Cell models that best mirror the surface of muscle cells crowded with acetylcholine receptors (AChR) are most helpful for understanding how self-reacting antibodies interrupt communication between nerve cells and muscles in myasthenia gravis (MG), a study reports.
Using these models, researchers found that some antibodies only recognize clustered receptors, gaining new insights into how muscle receptors are blocked.
The study, “Myasthenia gravis AChR antibodies inhibit function of rapsyn-clustered AChRs,” was published in the Journal of Neurology, Neurosurgery & Psychiatry.
MG is caused by problems in the transmission of nerve impulses to muscles. It occurs because the body’s immune system produces self-reacting antibodies, or autoantibodies, that disrupt communication between nerves and muscles at the neuromuscular junction.
Normally, nerve cell endings release a neurotransmitter, or chemical messenger, called acetylcholine, which binds to specific receptors (AChR) on the surface of muscle cells, inducing muscle contraction.
Many MG patients produce autoantibodies that mistakenly ‘attack’ these receptors. As a consequence, there are fewer working receptors available, so muscles cannot contract properly and easily become weak. These autoantibodies are known as anti-AChR.
Anti-AChR autoantibodies may disrupt nerve-muscle communication by damaging, destroying, or blocking acetylcholine receptors.
Blockage of such receptors is assumed to be rare. However, what scientists know about such blockage and how often it occurs could be flawed, as most studies used cell models that fail to replicate the natural conditions under which AChR is found in cells.
Specifically, they do not reproduce the dense packing of AChRs in muscle cells, helped by a protein called rapsyn, which anchors the receptors to a muscle cell’s membrane.
Researchers in the U.K. and Austria reasoned that looking at clustered AChRs would be the best approach to study the effects of MG antibodies on acetylcholine receptors.
To do that, they collected blood samples from 21 MG patients, ages 14 to 72, and tested this serum (the part of the blood that contains antibodies) against cells that contained either unclustered or clustered AChRs.
Researchers created these two cell models by adding, or not, rapsyn to cells using genetic engineering.
Eleven samples were positive and 10 were negative for anti-AChR antibodies. Five samples from healthy individuals were added as controls.
Acetylcholine receptors open upon binding of acetylcholine to create ion currents inside cells, which then set the stage for an electrical impulse to propagate over the muscle fiber and make it contract.
The effect of MG sera (blood serum) on AChR activity was measured by patch-clamp, a method that records ion currents in individual cells. According to the researchers, this was the first study to specifically look at the blocking effect of MG autoantibodies on human AChRs
Results showed that only two of the 11 anti-AChR positive samples blocked the activity of unclustered AChRs, while six samples rapidly blocked rapsyn-clustered receptors and did so in an irreversible manner.
None of the 10 samples negative for anti-AChR antibodies could block clustered receptors.
This work showed that the blockage was greater when AChRs were clustered. It also suggests that it was not mediated by loss of sensitivity of the receptor. Researchers think it probably happens because the antibody competes with acetylcholine for the receptor.
“The use of cells expressing clustered AChRs is an important development for the further characterization of MG antibodies, and here provides novel evidence that puts the well-known blocking mechanism of AChR-Abs in a new perspective,” they wrote.
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