MG: Out of Place

High levels of misplaced proteins may worsen the disease process in myasthenia gravis

by Quest Staff on August 25, 2009 - 12:22pm

Stepped-up production of fragments of acetylcholine receptors, the microscopic "landing pads" on muscle fibers that normally help process signals from the nervous system, may provoke the immune system and worsen myasthenia gravis (MG), new research shows.

In mice with an MG-like disease, these receptor fragments (which are proteins) are abundant but nonfunctional, and they end up in the wrong place in muscle fibers.

Matthew Meriggioli, who has MDA support to study new ways to regulate the immune system in MG, coordinated the study team (this study was conducted before his MDA grant took effect).

About MG

In most cases of MG, which is part of a large class of diseases known as "autoimmune," or "self-immune," disorders, the immune system mistakenly attacks the acetylcholine receptors (AChRs), destroying them faster than the body can replace them.

The result is that the nervous-system chemical acetylcholine, which normally lands on these receptors as the first step in transmitting nerve signals, often fails to do so. Signal failure causes fluctuating weakness in patients.

Current treatments for MG include suppression of the immune system, direct removal of immune-system proteins called antibodies, and enhancing the transmission of acetylcholine signaling with a medication that slows acetylcholine breakdown. These treatments can usually control the disease, but they often have unwanted side effects and don't always work as well as desired.

About the new findings

Investigators at the University of Illinois-Chicago have found that, in mice with a disease closely mimicking human autoimmune MG, nonfunctional, mislocated pieces of AChR produced in an effort to compensate for AChR loss, appear to stir up the immune system and may sustain the disease process. The results are published in the August 2009 issue of Muscle & Nerve.

MG occurs when the immune system destroys acetylcholine receptors (AChRs) on muscle cells (fibers), using antibodies as weapons. Treatments include immune-system suppression; siphoning off antibodies; and blocking the enzyme acetylcholinesterase (AChE), which normally breaks down acetylcholine (ACh) after it moves from nerve to muscle fibers.

New research suggests abnormally placed fragments of AChRs could be the result of the body's attempt to compensate for the loss of AChRs but could actually make the disease worse.

Previous studies in human MG patients have noted the presence of similar nonfunctional protein pieces of AChR, although their role in the maintenance of the disease has been unclear.

The investigators cite evidence from other autoimmune diseases that shows changes in the structure, location or level of a protein can alter the way the immune system responds to it.

In the MG mice, the new AChR pieces were not integrated into receptors (as they normally would be) and may therefore have appeared “misshapen” to the immune system. They were not able to provide landing pads for acetylcholine.

In addition, they were in some instances located extensively along the muscle-fiber membrane, not just at the correct place, which is where nerve and muscle fibers communicate, the so-called neuromuscular junction. That could be another red flag for the immune system.

MG mice with the most severe disease had the highest muscle-tissue levels of these AChR pieces. In the severely affected mice, proteins of the immune system were seen in similar locations as the receptor pieces, suggesting the pieces had become immunologic targets.

Reducing production of AChR pieces could become therapeutic option

Preventing or reducing production of the new AChR pieces, if their role in the disease process is confirmed in humans, could become a new goal for therapeutic development in MG.

In a study published last year, Meriggioli and colleagues describe a new approach for regulating the immune system in MG mice, using a compound called granulocyte-macrophage colony-stimulating factor (GM-CSF). This compound activated regulatory cells in the immune system, dampening the autoimmune response and lessening disease severity in the mice.

Meriggioli's current, MDA-supported work aims to move this strategy closer to application to human MG. "Essentially, our work will try to harness the immune system’s own regulatory network to bring MG under control, and possibly bring about long-term remissions,” Meriggioli said.

Meaning for patients

The new findings about the role of abnormal AChR pieces in mice with an MG-like disease have not been confirmed in human MG patients. If that occurs, treatment strategies that prevent the overproduction of AChR subunits could be investigated.

Homing in on abnormal immune responses to AChRs and AChR fragments, while leaving the rest of the immune system alone, by using GM-CSF or similar compounds, could allow more "bang for the buck" -- more benefit with lower doses and fewer side effects than in current MG therapies.

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