New research suggests that autoimmune diseases may be driven by DNA changes in immune cells that remove natural restraints on the immune system. The study, led by researchers from the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust, and the University of Cambridge, used advanced sequencing and related DNA analysis methods to identify previously unseen mutations that may contribute to thyroid autoimmunity.
The work, published in Nature, focuses on autoimmune disease as a broad category of conditions in which the immune system attacks healthy cells in the body. These diseases, which include rheumatoid arthritis, multiple sclerosis, lupus, and type 1 diabetes, affect an estimated 5 to 10% of the global population. Yet their molecular basis has remained poorly understood. The study points to somatic mutations, or DNA changes acquired during life rather than inherited, as an overlooked factor outside of cancer.
Somatic mutations have long been suspected to play a role in autoimmunity, but studying them has been difficult. Recent advances in DNA sequencing have made it possible to investigate these changes more precisely. In this study, the researchers used NanoSeq, a method they recently developed, to detect rare mutations that traditional sequencing methods would miss. They examined samples from patients with Hashimoto’s and Graves’ disease, two major causes of thyroid dysfunction, to see whether immune-cell mutations were present.
Their analysis found that many B cells carried inactivating mutations in genes that normally help regulate immune activity. Using additional techniques that examine single cells and microscopic regions of tissue, the team found that multiple B-cell clones in each patient carried several mutations. Two immune-checkpoint genes, TNFRSF14 and CD274, also known as PDL1, were repeatedly lost in separate clones. Some mutated clones had accumulated as many as six driver mutations over many years, suggesting that these changes built up long before symptoms appeared.
The findings provide the strongest evidence yet that somatic mutations may contribute to a common autoimmune disease. The researchers describe this as a hidden form of somatic evolution in B cells during autoimmunity. They also note, however, that more research is needed to determine whether the mutations directly cause disease or instead worsen it over time.
The study raises the possibility that sequencing-based approaches could eventually support more precise diagnosis and treatment. Since autoimmune disease is now often treated by broadly suppressing the immune system, identifying the specific mutations involved could open the door to more targeted strategies.
Publication details: Nicola, P.A., Lawson, A.R.J., Tidd, A. et al. Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity. Nature (2026). https://doi.org/10.1038/s41586-026-10493-9
The work, published in Nature, focuses on autoimmune disease as a broad category of conditions in which the immune system attacks healthy cells in the body. These diseases, which include rheumatoid arthritis, multiple sclerosis, lupus, and type 1 diabetes, affect an estimated 5 to 10% of the global population. Yet their molecular basis has remained poorly understood. The study points to somatic mutations, or DNA changes acquired during life rather than inherited, as an overlooked factor outside of cancer.
Somatic mutations have long been suspected to play a role in autoimmunity, but studying them has been difficult. Recent advances in DNA sequencing have made it possible to investigate these changes more precisely. In this study, the researchers used NanoSeq, a method they recently developed, to detect rare mutations that traditional sequencing methods would miss. They examined samples from patients with Hashimoto’s and Graves’ disease, two major causes of thyroid dysfunction, to see whether immune-cell mutations were present.
Their analysis found that many B cells carried inactivating mutations in genes that normally help regulate immune activity. Using additional techniques that examine single cells and microscopic regions of tissue, the team found that multiple B-cell clones in each patient carried several mutations. Two immune-checkpoint genes, TNFRSF14 and CD274, also known as PDL1, were repeatedly lost in separate clones. Some mutated clones had accumulated as many as six driver mutations over many years, suggesting that these changes built up long before symptoms appeared.
The findings provide the strongest evidence yet that somatic mutations may contribute to a common autoimmune disease. The researchers describe this as a hidden form of somatic evolution in B cells during autoimmunity. They also note, however, that more research is needed to determine whether the mutations directly cause disease or instead worsen it over time.
The study raises the possibility that sequencing-based approaches could eventually support more precise diagnosis and treatment. Since autoimmune disease is now often treated by broadly suppressing the immune system, identifying the specific mutations involved could open the door to more targeted strategies.
Publication details: Nicola, P.A., Lawson, A.R.J., Tidd, A. et al. Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity. Nature (2026). https://doi.org/10.1038/s41586-026-10493-9