Early diagnosis of MG is essential for treatment success, but the signs and symptoms may be difficult to acknowledgement.
Picture adapted from epainassist.com.
Now that we know the normal physiology of the neuromuscular junction (NMJ) and immune system, let's take a look at what part of that physiology goes wrong and leads to MG. Click the links to go to the 3 sections or just scroll.
Immune System and NMJ Mathematical Model Conclusion (5 steps)
Throughout the website keywords and definitions will be highlighted and italicized. You can click on them to show the definition. Or click below to see all definitions.
MG Pathophysiology
What changes in the immune system and NMJ?
Myasthenia gravis is an autoimmune disorder that consists of varying levels of muscular weakness.[1] The normal immune response is designed the ward off disease and infection. The immune system regulates its cells and eliminates any that create a response to normal host cells.[2]
In MG, the CD4 receptors of the helper T cells actually create a response to the acetylcholine receptors (AchR) on the postsynaptic membrane of the NMJ. The helper T cells do their job and stimulate B cells to differentiate and create memory and plasma cells that secrete antibodies. These antibodies (high affinity AchR) then travel to the neuromuscular junction.[3] The antibodies create different effects on the NMJ. The antibodies can bind directly to and block the AchR, which in turn does not allow the Ach to attach and create the end plate potential. The antibodies can also decrease the lifespan of the AchR, thereby decreasing the time that the AchR is available. The greatest effect is the complement mediated death of the receptors and distortion of the endplate structure.[4] This can lead to problems with any structure on the endplate, including the voltage-gated channels.
There are two other antibodies that could have a role in MG. One of which is anti-muscle-specific tyrosine kinase (anti-MuSK) which reduce the number of AchRs by effecting their clustering mechanism caused through agrin. Another is anti-Lipoprotein related protein 4 (anti- LRP4). We will focus on the anti-AchR antibodies however because the others account for roughly 6% of cases.[5] Below is a diagram detailing the steps in the pathophysiology of MG.[3] As you can see in Figure 1a below (adapted from [6]), MG has a significant effect on the NMJ and muscle function. Without the AchR and end plate potential the muscle cannot function. Typically in MG the muscle weakens with cyclic activity, with more weakness per repetition. This also depends on the severity of the damage caused to the NMJ.[7]
Another region of interest in MG is the thymus shown in Figure 1b. The thymus has a large population of CD4 cells which stimulate the B cells to create antibodies in MG. This can become swollen and depending on the patient can be removed to lower the amount of CD4 available for this pathway.[8]
Figure 1a: This figure (adapted from Feher) displays red symbols over the normal physiologic NMJ functions that are damaged or destroyed by the immune response in MG.
Changes to the Mathematical Model:
The model below in Figure 2 was described in the normal NMJ physiology section [9] and is changed by MG. The diffusive components do not change at first, but the reaction components definitely change with the lack of AchRs (shown as R in Figure 2) to bind to Ach (shown as A in Figure 2). The decrease in receptors will lead to larger amounts of Ach in the synaptic cleft. This may lead to decrease diffusion.
Figure 2: The above equation, adapted from Khaliq et al, provides a model for NMJ function. The red circles represent the parts of the equation effected by the AchR destruction or inhibition in MG.
Conclusion:
Below is a 5 step summary we have created to show what causes MG to occur. This chart was created from the steps found in literature to give an overview of the main contributors in MG.
Figure 1b: This picture from Alberts et al. shows the thymus which is sometimes removed to decrease MG symptoms due to the large amount of CD4 cells present in that area.
