Unveiling Hidden Drivers of Autoimmune Diseases Through Activated Immune Cells

Recent groundbreaking research has highlighted how activating immune cells can uncover hidden genetic factors that contribute to autoimmune diseases. Scientists from the Wellcome Trust Sanger Institute utilized a novel approach by stimulating macrophages—key immune cells responsible for engulfing harmful substances—to mimic infection and inflammation, revealing crucial insights into disease mechanisms.

In this extensive study, human induced pluripotent stem cells (iPSCs) from 209 healthy individuals were transformed into macrophages. These cells were then exposed to 24 different stimuli that simulate various infectious and inflammatory conditions, such as viral mimics and bacterial components. Researchers collected gene expression data at multiple time points post-stimulation, particularly at six and twenty-four hours, to analyze how gene activity changes during immune responses.

A significant outcome of this research is the creation of MacroMap, a large-scale dataset mapping genetic effects in immune cells under stimulated conditions. It demonstrated that many genetic variants linked to diseases, including inflammatory bowel disease and coronary artery disease, only show their influence when immune cells are activated. For instance, a genetic variant associated with coronary artery disease was found to elevate the activity of the gene CTSA after inflammatory stimulation—a connection missed when studying resting cells.

Complementing this, a parallel study within the MacroMap project explored RNA splicing variations in activated macrophages. The team identified over 5,000 genes with altered splicing patterns upon stimulation, with some variations tied to autoimmune disease risks. Notably, a genetic change affecting the expression of the inflammation regulator gene PTPN2 was linked to increased susceptibility to conditions like inflammatory bowel disease.

These findings emphasize the importance of studying gene behavior in dynamic, stimulated biological contexts rather than static resting states. Observing how genes become active during immune responses can significantly enhance our understanding of disease mechanisms and guide the development of targeted therapies, including RNA-based treatments. This research opens new pathways for investigating complex diseases by revealing otherwise hidden genetic influences, providing a more comprehensive map of disease risk factors.

Source: https://medicalxpress.com/news/2025-08-immune-cells-reveal-hidden-drivers.html