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Myasthenia Gravis and Its Immunologic Basis


Myasthenia gravis is an autoimmune disorder that results in progressive weakness of ocular, bulbar, limb, and/ or respiratory muscles due to a defect in neuromuscular transmission and subsequent contraction of skeletal muscles. The autoantibodies target the acetylcholine receptor on the postsynaptic membrane leading to a decrease in several receptors (Bird, 2010). This results in a defect in acetylcholine mediated neuromuscular transmission. The weakness is manifested as a steady yet progressive decrease in muscle power.

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It has a bimodal occurrence, manifesting itself in women in the third decade and men in the seventh decade of their lives (Drachman, 1994). Myasthenia gravis has a prevalence of up to 125 cases per million individuals (Bird, 2010). Management of Myasthenia gravis entails the use of drugs aimed at restoring the integrity of the postsynaptic membrane in terms of some acetylcholine and inhibition of the function of the autoantibodies. Examples of agents used include acetylcholinesterase inhibitors such as physostigmine, steroids such as glucocorticoids, and azathioprine (Drachman, 1994).

Myasthenia Gravis: The Junction

The pathogenesis of Myasthenia gravis entails a decrease in the number of nicotinic acetylcholine receptors at the postsynaptic membrane of the neuromuscular junction. Furthermore, other mechanisms such as changes in the folding pattern of the postsynaptic membrane and an extraordinarily large gap between the presynaptic nerve terminal and the postsynaptic membrane play a role in the causation of Myasthenia gravis.

To achieve potential in the postsynaptic membrane, acetylcholine is first released from the presynaptic nerve terminal into the junction space where some it is hydrolyzed by the acetylcholinesterase enzyme (Drachman, 1994). The remnant of the acetylcholine finds its way to the postsynaptic membrane, where it interacts with numerous nicotinic acetylcholine receptors to bring about muscle contraction. In Myasthenia gravis, the junction is usually wide, the synaptic folds fewer, and the postsynaptic membrane has few acetylcholine receptors even though the presynaptic nerve terminal is normal (Milind, 2004).

The physiologic manifestations of Myasthenia gravis are as a result of these structural and physiological abnormalities at the junction that are brought about by a state of autoimmunity. For successful neuromuscular transmission, acetylcholine has to adequately bind and interact with its receptors at the postsynaptic membrane. On binding, acetylcholine induces the opening of cationic ion channels on its receptor resulting production of an electrical end-plate potential that brings s about an action potential.

The action potential facilitates release calcium ions from cellular stores resulting in insufficient muscle contraction. However, in myasthenia gravis, few acetylcholine receptors are leading to a decrease in the generation of the end-plate potential that in turn fails initiation of the action potential in some of the muscle fibers. As such, there is a reduction in the power of the whole muscle resulting in a subjective feeling of weakness in the affected branch of the muscle (Drachman, 1994).

With frequent initiation of muscular contractions, there is a failure in the transmission of potential at numerous neuromuscular junctions due to the reduced number of acetylcholine receptors at these locations. With the repeated release of acetylcholine by the presynaptic nerve terminal, the store tends to be depleted and as such little acetylcholine can access the few acetylcholine receptors at the postsynaptic membrane of myasthenic patients resulting in prolonged and sustained muscle weakness. This is usually referred to as the “acetylcholine run down” (Drachman, 1994).

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The Acetylcholine Receptor

The affected receptor in myasthenia gravis is the nicotinic acetylcholine receptor found in skeletal muscles. It is made up of several individual subunits namely alpha, beta, delta, and gamma or epsilon. Alpha occurs as two subunits unto which acetylcholine binds initiating a conformational change that facilitates the movement of cations to bring about muscle contraction. In myasthenia gravis, antibodies against self (autoantibodies) mimic acetylcholine by binding on the immunogenic site of alpha subunits leading to a decrease in neuromuscular transmission. The postsynaptic nicotinic acetylcholine receptors are under constant replacement, a process believed to be under the influence of the motor branch of the nervous system (Milind, 2004).

