MG risk and immune system have a complex two-way connection
Cytokines may raise the risk of MG, which itself can increase cytokine levels
Certain inflammatory molecules known as cytokines may play a role in a person’s risk of developing myasthenia gravis (MG), according to a recent genetic study.
The research suggests some of these immune-system signaling molecules could increase the risk of the autoimmune disease, while others might offer protection. The findings, which offer new insights into MG and potential treatment avenues, also indicate that the disease itself can influence cytokine levels, including interleukin (IL)-1 alpha and tumor necrosis factor (TNF)-beta.
“Our results provided promising clues for the treatment of MG,” researchers wrote. “We evaluated the association between inflammatory cytokines and the disease by genetic informatics approach, which may help to better understand the underlying mechanisms of MG.”
The study, “Circulating inflammatory cytokines and the risk of myasthenia gravis: a bidirectional Mendelian randomization study,” was published in BMC Neurology.
Analyzing genetic links between inflammatory cytokines and MG
MG is an autoimmune disease characterized by symptoms such as muscle weakness and fatigue. It is caused by self-reactive antibodies targeting proteins involved in nerve-muscle communication, most commonly acetylcholine receptors (AChRs) in muscle cells.
Increasing evidence suggests inflammation mediated by cytokines released by immune cells is also involved in MG. However, “whether it is the cause or a downstream effect remains unclear,” the researchers wrote.
To learn more, researchers analyzed 91 inflammatory cytokines from a Genome-Wide Association Study (GWAS) database in Europeans, and genetic variants associated with MG in a GWAS database involving 1,873 people with AChR antibody-positive MG and 36,370 healthy individuals. In a GWAS, the entire set of genes (genome) of many people is scanned to find genetic variants that may be associated with a certain trait or disease.
Results showed some cytokines were associated with a significantly increased risk of developing MG, while others were linked to a lower risk. For example, CD40 ligand was associated with a 20% increased risk of developing MG, whereas IL-1 alpha, glial-cell-line-derived neurotrophic factor, osteoprotegerin, and TNF-beta were associated with a 20% to 26% lower risk of having MG.
Additionally, a reverse analysis showed MG influenced the levels of several cytokines, including TNF-beta, and IL-1 alpha.
Bidirectional causal relationship between certain cytokines, MG risk
“There is a bidirectional causal relationship between IL-1 [alpha] and TNF-[beta] and the risk of MG,” the researchers wrote.
In previous studies, IL-1 alpha has been associated with early-onset MG, shown to promote the differentiation of immune T- and B-cells, and assist in the production of self-reactive antibodies. In others, this cytokine was found to reduce the activation of autoimmune responses. In this study, the researchers found IL-1 alpha was associated with a lower risk of developing MG.
The cytokine TNF-beta, which is released by T-cells, elicits inflammation and induces cell death, with studies suggesting it may worsen MG symptoms. In this study, TNF-beta levels were generally associated with a lower MG risk.
“The reverse association of TNF-[beta] with the risk of MG in our study contradicts previous findings, and we suggested that it may be due to confounding bias in observational experiments or different genetic associations among different populations,” the researchers wrote.
They added that while “these correlation results need to be interpreted with caution, [they provide] a valuable direction for further research.”
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