‘Fiery death’-related genes may help guide diagnosis, treatment: Analysis
16 genes linked to cell death inflammation found atypically expressed in AS
More than a dozen genes related to inflammatory cell death were found to be expressed at atypical levels in ankylosing spondylitis (AS) patients in a new study, suggesting these genes could be used to help diagnose the disease.
The analyses also identified three small molecules that may help to normalize the activity of these genes, which could be potential treatments for the autoimmune disease.
“Our study will provide new insights into the molecular mechanism, diagnosis, and treatment of AS,” researchers wrote in the study, “Exploring hub pyroptosis-related genes, molecular subtypes, and potential drugs in ankylosing spondylitis by comprehensive bioinformatics analysis and molecular docking,” which was published in BMC Musculoskeletal Disorders.
Pyroptosis comes from Greek words meaning ‘fiery death’
Pyroptosis, from the Greek words meaning “fiery death,” is a form of cell death where a dying cell will spew out pro-inflammatory signaling molecules. Under normal circumstances, cells undergo pyroptosis when they are infected, which helps signal to the immune system that something is wrong — but accumulating evidence indicates that pyroptosis may also play a role in autoimmune disorders like AS.
In the study, a team of scientists from Henan University in China analyzed data from multiple genetic datasets looking for pyroptosis-related genes that are dysregulated in AS.
Results revealed 16 pyroptosis-related genes whose expression (activity) was altered in AS patients — six genes expressed at higher-than-normal levels, and 10 expressed at lower-than-normal levels.
Further analyses showed that levels of some of these genes correlated with levels of certain immune cells. For example, patients with higher levels of neutrophils (a type of immune cell that’s been implicated in the development and progression of AS) also tended to have higher levels of the pyroptosis-related genes NOD2, NLRP1, NLRP4, IRF2, IRF1, and IL18.
Based on these findings, the researchers said that “pyroptosis may affect the immune status of AS, and thus the progression of AS, and the abnormal expression of pyroptosis-related genes may be the beginning of autoimmunity and chronic inflammatory responses in AS,” though they noted that further research will be needed to fully understand these molecular mechanisms.
In further analyses, the scientists zeroed in on three of the pyroptosis-related genes that play central roles in this form of inflammatory cell death: TNF, NLRC4, and GZMB. The researchers created a mathematical model based on expression levels of these three genes with the aim of improving the diagnosis of AS.
To evaluate this model, the researchers calculated a statistical measure called the area under the receiver operating characteristic curve (AUC for short). AUC values can range from 0.5 to 1, with higher numbers reflecting a better ability to distinguish between two groups — in this case, people with or without AS.
‘Model could provide a valuable reference for the prediction of AS’
Results showed that the model based on the three genes had an AUC ranging from 0.713 to 0.881 in different tested datasets. These results indicate “that the model could provide a valuable reference for the prediction of AS,” the researchers wrote.
They also performed clustering analyses based on the original 16 pyroptosis-related genes, showing that patients could be broadly divided into two groups based on levels of these genes. The researchers noted that patients in the first group tended to have higher numbers of overall inflammatory immune cells, though patients in the second group had more neutrophils.
“Based on the characteristics of the two pyroptosis clusters, the powerful ability of different pyroptosis clusters to discriminate immune [profiles] was confirmed,” the team wrote.
In a final set of analyses, the researchers looked for potential therapies that, based on available data, might be expected to reverse AS-related changes in gene expression. This revealed three potential candidates: ascorbic acid (also known as vitamin C), RO 90-7501, and celastrol.
“These three drugs may have potential therapeutic value for AS and may even have different therapeutic effects for different pyroptosis subtypes of AS,” the researchers concluded, though they stressed that additional research will be needed to validate these findings.