Diabetes may worsen MG by activating antibody-producing cells
Study identifies signaling pathway as potential therapeutic target
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- Diabetes may worsen myasthenia gravis by activating antibody-producing B-cells.
- High blood sugar creates harmful compounds (AGEs) that activate the RAGE-HIF-1alpha-HK2 pathway.
- This pathway increases B-cell CD40 levels, making it a potential therapeutic target for MG with diabetes.
Diabetes, a condition marked by chronically high blood sugar (glucose) levels, may worsen symptoms in people with myasthenia gravis (MG) by promoting the activation of B-cells, the immune cells that produce the disease-causing antibodies, a study suggests.
The researchers found that harmful compounds that accumulate when excess sugar molecules bind to proteins and other molecules activate a signaling pathway, called RAGE-HIF-1alpha-HK2, that ultimately increases the levels of CD40, a receptor protein on B-cells that is essential for their activation.
The findings point to the RAGE-HIF-1alpha-HK2 pathway as a “potential therapeutic target for MG patients with [diabetes],” researchers wrote.
The study, “Diabetes mellitus exacerbates myasthenia gravis by upregulating CD40 expression on B cells through the RAGE–HIF-1α–HK2 pathway,” was published in Neuroimmunology.
Diabetes can alter immune responses in MG patients, studies show
MG is an autoimmune disease in which the immune system mistakenly produces self-reactive antibodies that target proteins needed for communication between nerves and muscles, leading to symptoms such as muscle weakness and fatigue. B-cells, the immune cells that produce antibodies, play a central role in driving the disease.
Previous studies have shown that diabetes can alter immune responses in MG patients and worsen MG in animal models.
CD40 is a receptor protein on the surface of B-cells that, when activated by its partner protein, stimulates the cells to become activated and produce antibodies. In MG, CD40 signaling plays a key role in generating the self-reactive antibodies that drive the disease. Increased CD40 activity can also amplify inflammation and further fuel autoimmune responses.
Yet, “the effects of [diabetes] on B-cell subsets and CD40 molecules in patients with MG remain unclear,” the researchers wrote.
Diabetes independently associated with more severe MG
To better understand how diabetes affects MG, a team of researchers conducted a study involving 56 people — 25 with diabetes, 31 without — diagnosed with MG at a single Chinese hospital between January 2022 and December 2023.
They analyzed blood samples to compare B-cell populations and CD40 levels between the two groups, and complemented these findings with animal and lab experiments to investigate the underlying biological mechanisms.
Although the two groups were similar in age, people with diabetes had been living with MG for significantly longer and, as expected, had higher glucose levels. They also had significantly greater muscle weakness and more difficulty performing everyday activities, as assessed with validated measures.
Even after accounting for differences in sex, disease duration, and previous treatments, diabetes remained independently associated with more severe MG.
When examining B-cell populations, the researchers found that most were present at similar levels in people with MG regardless of whether they had diabetes. However, those with diabetes had higher levels of certain B-cell populations, including antibody-producing cells.
MG people with diabetes also had significantly higher blood levels of interleukin 6, a proinflammatory molecule, and APRIL, a signaling molecule that helps B-cells survive and produce antibodies.
Together, these findings suggest that diabetes alters the balance of B-cell populations in ways that may promote antibody production and inflammation, potentially contributing to more severe MG.
The [RAGE–HIF-1alpha–HK2] signaling pathway, activated by AGEs, is strongly implicated in modulating CD40 [levels] and may represent a potential therapeutic target for MG patients with [diabetes].
Consistent with this idea, several B-cell populations, including antibody-producing cells, from people with both MG and diabetes had significantly higher levels of CD40 than those from participants with MG alone. Further statistical analyses showed that higher glucose levels were significantly associated with increased CD40 levels, which in turn were linked to more severe MG.
Similar increases in CD40 levels were seen on B-cells from a rat model of MG with diabetes, supporting the observations in people. The animals have experimental autoimmune MG, a condition that mimics many aspects of the human disease.
The researchers then investigated what was driving the increase in CD40. Experiments in lab-grown human B-cells showed that the key trigger was not high glucose itself, but advanced glycation end products (AGEs) — harmful compounds that accumulate when excess sugars bind to proteins and other molecules in the body. Exposure to AGEs increased CD40 levels on B-cells, whereas high glucose alone did not.
Further experiments revealed that AGEs increased CD40 levels through a chain of molecular signals involving the proteins RAGE, HIF-1alpha, and HK2. Blocking any step in this pathway prevented the AGE-induced increase in CD40, identifying the RAGE-HIF-1alpha-HK2 pathway as a potential driver of the heightened B-cell activation seen in people with both MG and diabetes.
“The [RAGE–HIF-1alpha–HK2] signaling pathway, activated by AGEs, is strongly implicated in modulating CD40 [levels] and may represent a potential therapeutic target for MG patients with [diabetes],” the researchers wrote, while noting that further studies are needed to confirm the study’s findings.
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