Hidden DNA Mutations in Immune Cells Linked to Autoimmune Disease

A Decades-Old Hypothesis Finally Proven

Researchers at the Wellcome Sanger Institute, Cambridge University Hospitals, and the University of Cambridge have published findings in Nature that provide the strongest evidence yet for a hypothesis first proposed in the 1950s: that DNA mutations acquired during a person's lifetime can cause autoimmune disease.

What the Study Found

Using NanoSeq, an ultra-accurate single-molecule DNA sequencing method, the team analysed thyroid tissue from patients with autoimmune thyroid disease. They discovered that B cells had independently accumulated loss-of-function mutations in two critical immune checkpoint genes, TNFRSF14 and CD274 (PD-L1), across multiple clones in each patient. Some clones carried as many as six driver mutations that had built up silently over years before symptoms appeared, a pattern previously seen only in cancer.

These mutations effectively removed the molecular safeguards that prevent the immune system from attacking the body's own tissues. In highly inflamed biopsies, tens to hundreds of independent immune checkpoint mutant clones were detected.

Why It Matters

Autoimmune diseases affect 5-10% of the global population, yet current treatments broadly suppress the entire immune system, leaving patients vulnerable to infections. If confirmed, these findings could enable precision therapies that target only the mutant immune cells responsible for the attack.

Expert Reaction

Professor Chris Goodnow of the Garvan Institute called the study "a huge leap forward" that "changes everything." Senior author Dr. Inigo Martincorena said the process appears "far more widespread than we anticipated" and that the team has begun observing similar patterns in other autoimmune diseases.

What Comes Next

The polyclonal nature of the mutations, scattered across many small B cell clones rather than a single dominant clone, presents a therapeutic challenge. Future treatments would need to address a diverse population of mutant cells, but the discovery opens an entirely new chapter in autoimmune research.