Activated immune cells reveal hidden drivers of autoimmune diseases
By stimulating macrophages – a type of white blood cell – with biological factors that mimic infection, researchers have uncovered genetic drivers of complex diseases such as inflammatory bowel disease (IBD), in one of the largest studies of its kind.
Published today (27 August) in Nature Communicationsi, scientists from the Wellcome Sanger Institute reveal insights into how our genes influence the risk of developing common diseases, by studying immune cells that have been activated by 24 stimuli mimicking real-life conditions.
The findings have resulted in a large dataset known as MacroMap, which provides a new map of genetic effects in immune cells. The results also pave the way for future studies that aim to explore genes in certain disease contexts in a more realistic and representative way.
Many genetic variants – changes in DNA – associated with disease are thought to influence the extent to which genes are turned on or off. However, these changes are often missing from current databases that map genetic differences that influence gene expression. One reason for this is because studies often use ‘resting’ cells. This means the cells have not been activated by different stimuli – for example, by bacterial or viral infections. This does not give the full picture of gene activity when cells are activated during a normal immune response.
In a new study, researchers from the Sanger Institute sought to understand how genetic differences between people affect the behaviour of a type of immune cell, called a macrophage, when stimulated to different conditions and stressors. Macrophages are a form of white blood cell responsible for engulfing and digesting harmful substances or cellular debris.
Firstly, the researchers used human induced pluripotent stem cells (iPSCs), which are cells taken from adult tissue that can be programmed to become many different cell types. They took these stem cells from 209 healthy people and turned them into macrophages.1 Then, to study how genes behave under different conditions, they activated the macrophages with 24 different stimuli that trigger an immune response and mimic infections and inflammation. These stimuli include components such as viral mimics, bacterial elements and immune signalling molecules. They then collected RNA from the cells six and 24 hours after stimulation to measure gene expression to see which genes were turned on or off in response to each stimulus.
The large-scale dataset produced from the study, called MacroMap, revealed that many links between genes and diseases were only visible after stimulation. They found 1,955 instances where gene activity overlapped with genetic variants that are associated with disease, and over half of these – 51 per cent – would have been missed using unstimulated cells. For example, a genetic variant associated with coronary artery disease was found to increase the activity of a gene called CTSA, but only when macrophages were stimulated with inflammatory signals.2
In a complementary study, which is also part of the MacroMap project and published today in Nature Communicationsii, the same team looked at RNA splicing – a process where cells cut and rearrange RNA, which is the instructions from DNA to make proteins. The researchers aimed to understand how genes were spliced under the same 24 stimuli and how people’s genetic differences influenced splicing patterns.
They found that over 5,000 genes changed their splicing patterns when macrophages were activated by stimuli and that genetic risk factors for autoimmune diseases were linked to differences in splicing. One genetic change was found to increase the use of a rare version of a gene called PTPN2, which normally helps control inflammation, and so it is suggested that this change may increase the risk of developing IBD.
Together, these studies highlight the importance of studying genes in the right biological context. What the researchers saw is that many disease-related genetic effects are invisible in resting cells, so future studies may increasingly focus on dynamic or stimulated cells to uncover the full picture of how genes influence health and disease. By revealing how certain genes only become active during immune responses, this research may also inform treatment research such as RNA therapeutics, which offer a novel approach to targeting diseases that are difficult to treat with traditional medicines.
“Our project, MacroMap, provides a valuable reference point as it’s a rich dataset that researchers can use to explore genetic mechanisms behind a wide range of diseases. MacroMap extends beyond autoimmune diseases, as immune cells such as macrophages are found throughout the body, so we hope we and many other researchers can use MacroMap for studying other diseases. Additionally, by studying alternative splicing, MacroMap not only investigates which genes are turned on/off but also which versions of genes are expressed. We trust that our study shows that the macrophage response changes gene expression both quantitatively and qualitatively.”
Dr Omar El Garwany, co-first author at the Wellcome Sanger Institute
“In this study, we aimed to take a more realistic approach to studying autoimmune conditions by using different stimuli to mimic what naturally occurs in disease-relevant contexts. For example, when you have an infection, a specific pathway is triggered, so we stimulated the cells to replicate that response. We hope our study will serve as a stepping stone towards providing a more comprehensive picture of the cellular and molecular processes during disease and how genetic differences between people influence these processes.”
Dr Nikolaos Panousis, co-first author, formerly at the Wellcome Sanger Institute
“By uncovering how our genes behave during more realistic immune response scenarios, our research brings us closer to understanding the genetics behind why some people are more vulnerable to certain diseases. We hope our research will help enable more effective prevention and treatment of diseases in the future.”
Dr Carl Anderson, senior author at the Wellcome Sanger Institute
More information
Notes to Editors
- In 2012, the Wellcome Sanger Institute and five other institutes came together to develop a unique resource: a global portal with induced pluripotent stem cells containing information from hundreds of individuals. This crystalised into the Human Induced Pluripotent Stem Cell Initiative (HipSci) project, which generated what is still today the largest induced pluripotent stem cell resource available worldwide and was made possible by a grant from Wellcome and the Medical Research Council (MRC). To read more about this project, please see here: https://sangerinstitute.blog/2024/07/03/one-cell-to-rule-them-all/
- CTSA provides instructions for making the cathepsin A protein, which is an enzyme involved in breaking down materials, and it is also thought to contribute to the development of artery plaques.
Publications
i. Panousis, N. et al. (2025) ‘Gene expression QTL mapping in stimulated iPSC derived macrophages provides insights into common complex diseases.’ Nature Communications. DOI: 10.1038/s41467-025-61670-9
ii. El Garwany, O. et al. (2025) ‘Low-usage splice junctions underpin immune mediated disease risk.’ Nature Communications. DOI: 10.1038/s41467-025-61669-2
Funding
These studies were supported in part by Wellcome and the Medical Research Council. A full list of funders can be found in the acknowledgement section of each publication.
