Newly Found Cellular Changes May Underlie MG in Thymoma Patients

Cells known as mTECs may play role in MG development

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Researchers have found that a set of cells called medullary thymic epithelial cells, or mTECs, may play a role in the development of myasthenia gravis (MG) in thymoma patients — people with thymus tumors.

Changes in the function of these cells were observed in thymoma tissues collected from people who also had MG, suggesting they could underlie the link between the two conditions. That link has thus far been poorly understood.

According to researchers, other factors, such as immune cell changes and environmental factors, also likely interact to spur MG development.

The study, “Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma,” was published in the journal Nature Communications.

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Autoimmune responses in MG are driven by the body’s erroneous attack on proteins, called neuromuscular proteins, involved in nerve-muscle communication. Usually, these antibodies target proteins called acetylcholine receptors (AChRs).

While the exact mechanisms underlying these aberrant attacks are not known, abnormalities in the thymus gland, an organ that is part of the immune system, are thought to be involved.

Investigating cellular mechanisms of MG

MG and thymomas are closely linked. It is estimated that about 21% of MG patients have a thymoma, and that a quarter of people with a thymoma develop MG.

Evidence suggests that immune cells involved in the production of MG-causing antibodies are increased in the thymomas of people who also have MG. However, why this happens has not been determined.

Now, researchers at Osaka University, in Japan, sought to pinpoint the underlying cause through genetic analysis. Their aim was to compare thymoma cells taken from patients who either did or did not develop MG. The analysis was designed to detect differences in the expression, or activity, of genes between these two groups of patients.

“At a very basic level, many diseases are ultimately fueled by abnormal gene expression patterns,” Yoshiaki Yasumizu, the study’s first author, said in a university press release.

Yasumizu also noted that the team hoped the analysis would help them zero in on “specific genes directly involved in [MG].”

Surgically-resected thymoma tissues from 116 people were analyzed by the researchers. Among these patients, 34 developed MG.

Overall, 93 genes were found to be expressed at higher levels in MG samples, while 91 were expressed at lower levels. Several genes that had higher expression levels were associated with neuromuscular proteins — including the gene responsible for producing AChRs.

Further analyses showed the expression of neuromuscular molecules was particularly high in a subset of mTECs. The researchers dubbed them neuromuscular mTECs or nmTECs.

Normally, immune responses happen when a foreign substance, called an antigen, is presented to the immune system. Simply put, immune T-cells respond to the antigen, and help activate B-cells, which produce antibodies against that substance.

mTECs are normally involved in preventing the activation of T-cells that will be self-reactive, or those that will elicit unwanted autoimmune attacks against the body’s own cells.

In thymoma-associated MG, however, these cells appear to show an ability for antigen presentation, meaning that mTECs could express the neuromuscular proteins on their surface, enabling T-cells and B-cells to launch an immune response against them.

The researchers noted that other cellular changes in immune cell populations were observed that also are likely involved in mediating autoimmunity in thymoma-associated MG. For example, they found the abnormal accumulation of germinal centers. These structures can be found in immune organs and are the place where B-cells begin to grow, mature, and prepare to produce antibodies.

Normally, germinal centers are produced in response to infection, but the team hypothesized that the presentation of neuromuscular molecules on mTECs in the thymoma likely triggered their aberrant formation in MG.

Other changes, including some in T-cells, also were observed that likely create “a microenvironment that can support autoimmune outcomes,” Yasumizu said.

Together, the findings link this unusual mTEC behavior to the emergence of MG in thymoma patients, the researchers noted.

However, since some patients who displayed increased expression of neuromuscular genes did not develop MG, it is likely that mTECs alone are not enough to trigger the neuromuscular condition.

The team hypothesized that MG may be “cooperatively developed by the expression of neuromuscular-related antigens, skewed immune microenvironment, genetic backgrounds, and environmental factors including virus infections.”

“Further analysis will be required for addressing the stepwise development of MG,” they wrote.

The researchers said they hope their work will help lead to new treatments for myasthenia gravis in thymoma patients.

“We characterized the complex relationship between MG and thymoma from a view of cell composition and the source of neuromuscular molecules causative for MG,” they concluded.