MYASTHENIA
GRAVIS
Genetics involved in Myasthenia gravis
Although MG is not considered a genetic disease, because it is not directly inherited nor is it the direct result of a genetic mutation, there are certain HLA (human lymphocyte antigens) associations. In people < 40 there is a higher incidence of HLA A1, B8, and DRW3 in patients with MG, and in those > 40 there is a correlation with HLA A3, B7, and DRW2. In patients with thymoma there is no HLA association. Although no direct link has been found, this HLA association, along with the fact the MG patients have a higher incidence of other autoimmune diseases, suggests an inherited defect in immune regulation.
Causes
Myasthenia Gravis is an autoimmune disorder and usually caused by a malfunction of the immune system. The causative factor is unknown, but the disorder may have a genetic link.
Myasthenia Gravis is a disorder of neuromuscular junction. Acetylcholine at neuromuscular junction is a neurotransmitter that is involved in the transfer of information to muscle tissue from nerves. In myasthenia gravis, there is destruction of acetylcholine receptors, preventing nerve impulses from reaching the muscles. This results in weakness and rapid fatigue in affected muscles.
In order to understand what causes MG, we must first describe what constitutes normal neuromuscular transmission.
Normal Neuromuscular Transmission:-
Acetylcholine (ACh) is synthesized in the nerve terminal by action of the enzyme choline acetyltransferase. ACh is then stored in vesicles, forming a quantum, containing about 10,000 molecules of ACh. Quanta of ACh are released into the nerve terminal by calcium dependent exocytosis - the fusing of the vesicles with the outer membrane wall. ACh then binds to the post-synaptic ACh receptor, resulting in a transient increase in membrane permeability to Na, K, Ca, and Mg, leading to an Endplate potential (EPP). Spacial and temporal summation of the EPPís are usually sufficient to reach threshold and cause a muscle membrane action potential. Acetycholinesterase and diffusion deactivates the ACh and terminates neuromuscular transmission.
Acetylcholine Receptor Antibody
The culprit in MG is an abnormally created antibody which has activity against the acetylcholine receptor, which is why MG is classified as an autoimmune disease. The AChR antibody is polyclonal and is present in 85-95% of MG cases. The antibody blocks neuromuscular transmission by several mechanisms - blockade of receptor sites by steric hindrance, destruction of AChR (complement mediated), and crosslinking of AChR which causes increased turnover by endocytosis (from 5-6 days to 2.5 days).
These effects collectively decrease the number of acetylcholine molecules binding to receptors, therefore decreasing the number of EPP's, and decreasing the likelihood of the muscle fiber reaching threshold depolarization and contracting. The resulting decrease in the number of muscle fibers firing is what causes weakness.
Structural Changes
The chronic inflammation of MG causes several changes in the structure of the Neuromuscular Junction which also inhibit transmission and contribute to weakness. These include flattening out of the junctional folds, spreading out of AChR and Acetylcholinesterase, a 66% decrease in number of AChR, and an increased junctional gap.
Role of thymus gland in Myasthenia gravis:-
The thymus gland, found in the upper chest area beneath the breastbone, is a part of the body's normal immune system. In most adults with MG, the thymus gland is abnormal. Some people with MG develop thymomas or tumors on the thymus gland. Generally thymomas are benign, but they can become malignant (cancerous). The relationship between the thymus gland and MG is not yet fully understood. Although the relationship is not understood, scientists believe that it gives incorrect instructions to developing immune cells ultimately resulting in autoimmunity and the production of acetylcholine receptor antibodies, thereby setting the stage for the attack on the neuromuscular transmission.
Evidence for the thymus playing a role includes the fact that the thymus contains myoid cells which can express AChR. B and T lymphocytes taken from MG thymus are reactive to AChR. 65% of patients with MG are found to have thymic dysplasia and 15% of cases are associated with thymoma. Finally, there is definite clinical improvement if the thymus gland is removed.
There are several other interesting pathological features of MG. MG is associated with certain HLA types, specifically B8, DRW3, DQW2, A1, A3, B7, DRW2. There is also an association with other autoimmune diseases. These two facts suggest a heritable defect in immune regulation. Some speculate that there might also be a viral trigger, although this has not been proven. This means that a viral infection may cause an autoimmune response against AChR through molecular mimicry, or a chance similarity between proteins on the virus and the ACh receptor. Homology found between herpes simplex virus and antibody from 6/40 MG patients is some evidence for a possible viral association.
Figure 4 :- Structural changes
Figure 5:- What happens in Myasthenia gravis?