MG may be driven by immune cells in thymus gland going rogue
Research findings provide 'entirely new framework' for potential treatments
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- New research suggests that the autoimmune disease myasthenia gravis may be fueled by rogue B-cells in the thymus gland.
- These cells may evade normal survival checkpoints and ultimately help cause the muscle weakness that marks MG.
- The scientists say their findings may help clinicians and researchers to better understand and, hopefully, treat MG.
Myasthenia gravis (MG) may be driven by antibody-producing immune B-cells going rogue in the thymus gland and developing escape mechanisms that allow them to attack the body’s own healthy tissues, according to new research by U.S. scientists.
“Our study suggests there’s more to myasthenia gravis than antibodies alone,” Ankit Bharat, MD, the study’s senior author at the Northwestern Medicine Canning Thoracic Institute, said in a university news story detailing the research results.
In this autoimmune disorder, self-reactive antibodies block communication between nerve and muscle cells, leading to symptoms such as muscle weakness and fatigue. Many patients undergo a thymectomy, or the surgical removal of the thymus gland, located in the upper chest.
“We found evidence that the thymus may create an abnormal immune environment that helps certain B-cells survive and persist, even after the thymus is removed,” Bharat said.
These findings may help explain longstanding paradoxes in MG, such as why levels of disease-driving autoantibodies aren’t closely linked with disease severity, or why thymectomy is effective for some MG patients but not others, the researchers noted.
“Understanding that [abnormal thymic] environment gives us an entirely new framework for studying and possibly treating the disease,” Bharat said.
The study, “Myasthenia thymus reprograms class-switched B cells into BAFF-dependent survivors,” was published in the journal Science Advances.
Although it’s well established that self-reactive antibodies drive MG, higher antibody levels aren’t closely linked with worse symptoms, and it’s long been unclear why.
At a fundamental level, the immune system’s job is to leave the body’s own healthy tissue alone — called immune tolerance — and attack everything else. The thymus acts like a boot camp for immune T-cells, advancing the survival of those that correctly target microbes or foreign molecules and promoting the death of those that target the body’s own molecules.
Researchers focus on B-cell workings
A small number of B-cells, the type of immune cell that produces antibodies, lives inside the thymus. They help present the body’s own molecules to T-cells to assist with the negative selection of self-reactive T-cells.
However, increasing evidence suggests that a second group of B-cells, which also produces antibodies, accumulates in the thymus during normal aging and organizes in germinal centers, or specialized structures that act as command centers of the immune system.
Autoimmune diseases like MG are fundamentally defined by a breakdown of immune tolerance in the thymus. While thymectomy may help treat MG by removing a source of tolerance breakdown, in some MG patients, the disease comes back nevertheless. It’s difficult for clinicians now to predict who will benefit from thymus removal and who won’t.
To learn more about the underlying mechanisms of MG, the researchers analyzed 18 thymus tissue samples from people with and without the rare condition. The team conducted detailed experiments to evaluate the activity of individual immune cells within the thymus, and found that MG is marked by changes in the activity of B-cells.
Under normal circumstances, B-cells need to interact with other immune cells to grow and trigger attacks. Like a buddy system, these interactions normally help keep cells in check, maintaining immune tolerance and preventing immune attacks against the body’s own tissues.
The researchers found that people with MG appeared to have reduced immune regulation due to dampened B cell-mediated presentation of molecules to other cells, including T-cells, in thymic germinal centers. These can result in fewer immunoregulatory interactions between these cells, the scientists noted.
Because this buddy system is broken, B-cells stop receiving needed signals from other cells, and instead essentially go rogue, activating their own self-perpetuating survival systems. These survival systems were found to be highly dependent on a signaling molecule called B-cell activating factor (BAFF), the scientists noted.
Results suggest ‘fundamental shift’ in understanding MG development
This work may be game-changing for how researchers and clinicians understand and treat MG, per the team.
“This study suggests a fundamental shift in myasthenia gravis [disease development],” the researchers wrote.
According to the scientists, “rather than resulting from simple … [growth of self-reactive] B cells, MG arises from a reprogramming of immune tolerance checkpoints within the thymus.”
The findings led the researchers to “suggest that [disease-driving] B cells escape normal selection pressures by switching from classical T-cell dependent activation to an innate survival program driven by BAFF signaling.”
Because these B-cells may persist in the thymus or other tissues even when the blood levels of self-reactive antibodies are relatively low, these data may help explain the disconnect between antibody levels and disease severity in MG.
Our hope is that we can now identify [MG] patients … who are at risk of having a recurrence after … thymectomy and after treatment. … What we’re hoping to do is … ultimately design clinical interventions that can kill those [disease-driving] cells and then prevent the recurrences.
The data may also have important implications for understanding which patients will or won’t benefit from thymectomy and other medical treatments — and identifying new treatment strategies.
“Our hope is that we can now identify patients … who are at risk of having a recurrence after the thymectomy and after treatment,” Bharat said. “What we’re hoping to do is identify those patients who are at risk and then ultimately design clinical interventions that can kill those cells and then prevent the recurrences.”
The researchers stressed that additional studies are needed to validate these results and expand on the potential therapeutic implications.
“This study gives us a map,” Bharat said. “The next step is to determine whether these pathways actively drive disease and whether they can be targeted to restore immune tolerance. That’s the promise of this research.”
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