For decades, scientists developing medicines for autoimmune diseases have relied heavily on blood samples to understand how the immune system behaves. A landmark study published in Nature Immunology now suggests that approach may reveal only part of the picture. Researchers at the La Jolla Institute for Immunology (LJI) have identified more than 1,000 disease-linked genetic changes hidden inside immune cells that permanently live in lung tissue—changes that cannot be detected in standard blood tests and could reshape future drug discovery.

The study analysed more than 1.1 million tissue-resident immune cells—immune cells that stay inside the lungs rather than circulate in the bloodstream—from healthy sections of lung tissue donated by 128 patients undergoing surgery for newly diagnosed lung cancer. Using single-cell RNA sequencing, a technique that examines the activity of individual cells one at a time, scientists created what they describe as the highest-resolution map yet of lung immune cells.

“These immune cells are meant to protect the body, but in some people they become dysfunctional and drive chronic inflammation,” said Dr Pandurangan Vijayanand, William K. Bowes Distinguished Professor at LJI. “This is a foundational paper for any researcher asking whether genetics has a role in an autoimmune disease.”

The findings may help explain why drug development for conditions such as lupus, rheumatoid arthritis and scleroderma has often proved difficult. Many patients with these diseases develop persistent lung inflammation, yet medicines are frequently designed and monitored using blood-based biomarkers. The new research suggests the immune cells living inside affected organs may behave very differently from those circulating in blood, meaning key disease signals could be missed.

Researchers also discovered around 1,700 genes whose activity differed between women and men. Many of these genes influence inflammatory pathways and may help explain why autoimmune diseases occur far more often in women. The findings raise the possibility that future treatments and dosing strategies could become more personalised, although the researchers caution that more work is needed before such approaches reach clinical practice.

“This dataset is unprecedented in both scale and resolution,” said Dr Benjamin Schmiedel, Assistant Professor at LJI. “No study has produced and analysed a dataset at this scale and resolution before.”

The work forms part of the Database of Immune Cell Epigenomics (DICE) project, an open scientific resource designed to connect genetic variation with immune cell function and accelerate the search for new therapeutic targets.

The findings are consistent with a growing body of research showing that tissue-resident immune cells play distinct roles in inflammation and organ-specific disease. At the same time, studies published in journals including Nature Reviews Rheumatology and The Lancet Rheumatology indicate that blood biomarkers such as C-reactive protein and circulating immune cells remain valuable for diagnosing disease, monitoring treatment response and predicting flares. Experts increasingly view tissue and blood analyses as complementary rather than competing approaches.

Although the study is observational and requires validation in broader populations and additional functional experiments, it offers a detailed genetic roadmap that could guide the development of more precise therapies aimed directly at inflamed organs instead of broadly suppressing the immune system.