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One of the characteristics of idiopathic inflammatory myopathy (IMM) — a group of disorders causing inflammation of the skeletal muscles — is the presence of a large number of autoantibodies. The cause of development of these autoantibodies and the exact role they play in the pathology of IMM has largely been enigmatic.
Now, research at The Ohio State University Wexner Medical Center may have solved one mystery — and possibly found a new target for future therapies. The research, conducted with mouse models and serum samples from IMM patients, shows that some of the antibodies are targeting proteins that are important in repair of the cell membrane in muscle cells.
"What we’ve found is that these autoantibodies bind to certain proteins that normally repair injuries to muscle cells that can occur every day, suppressing their function,” says Wael Jarjour, MD, director of the Division of Rheumatology and Immunology. “That can potentially cause muscle cells to break apart, damaging the overall muscle structure and exacerbating the disease. When a muscle cell breaks apart and the membrane surrounding the cell is gone, proteins that were inside the cell are released out into the extracellular space where the immune system can see them and promote more autoantibody production. It creates a vicious cycle that can accelerate disease progression.”
The researchers, led by Dr. Jarjour and Noah Weisleder, PhD, professor of physiology and cell biology, identified autoantibodies targeting the protein TRIM72 (formerly known as MG53) in myositis patient sera and showed a direct causal effect of the antibodies on membrane repair seen in IMM. In healthy skeletal muscle subjected to injury, patient sera with high levels of these autoantibodies suppressed muscle membrane repair, but the membrane repaired successfully in the presence of these same serum samples when the antibodies were depleted from the samples.
New knowledge could lead to new therapies
Dr. Jarjour started looking at membrane defects as a contributor to IMM 15 years ago, after treating a patient with a form of myositis that, at the time, was not well-characterized and that occurred following treatment with a statin. If ongoing research confirms the results of the new discovery, this knowledge could help patients by leading to new targets for therapy to fight IMM and to stop its progression.
“There are therapeutic agents such as poloxamer compounds and the recombinant form of the TRIM72 protein, rhMG53 — experimental drugs that can increase the ability of the muscle membrane to repair,” Weisleder says. “Such drugs are being explored for treatments in various muscle diseases like muscular dystrophy, so this opens the possibility that we could also target IMM using those same sorts of approaches.”
Weisleder notes that their successful collaboration and discovery demonstrate the value of academic medical centers in facilitating research that can ultimately lead to better patient care.
“My lab is more of a basic science laboratory, and Dr. Jarjour is a clinical investigator, so he's more focused on the clinical aspects of disease. When I moved my laboratory here almost seven years ago, he was working on developing new mouse models for IMM, and the models he was looking at relate to some of the processes that we were studying in my laboratory. So it was a situation where we were in the right place at the right time, and we started working on this project together. One of the great advantages of having a world-class academic medical center like Ohio State is the fact that you're able to find great collaborators in your area, just down the hall or in the next building over, and be able to find some really fundamental discoveries that help move therapeutic interventions forward.”
To read the full publication, click here.
