Dr James Howard on the Malfunctions in the Neuromuscular Junction


James F. Howard Jr, MD, professor of neurology at the University of North Carolina at Chapel Hill, explains how nerve and muscle signaling in the neuromuscular junction go awry in myasthenia gravis.

James F. Howard Jr, MD, professor of neurology at the University of North Carolina at Chapel Hill, former chief of the Neuromuscular Disorders Division, and former James F. Howard Distinguished Professor of Neuromuscular Disease, explains how nerve and muscle signaling in the neuromuscular junction go awry in myasthenia gravis.


What is happening in the neuromuscular junction with myasthenia gravis—can you explain to a layperson what is going on in that space that is causing this cascade?

The target in myasthenia is what we call the neuromuscular junction. It's the contact point between the tip at the end of the nerve and the muscle fiber itself. In other words, a small, infinitesimally small, gap between the two. As the brain sends a signal down the nerve, through the spinal cord, down the nerve, it reaches the end of the nerve and then releases packets of neurotransmitter that's called acetylcholine, that then floats across this little space and attaches to receptor sites of which there are tens of thousands on the surface of that 1 muscle fiber. Those interactions of transmitters to the receptor, open up a core, a channel, if you will, that allows ions to flow that then allow the muscle fiber to contract.

And this is a very dynamic process, going all the time among thousands of muscle fibers in any given muscle. So to lift my finger, for instance, I'm telling a muscle in my forearm to be activated, releasing that chemical interacting.

We don't know the trigger, but for reasons that we don't fully understand, that region has been misidentified by the body as not belonging to you. Much like if someone has a kidney or heart transplant, take a donor—accident victim, usually—and donate it, it's implanted into the individual. The body instantly recognizes that kidney or heart is not theirs and tries to reject it.

And that's exactly what's going on in myasthenia. The contact point between nerve and muscle, the neuromuscular junction, this receptor, if you will, has been recognized as foreign and the body is mounting an immune attack to destroy it.

And so our goal is to try and downregulate that immune attack and allow that interaction between nerve and muscle to continue unfettered from this immune attack.

What’s also interesting in myasthenia is that as these proteins or antibodies that cause this attack bind to these receptor sites, it also activates another part of our immune system called complement. And complement has good points and bad points. And when it's overstimulated, such as in myasthenia, it forms a ring-like structure that binds to the surface of the muscle, literally drills a hole through it, leaks all of its contents out, and then destroys the muscle fiber.

And so in addition to having antibody proteins blocking nerve-muscle communication, we've also turned on a system where we're physically, architecturally, structurally destroying this region as well. And so prior to 2013, we had no such therapies to address that, in part because we didn't know the full existence prior to that time. And now we have targeted therapies that will interfere with this terminal complement complex, as we call it, and prevent it from destroying the tissue membrane.

Its effectiveness has been demonstrated in those patients who have antibody to the acetylcholine receptor. [Muscle-specific tyrosine kinase] patients don't activate complements, so they're not a candidate for this drug. We don't have data in this serum negative population or Lrp4 population yet, and hopefully that will come with time, to see if we can broaden its use out. And so the treatment is multifold. We need to address each of the components to get the best response for the patient to give them the best quality of life.

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