In myasthenia gravis, there is an elevation in the transcription of the acetylcholine receptor genes due to the dysfunctional transmission of the impulse. As such, in myasthenia gravis, the motor system is primed and results in the observed elevation of transcription of acetylcholine receptors in animal models of myasthenia gravis. The electric eel has been used in mapping out the subunits that are the main targets of autoantibodies in myasthenia gravis (Drachman, 1994).

Immunologic Basis of Myasthenia Gravis

Myasthenia gravis is a consequence of a myriad of processes that are a result of the interaction of the acetylcholine receptor and antibodies against self. The five criteria for autoimmune conditions qualify myasthenia gravis to be an autoimmune condition. The Immunoglobulin G (IgG) promotes the rapid breakdown of the acetylcholine receptor by linking two receptors to facilitate the rapid endocytosis and subsequent breakdown (Allan, 2010).

This phenomenon occurs in both animal and human models. Also, the IgG antibodies against self result in a steric blockade of the acetylcholine receptors. This is probable since, the receptor is known to be of small size and it has an antibody binding site adjacent to the cation entry port (Allan, 2010). Once the antibodies bind to the receptor, they induce activation of the complement immune system. The complement system, in turn, generates the membrane attack complex that results in the degradation of the internalized acetylcholine receptors. As such the number of acetylcholine receptors available to interact with the substrate is decreased and this results in progressive loss of skeletal muscle tone in myasthenic patients (Allan, 2010).

A small fraction of myasthenic patients do not have autoantibodies in their serum and this is attributed to the possibility of another target for these antibodies in the causation of Myasthenia gravis. The receptor-associated proteins are the target for this subset of autoantibodies. The muscle-specific receptor tyrosine kinase (MuSK) has been identified as the main target of these antibodies. The MuSK proteins are crucial for the formation and maturation of acetylcholine receptors as they foster aggregation of these receptors after induction by agrin, a proteoglycan of the nervous system (Allan, 2010). MuSK-directed antibodies play a role in the pathogenesis of Myasthenia gravis and these autoantibodies have a significant inhibitory effect on the function of this protein. MuSK antibodies have been shown not to activate the complement pathway and as such are act via a yet identified mechanism in the degradation of the acetylcholine receptors (Allan, 2010).

Postulations on the role of MuSK proteins in Myasthenia gravis indicate antibodies against MuSK proteins result in inhibition of aggregation of acetylcholine receptors and subsequent disruption of the whole neuromuscular junction. Also, the antibodies initiate and maintain structural damage to the postsynaptic membrane by autoantibodies directed against MuSK proteins (Allan, 2010).

T cells have been implicated in Myasthenia gravis concerning their ability to initiate antibody production by B lymphocytes. Furthermore, the thymus contains a population of unique cells called the “myoid cells” that acetylcholine receptors on their cell membrane surfaces. The presence of these cells and the comorbidity of thymic abnormalities and myasthenia gravis, has led many to believe that the thymus plays a role in the causation of myasthenia gravis. Also, studies have shown better prognosis of the condition in patients who have had thymectomy (Allan, 2010).

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Myasthenia gravis is a well researched autoimmune condition. However, there is a lack of consensus on all the factors that lead to this condition. Hence, further research is required to map out all the factors that are suspected to cause or promote the progression of Myasthenia gravis. This will facilitate the designing of better novel treatment modalities based on the causes of the condition.


Allan, W. (2010). Pathogenesis of myasthenia gravis. In: J.F. Dashe (Ed.), UpToDate. Web.

Bird, S.J. (2010). Clinical manifestations of myasthenia gravis. In: J.F. Dashe (Ed.), UpToDate. Web.

Drachman, D.B. (1994). Medical progress: Myasthenia gravis. The New England Journal of Medicine, 330(25), 1797-1810.

Milind, J. K. (2004). Myasthenia gravis. Journal of the American Osteopathic Association, 104(9), 377-384.

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