Key Element Influencing Neuromuscular Disease Found Dr. Premkumar Christadoss "For myasthenia, however, we know the acetylcholine receptor is the antigen, and that one single antigen is important for the development of the disease, the autoimmunity," Christadoss says. "Therefore, it's a good prototype to study the other diseases, a very nice classical model for a lot of autoimmune diseases."

Researchers here have identified a critical element in the molecular process responsible for the neuromuscular disease myasthenia gravis. The discovery could lead to a possible cure for the muscle-weakening disease and to important insights into other autoimmune disorders such as rheumatoid arthritis, type 1 diabetes, lupus and multiple sclerosis.

Myasthenia gravis, which afflicts about 36,000 Americans, causes a loss of muscle strength, which at worst can make even the smallest movements difficult. It occurs when the immune system mistakenly attacks molecules called acetylcholine receptors that muscle cells use to receive chemical signals from nerves. In an article appearing April 15 in The Journal of Clinical Investigation, scientists Premkumar Christadoss, Huan Yang, Elzbieta Goluszko, Teh-Sheng Chan and Mathilde Poussin, all of the University of Texas Medical Branch at Galveston (UTMB), pinpoint the specific part of the human acetylcholine receptor that evokes the strongest response from the human immune cells initiating such "friendly fire" attacks.

To identify the relevant part of the receptor, the UTMB researchers refined an experimental technique that uses acetylcholine receptors from a sea creature called the Pacific torpedo ray to induce myasthenia gravis in mice genetically modified to produce human immune system molecules. Instead of employing torpedo ray receptors, they induced the condition with human acetylcholine receptors -- the first time this had been done -- thus creating a more accurate model of the molecular interactions involved in human myasthenia gravis. Immune cells from the transgenic mice were then exposed to different tiny segments of the alpha subunit of the human acetylcholine receptor to determine which segments would incite the most powerful reaction.

"We looked at the proliferative response, the T-cell expansion for different specific peptides, amino acid sequences, from the human acetylcholine receptor alpha subunit," Christadoss says. "One peptide gave a dominant response."

That peptide, known as the H-a320-337 sequence, produced similar results when tested against immune cells from groups of mice with different human genes. T cells from mice with the gene to produce the human leukocyte antigen (HLA) molecule DQ8 and mice with the gene to produce the HLA molecule DR3 (both of which increase susceptibility to myasthenia gravis) both showed a powerful reaction to the peptide, growing and sending out signals to produce acetylcholine-receptor-destroying antibodies. The same was true of cells taken from crossbreeds of the DQ8 mice and other mice possessing a gene that made them resistant to myasthenia gravis.

This "promiscuity" of the H-a320-337 peptide suggests that it may be involved in provoking harmful immune responses against acetylcholine receptors in patients with a wide variety of genetic backgrounds. It also opens up the possibility that the peptide could be the key to a new treatment for myasthenia gravis. In earlier experiments, UTMB researchers used high-concentration doses of torpedo-ray acetylcholine receptor alpha subunit peptide to over-stimulate the specific T cells directing the autoimmune attack that causes the disease, driving those cells to commit suicide in the process known to scientists as apoptosis. According to Christadoss, such experiments have been about 50 percent successful in preventing myasthenia gravis in mice, and the newly identified peptide -- derived from experiments using a transgenic mouse model that more closely resembles human myasthenia gravis -- could be more successful in doing the same job. "What we are planning to do next is give a high dose of this peptide and see whether we can prevent the disease in transgenic mice," Christadoss says. "If we can do that, prevent or even suppress ongoing disease, then this peptide could be used as a vaccine to cure myasthenia gravis."

In addition to the possibility that it might lead to better therapy for a specific disease, Christadoss says that the research has implications for the study of autoimmune diseases as a whole. In many autoimmune disorders, scientists do not yet know the antigen, the entity that provokes the immune response. In some cases, such as those of rheumatoid arthritis and type 1 diabetes, they believe multiple antigens may be involved, complicating matters even further.

Source: Adapted from: Psychiatry Res 2002 Mar;109(2):143-8; Karege F, et al. Laboratory of Biochemistry, Division of Neuropsychiatry, Geneva University Hospitals

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