MG: Can the Immune Response Be Tamed?

It can start with nothing more than a drooping eyelid or a slight slurring of speech, either of which can come and go and improve with rest. But it can progress, often gradually over weeks or months, to affect all the voluntary muscles, including those controlling breathing. Weakness may be minimal early in the morning after a good night's sleep and worsen throughout the day, especially after periods of activity.

A Closer Look: MG Slideshow
MG Slideshow

In the past — and even occasionally now — the condition was thought to be psychological in origin, related to depression or anxiety, and patients were steered toward psychotherapy.

But today we know that this disease — myasthenia gravis (MG)— is not psychological in origin, but results from a misguided attack by the body's immune system against some of its own tissues; namely, the neuromuscular junctions, the places where nerve fibers send out activating signals and muscle fibers receive them.

This article takes a look at what we currently understand about MG, and it looks at the MDA-funded research seeking to extend that knowledge and develop more effective treatments for this difficult disease (check out the slideshow).

Renegade immune system

Since the 1970s, it's been understood that most MG is due to the immune system's mistaken attack on multiprotein structures called acetylcholine receptors, docking sites on muscle fibers that receive a chemical called acetylcholine from nerve cells. Normally, the presence of acetylcholine causes a muscle fiber to contract, allowing muscle activity to occur.

In most cases of MG, the immune system's inappropriate target is these docking sites. An immune response, in the form of immune system proteins called antibodies, blocks or destroys the acetylcholine receptors, preventing them from receiving the "go" signal from acetylcholine.

In fact, MG is a classic autoimmune disease, a type of disorder in which the body produces an immune response against itself.

These days, it's known that the acetylcholine receptors are the most common but not the only target of the immune system in MG. In some people with MG, the target is a protein known as muscle-specific kinase, or MuSK. In still others, it's a protein called LRP4. Symptoms are similar in all three types of MG, because the acetylcholine receptors, MuSK and LRP4 all play roles at the neuromuscular junction, and when they're blocked or damaged, they can no longer make sure that signals from the nervous system get through to muscles.

(Note: There are some forms of myasthenia -- weakness due to problems at the neuromuscular junctions -- that are not autoimmune but instead are genetic. These are known as congenital myasthenic syndromes. Treatments that modulate the immune system are not used to treat these forms of myasthenia.)

Prolonging the signal, thwarting the immune system

For several decades, the mainstays of treatment for MG have focused on two goals:

  • enhancing the nerve-to-muscle activating signal, usually by prolonging the action of acetylcholine with a drug called pyridostigmine; and
  • interfering with the immune attack on neuromuscular junction proteins with drugs that suppress the immune system, such as corticosteroids, methotrexate, azathioprine and many others.

Both those strategies can control the disease to some extent, but usually not completely. And they both — particularly the immunosuppressants — come with unwanted side effects.

Wanted: More selective blocking of the immune system

The challenge in MG has been to develop a treatment that targets only the part of the immune system that's misbehaving — the part that's attacking the neuromuscular junction proteins — leaving the rest of the system intact to perform its normal function, which is protecting the body from bacteria and viruses.

With the explicit goal of developing kinder, gentler, but highly effective MG treatments, MDA is currently funding 11 researchers. For more information, view the slideshow of MDA-funded MG grants below (each slide has a “read more” feature for even more grant details.)

Two of the current MG grants are to evaluate the possibility that granulocyte-macrophage colony-stimulating factorGM-CSF— may provide a more nuanced approach to changing the immune system than currently available drugs.

Another grant investigates the possibility that blocking activation of specific proteins that are part of the complement system— a branch of the immune system — may bring MG under control without the side effects of currently available medications.

And yet another is studying the use of a "decoy" that distracts the immune system from its target.

Some of the remaining current MDA funding for MG is going toward understanding the recently identified forms of the disease that are caused by an immune response to either the MuSK or the LRP4 proteins.

