell areas and germinal centers (GCs).In MuSK MG, the thymus shows age-related changes, and hyperplastic changes are very uncommon. In seronegative MG, infiltrates can be seen in half of the patients.[9] These findings of thymic epithelial hyperplasia and T-cell infiltrate suggest thymus is involved in the production of autoantibodies against the muscle proteins.