4 genes linked to inflammatory cell death very active in Sjögren’s
Pyroptosis genes ID'd as possible biomarkers, targets
Four genes involved in a form of cell death called pyroptosis are highly active in people with Sjögren’s disease and may serve as disease biomarkers or therapeutic targets, a study reports.
By examining the activity of each of the genes — PECAM1, IFI16, AIM2, and MPEG1 —the researchers were able to differentiate between people with Sjögren’s and those without accurately. Based on the genes’ potential involvement in several immune processes, the researchers hypothesized that they may provide insights into the underlying mechanisms of Sjögren’s disease.
“Targeting these pyroptosis-associated genes may provide novel therapeutic avenues for modulating immune responses in [Sjögren’s], warranting further investigation into their functional roles in disease [development] and treatment strategies,” they wrote. The study, “Identification and Validation of Pyroptosis-Associated Gene Signature in Primary Sjögren’s Syndrome,” was published in Mediators of Inflammation.
In Sjögren’s, the immune system mistakenly attacks the body’s cells, most often in the glands that produce saliva and tears, resulting in inflammation and dry eyes and mouth.
The condition may occur on its own, known as primary Sjögren’s or simply Sjögren’s, or alongside another autoimmune disease, referred to as secondary Sjögren’s.
Pyroptosis’s link to developing Sjögren’s
Pyroptosis is a programmed form of inflammatory cell death, where actual or perceived immune threats trigger the assembly of inflammatory proteins, causing the cell to swell and eventually burst, releasing its contents, including additional inflammatory molecules.
Previous research has implicated pyroptosis in a number of inflammatory and autoimmune diseases. Also, Sjögren’s has been associated with high levels of inflammatory components involved in pyroptosis, “suggesting a potential link between pyroptosis and [Sjögren’s development],” the researchers wrote.
The potential role of pyroptosis in Sjögren’s is still unknown, however. In this study, researchers in China said they set out to “identify pyroptosis-related gene (PRG) signatures in [Sjögren’s] through bioinformatic analysis and experimental validation, laying a foundation for future studies exploring their roles in disease mechanisms and as potential therapeutic targets.”
The researchers sought to identify significant differences in gene activity between people with Sjögren’s and healthy controls using gene activity data from relevant glands. Of the hundreds of genes with different activity patterns, 22 were related to pyroptosis. Further analyses showed the genes were also involved in regulating the immune system and inflammatory signaling, suggesting they “contribute to inflammatory and immune responses in [Sjögren’s].”
Diagnosing Sjögren’s
From this set of 22 potential PRGs, computational models found eight with the strongest possible value in diagnosing Sjögren’s: CRTAC1, PECAM1, IRF2, GZMA, IFI16, AIM2, TNF, and MPEG1. The models generated a Sjögren’s risk score by comparing relative levels of these genes.
In two different data sets, levels of each of these eight genes allowed researchers to discriminate people with Sjögren’s from healthy controls with an accuracy that ranged from 62% for CRTAC1 to 94% for MPEG1.
“Together, these results indicate that the eight-gene diagnostic model is both accurate and generalizable and may serve as a promising tool for the early diagnosis of [Sjögren’s],” wrote the researchers, who used the model to separate Sjögren’s patients into high-and low-risk. Several immune cell types, including specific B-cells and T-cells, were more active in the high-risk group, they found.
“Several key genes, including IFI16, PECAM1, and AIM2, were positively associated with activated immune cell subsets, particularly within the high group,” they wrote, noting the results indicated the eight key PRGs may serve as diagnostic markers, and also “contribute to shaping the immune landscape in [Sjögren’s].”
To validate their findings, the researchers analyzed tissue samples from Sjögren’s patients and a mouse model, along with those from their healthy counterparts. Four of the eight PRGs — PECAM1, IFI16, AIM2, and MPEG1 — were significantly more active in samples from both Sjögren’s patients and mice.
“These findings … provide robust validation of PECAM1, IFI16, AIM2, and MPEG1 as pyroptosis-associated biomarkers in both experimental and clinical contexts of [Sjögren’s],” the researchers wrote. “Given their involvement in pyroptosis and immune regulation, these four key genes hold potential as clinical biomarkers and therapeutic targets for [Sjögren’s].”
While the remaining four PRGs showed no significant differences in terms of activity between patients and healthy controls, they “may still contribute to disease progression through regulatory or signaling interactions with other PRGs, despite lacking strong differential [levels],” the researchers wrote.
They said studies of larger groups of patients are needed to confirm these findings, and studies could also more thoroughly investigate the biological pathways in which each of these genes is involved. The findings may support using these genes in diagnostic testing, tracking disease activity, or as therapeutic targets.
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