Myasthenia gravis (MG) is an autoimmune disease — a disease that occurs when the immune system attacks the body’s own tissues. In MG, that attack interrupts the connection between nerve and muscle — the neuromuscular junction.

The disease first appeared in medical reports in 1672, but didn’t earn its name, which literally means “grave muscular weakness,” until the 1880s.

David Richman, M.D.

Grant effective: Feb. 1, 2013

David Richman, professor of neurology at the University of California, Davis, was awarded an MDA research grant totaling $412,500 over a period of three years to study the anti-MuSK myasthenia (AMM) form of myasthenia gravis (MG).

Muthusamy Thiruppathi, Ph.D.

Grant effective: Feb. 1, 2013

Muthusamy Thiruppathi, a postdoctoral research associate in microbiology and immunology in the College of Medicine at the University of Illinois at Chicago, was awarded an MDA development grant totaling $180,000 over a period of three years to pursue ways to restore normal immune system function in myasthenia gravis (MG).

Socrates Tzartos, Ph.D.

Grant effective: Feb. 1, 2013

Socrates Tzartos, professor of biochemistry at the Hellenic Pasteur Institute in Athens, Greece, was awarded an MDA research grant totaling $345,033 over a period of three years to develop diagnostic tools for diagnosis of the low-density lipoprotein receptor-related protein 4 (LRP4) form of myasthenia gravis (MG).

Feng Lin, Ph.D.

Grant effective: Aug. 1, 2012

Feng Lin, associate professor in the department of pathology at Case Western Reserve University School of Medicine in Cleveland, Ohio, was awarded an MDA research grant totaling $390,000 over three years to study a potential new cell-based therapy for myasthenia gravis (MG).

Lin Mei, M.D., Ph.D.

Grant effective: Aug. 1, 2012

MDA awarded a research grant totaling $390,000 over three years to Lin Mei, professor and director of the Institute of Molecular Medicine and Genetics at Georgia Health Sciences University in Augusta. The funds will help support Mei’s research on the role of a protein called LRP4 in myasthenia gravis (MG).

JianRong Sheng, Ph.D.

Grant effective: Aug. 1, 2012

JianRong Sheng, assistant professor in the department of neurology and rehabilitation at the University of Illinois at Chicago Medical Center, was awarded an MDA research grant totaling $317,058 over three years. The funds will help support Sheng's study of potential therapeutic treatments for myasthenia gravis (MG).  

Premkumar Christadoss, M.B.B.S.

Grant effective: Feb. 1, 2012

Premkumar Christadoss, a professor in the department of microbiology and immunology at the University of Texas Medical Branch in Galveston, was awarded an MDA research grant totaling $390,000 over a period of three years to study the potential for gene therapy as a treatment in myasthenia gravis (MG).

Matthew Meriggioli, M.D.

Grant effective: March 2011

Matthew Meriggioli, now a senior investigator at Novartis Institutes for BioMedical Research in Cambridge, Mass., received a three-year grant totaling $530,480 from MDA’s translational research program to study an immune system modulator called GM-CSF in a mouse model of myasthenia gravis (MG) and to conduct a clinical trial of the drug in a small group of patients with the disorder. At that time (March 2011), he was at the University of Illinois, Chicago.

Chi Wai Lee, Ph.D.

Grant effective: Feb. 1, 2011

MDA has awarded a research development grant totaling $180,000 over three years to Chi Wai Lee, postdoctoral fellow in the department of cell biology at Emory University School of Medicine in Atlanta. The grant will help support Lee’s research into therapeutic strategies to ameliorate the symptoms in myasthenia gravis (MG).

Jon Lindstrom, Ph.D.

Grant effective: Feb. 1, 2011

MDA has awarded a research grant totaling $450,000 over three years to Jon Lindstrom, professor of neuroscience and pharmacology at the Medical School of the University of Pennsylvania in Philadelphia. The new funds will help support Lindstrom’s continued efforts to develop an immunosuppressive therapy for myasthenia gravis (MG).

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