Four-gene signature may help identify Sjögren’s disease, study finds

Four genes related to an immune signaling protein called interferon-gamma (IFN-gamma) are more active in people with Sjögren’s disease, and measuring their activity levels may help distinguish patients from healthy individuals, a study found.

Further analysis pointed to macrophages — immune cells involved in inflammation, tissue repair, and IFN-gamma signaling — as potentially important players in the disease, showing altered developmental states and stronger predicted communication with other immune cells.

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IFN-gamma pathway tied to immune dysregulation

“Collectively, this study established an [IFN-gamma-associated] diagnostic model for [Sjögren’s] and implicated macrophages as potential key contributors to immune dysregulation,” the researchers wrote.

The study, “Single-Cell RNA Sequencing Revealed the Role of Interferon-Gamma Related Genes in Primary Sjögren’s Syndrome,” was published in the Journal of Cellular and Molecular Medicine.

While the underlying mechanisms of Sjögren’s, an autoimmune disease, remain incompletely understood, abnormalities in different parts of the immune system are thought to be involved.

IFN-gamma is a key signaling protein produced by several types of immune cells and helps coordinate immune responses. It activates genes involved in inflammation and immune defense, and previous research suggests that IFN-gamma signaling may be implicated in Sjögren’s.

However, the molecular mechanisms behind IFN-gamma’s potential role in Sjögren’s “remain incompletely characterized,” the researchers wrote.

Three researchers in China aimed to identify IFN-gamma-related genes associated with Sjögren’s and determine which immune cells and biological processes might connect these genes to the disease. They also explored whether the genes could form the basis of a potential diagnostic model.

They first analyzed publicly available blood gene-activity data from 30 people with Sjögren’s and 30 healthy controls (training dataset). Findings were then tested in an independent validation dataset with data from 11 Sjögren’s patients and 16 healthy controls.

In the training dataset, initial analyses identified 915 genes whose activity differed between patients and controls. Of these, 74 overlapped with IFN-gamma-related genes and were especially associated with antiviral and inflammatory processes.

“These results collectively indicated that [IFN-gamma] dysregulation in [Sjögren’s] might drive a pronounced antiviral and inflammatory [molecular] program,” the researchers wrote.

Four-gene signature performs well in validation

Using two machine-learning methods to narrow the candidates with greater diagnostic potential, the researchers identified seven genes that performed well in the training dataset. Four of them — HERC6, IL15, CD58, and PTGS2 — also showed good discrimination between patients and healthy controls in the independent validation dataset.

In addition, these four genes showed consistently higher activity in Sjögren’s patients than in controls in both datasets.

These four genes were therefore used to build a diagnostic model, whose performance was assessed using the area under the curve (AUC), a statistical measure in which a value of 1 represents perfect separation between patients and controls, while 0.5 is no better than chance.

The diagnostic model had an AUC value of 0.994 in the training dataset and 0.983 in the validation dataset, indicating very strong ability to distinguish patients from controls in these datasets.

Further analyses also suggested substantial differences in multiple metabolic and immune signaling pathways between patients and controls.

Several immune cell populations, including macrophages and certain dendritic and T-cell populations, were estimated to be more abundant in Sjögren’s patients than in healthy controls. Higher activity of each of the four genes was significantly associated with a greater estimated presence of macrophages.

The team then analyzed publicly available single-cell RNA sequencing data from blood immune cells from five patients and five healthy controls. The technique measures gene activity in individual cells rather than averaging signals across an entire sample. Among the immune cells examined, macrophages had the highest average activity of all four key genes.

Single-cell analysis reveals altered macrophage states

Researchers identified 386 genes with altered activity in Sjögren’s macrophages, with many involved in cell death, immune signaling, interactions between immune cells, and processes related to fatty molecules.

Further analyses showed that macrophages from people with Sjögren’s were enriched in early stages of development. The researchers said this might reflect disrupted macrophage development or accelerated entry into differentiation pathways.

Macrophages also showed particularly strong predicted communication with other immune cells, including dendritic cells and T and B cells, supporting the idea that they may serve as signaling hubs within the abnormal immune environment.

Finally, the scientists measured the activity of the four genes in blood cells collected from a new group of 65 people with Sjögren’s and 30 healthy controls. HERC6, IL15, and PTGS2 were significantly more active in patients. CD58 trended higher, but the difference was not statistically significant.

The findings “offer additional insight into the [immune-related] mechanisms underlying [Sjögren’s] and highlight candidate molecular targets for therapeutic intervention,” the researchers concluded.