Immune changes seen in late-onset Pompe may affect treatment response
T-cell activity and immune balance changes seen in patients and mice
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Certain immune cells in people with late-onset Pompe disease (LOPD) show abnormal activation that may be linked to differences in how patients respond to treatment, a new study suggests.
Researchers found that T-cells, a type of immune cell that helps coordinate the body’s response to infections and other threats, show increased activation when stimulated in people with LOPD, with greater growth and production of proinflammatory molecules. These findings were supported by experiments in mice, which showed broader disruptions in immune balance.
Immune changes may influence response to Pompe treatment
Such changes could lead to unexpectedly strong immune responses that may affect how well treatments work, including enzyme replacement therapy (ERT), the mainstay of Pompe treatment, the researchers noted.
“Our observations indicate that immune [balance] is altered in [Pompe disease],” the researchers wrote, adding that such findings offer new insights into immune dysfunction linked to the condition and highlight the need for further studies to better understand its role in the disease.
The study, “Identification of alterations of immunometabolism associated with Pompe disease,” was published in Cellular and Molecular Life Sciences.
Pompe disease is caused by mutations that result in a deficiency of acid alpha-glucosidase (GAA), an enzyme needed to break down the complex sugar molecule glycogen. Without enough GAA, glycogen builds up to toxic levels in muscle cells, leading to progressive muscle weakness and other symptoms. In LOPD, symptoms typically begin after age 1 and can appear through adulthood.
In muscle cells, glycogen builds up inside lysosomes, the compartments that break down cellular waste. Over time, excess glycogen disrupts autophagy — the cell’s recycling system — leading to a buildup of waste products. It also impairs the clearance of worn-out mitochondria, the cell’s energy-producing structures, which can contribute to reduced energy production.
“Whereas most research addressing the [Pompe disease features] is focused on the impact of glycogen accumulation and autophagic buildup on muscle impairment, there are no reports on how [disease-causing] glycogen accumulation affects the regulation of immune cells,” the researchers wrote.
Cellular processes tied to immune function in Pompe
This question is particularly important because glycogen production supports the formation and survival of certain T-cells, while autophagy and proper mitochondrial function are essential for the activation and development of regulatory T-cells, or Tregs, a group of immune cells that help keep the immune system in check.
Because these processes are central to immune function, they may also be linked to differences in how patients respond to treatment. Immune responses against the enzyme delivered through ERT, which replaces the missing enzyme in Pompe, can sometimes reduce how well the therapy works. Previous studies by the researchers have shown that immune cells from certain people with LOPD can mount strong inflammatory responses even without prior exposure to the therapy, supporting further investigation.
The team, led by researchers in France, analyzed immune cells from people with LOPD and compared them with those from healthy donors. They also conducted detailed immune profiling in a Pompe mouse model lacking the GAA enzyme.
When stimulated in the lab, T-cells from people with LOPD showed higher levels of activation markers compared with those from healthy individuals, while no differences were observed at rest. These cells also produced higher levels of proinflammatory molecules and grew more rapidly. Together, these findings indicate an increased activation state of T-cells in people with LOPD.
In contrast, T-cells from Pompe disease mice showed increased activation even without stimulation. At the same time, Tregs showed impaired activation along with a reduced ability to suppress immune responses. These findings point to a disruption in immune balance.
Cellular defects linked to immune changes in Pompe
Further analyses revealed that these immune changes were linked to underlying cellular defects. T-cells from Pompe mice showed disrupted autophagy and impaired clearance of mitochondria, along with increased glycogen levels, changes similar to those seen in affected muscle cells. These defects were also associated with reduced energy production.
The researchers also found a lower frequency of a subset of dendritic cells (DCs), known as cDC1, along with increased production of inflammatory molecules and reduced expression of IDO1, a protein that helps regulate immune responses. DCs are immune cells that help detect threats and activate T-cells.
These changes were associated with increased T-cell activation and growth, suggesting that GAA deficiency may impair the normal development and function of regulatory DCs and “contribute to the steady-state inflammatory profile” of T-cells in Pompe, the researchers wrote.
“Our studies provide the first evidence that autophagy and metabolic defects reported in [Pompe] muscle tissue also occur in T cells, and possibly in other immune cells such as DCs,” the researchers wrote. They added that, although these findings should be confirmed in patient samples, they “underscore the importance of understanding the immune system in [Pompe]” and of developing “strategies to harness Treg induction” to improve the effectiveness of ERT and emerging gene therapies.
