For years, doctors assumed that DNA mutations in our cells were mainly the stuff of cancer. Now, researchers in Cambridge are revealing a quieter, more sinister role for these genetic changes—one that may drive autoimmune diseases long before symptoms ever appear. A new study published in Nature shows that some B cells accumulate mutations silently, building up genetic changes over many years before the immune system begins attacking the body's own tissues.
The research, led by scientists at the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust, and the University of Cambridge, focused on thyroid autoimmune disease—including Hashimoto's and Graves' disease, two leading causes of thyroid dysfunction worldwide. Using advanced DNA sequencing techniques, including a method called NanoSeq that can detect rare mutations invisible to traditional approaches, the team found something striking: many B cells in patients carried inactivating mutations in genes that normally act as crucial brakes on the immune system.
Two genes in particular stood out. TNFRSF14 and CD274 (also known as PDL1) were frequently mutated across multiple clones of B cells in each patient studied. Some of these mutated clones had accumulated as many as six driver mutations—changes that built up quietly over years, sometimes decades, before disease ever surfaced. This silent accumulation was entirely unexpected outside the context of cancer.
"This research reveals a hidden world of somatic evolution in B cells during autoimmunity," the researchers noted, describing it as the strongest evidence yet for an important role of these acquired mutations in a common autoimmune disease. The findings challenge a assumption that has persisted since the 1950s, when scientists first speculated that mutations in white blood cells might lift the brakes on the immune system.
Autoimmune diseases—including rheumatoid arthritis, multiple sclerosis, lupus, and type 1 diabetes—affect between 5 and 10 percent of the global population. Yet their molecular basis has remained poorly understood. The Cambridge team's work opens a new avenue: if these mutations are indeed driving disease, they could become targets for precision treatments tailored to individual patients. The fact that artificial inactivation of TNFRSF14 and CD274 is already known to cause thyroid autoimmunity during cancer immunotherapy lends additional weight to the findings.
Further research is needed to confirm the mechanism and explore whether it applies to other autoimmune conditions. But for the millions living with these diseases, the study offers something rare—a concrete clue where before there was mostly mystery.
"Some of these clones had even acquired as many as six driver mutations over many years, silently building up changes in DNA before symptoms appeared, a highly unexpected observation outside of cancer."