Summary: A groundbreaking discovery has finally provided evidence for a 70-year-old theory. Researchers found that autoimmune diseases—specifically thyroid conditions like Hashimoto’s and Graves’ disease—may be driven by somatic mutations. These are DNA changes acquired during a person’s life, rather than inherited.
Using ultra-accurate sequencing, the team discovered that immune cells (B cells) accumulate mutations that “cut the brakes” on the immune system, allowing it to attack the body’s own healthy tissues. This reveals a “hidden world” of evolution within our immune system that mimics the early stages of cancer development.
Key Facts
- A New Paradigm: This is the strongest evidence to date that somatic mutations—previously thought to primarily cause cancer—are a fundamental driver of common autoimmune diseases.
- Thyroid Focus: The study focused on Hashimoto’s and Graves’ disease, the leading causes of thyroid dysfunction, but researchers are already seeing similar patterns in other autoimmune conditions.
- Precision Medicine: Currently, autoimmune diseases are treated by broadly suppressing the entire immune system. This discovery opens the door for precision medicine that targets only the specific mutated cell clones.
- Historical Validation: Scientists first speculated about this “forbidden clone” theory in the 1950s, but lacked the technology to prove it until now.
- Global Impact: Autoimmune diseases affect 5% to 10% of the global population, making this a high-priority area for new diagnostic tools.
Source: Wellcome Sanger Institute
New research suggests that autoimmune diseases may be driven by DNA mutations in immune cells that remove the natural brakes on the immune system. It reveals a previously hidden role for somatic mutations — DNA changes acquired throughout life — in diseases beyond cancer.
Researchers from the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust (CUH), the University of Cambridge, and their collaborators used a series of cutting-edge techniques to identify previously unseen changes in DNA that may contribute to thyroid autoimmunity, where the immune system attacks the thyroid gland.
Reported today (14 April) in Nature, the findings could change the way we think about autoimmune diseases and provide a potential path towards precision medicine.
Autoimmune disease is an umbrella term for a long list of diseases in which the immune system mistakenly attacks the body’s own healthy cells, believing they are foreign pathogens.
Examples include rheumatoid arthritis, multiple sclerosis, lupus and type 1 diabetes. Autoimmune diseases affect five to 10 per cent of the global population, however their molecular basis remains poorly understood.
Somatic mutations are changes in DNA that occur in our cells over time and are not inherited. They are responsible for cancer and have long been speculated to contribute to other diseases. But studying these mutations outside of cancer has been technically challenging. Recent advances in DNA sequencing methods, including some spearheaded by the Sanger Institute over the last decade, now make their study across diseases possible.
Since the 1950s, some scientists have speculated that somatic mutations in lymphocytes – types of white blood cells, including B cells – could lift the brakes on the immune system, allowing it to attack the body’s own tissues during autoimmunity. Unlike cancer, which usually starts when a single mutated cell multiplies uncontrollably into a tumour, autoimmune diseases are driven by many different groups of immune cells acting together. This complexity has made the search for mutations in lymphocytes difficult.
In a new study, researchers at the Sanger Institute and their collaborators tested this idea, using a series of cutting-edge methods to investigate whether somatic mutations contribute to diseases beyond cancer.
The researchers studied thyroid autoimmune disease, including samples from consenting patients with Hashimoto’s and Graves’ disease, which are leading causes of thyroid dysfunction in the population.
The researchers used several advanced DNA analysis techniques. Firstly, they used a method called NanoSeq, which they recently developed and allows detection of rare mutations, invisible to traditional DNA sequencing methods, to look for genetic changes that may drive the disease. They found that many B cells had developed inactivating mutations in key genes that normally control the immune system.
Next, using additional methods that look at the DNA of individual cells and microscopic areas of tissue, the researchers found that many B cells in each patient carried several mutations in key genes.
Two critical immune-checkpoint genes, TNFRSF14 and CD274 (or PDL1), were often lost independently in multiple clones of mutated B cells in each patient. 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.
Importantly, artificial inactivation of these genes, in experimental studies or during cancer immunotherapy, is known to cause thyroid autoimmunity. The researchers have now found frequent mutations in these genes occurring in autoimmune patients.
This research reveals a hidden world of somatic evolution in B cells during autoimmunity and provides the strongest evidence to date for an important role of somatic mutations in a common autoimmune disease.
However, further research is required to confirm if these mutations are the root cause of autoimmune disease or perhaps just contribute to its exacerbation over time. The research team has also started to see similar results in other autoimmune diseases, but these are preliminary findings and require more investigation.
Dr Andrew Lawson, co-first author at the Wellcome Sanger Institute, said: “Our study suggests that somatic mutations in immune cells may play an important role in autoimmune disease, an idea first proposed in the 1950s that we have lacked the techniques to investigate.
“Now that we have NanoSeq, which we developed in the last few years, we can study somatic mutations with ultra-high accuracy and explore their contribution to autoimmune diseases, not just cancer.”
Dr Pantelis Nicola, co-first author formerly of the Wellcome PhD Programme for Clinicians in Cambridge, and currently a NIHR clinical lecturer at The Christie in Manchester, said: “Autoimmune diseases are currently treated by broadly suppressing the immune system, which can leave patients vulnerable to infections as well as a long list of other complications. If these findings are confirmed, they could eventually enable more precise diagnoses and treatments leading to better patient outcomes.”
Professor Chris Goodnow, Bill and Patricia Ritchie Chair, Professor at the Garvan Institute and University of New South Wales Sydney, who was not involved in the study but has pioneered the study of somatic mutations in autoimmunity for the last 20 years, said: “This is a huge leap forward into the pathogenesis of autoimmune disease.
“It changes everything, and explains so much that was up in the air. It reminds me of when NASA fixed the optics on the Hubble Telescope: suddenly all the stars and galaxies are crystal clear, and there is a lot more going on than we had ever imagined.”
Dr Iñigo Martincorena, senior author at the Wellcome Sanger Institute, said: “For decades, researchers have wondered whether somatic mutations might contribute to autoimmune disease, but evidence has been elusive.
“Our findings suggest this process is far more widespread than we anticipated. While we need further studies to confirm the role of these mutations, this work could mark the beginning of a new phase in understanding autoimmune disease.”
Funding:
This research was supported in part by Wellcome. A full list of acknowledgements can be found in the publication.
Key Questions Answered:
A: In a way, yes. Both involve cells that develop DNA mutations and escape normal biological controls. However, while cancer cells grow into a tumor, these “rogue” immune cells stay in the bloodstream and tissues, coordinating an attack against your own organs instead of multiplying uncontrollably.
A: No. These are somatic mutations, meaning they are “accidents” that happen in your DNA as you live and age. They aren’t passed down from your parents, which explains why someone can develop an autoimmune disease even if there is no family history.
A: Currently, we “blanket” the immune system with suppressants, which leaves you vulnerable to infections. This discovery could lead to targeted therapies—similar to how we treat specific cancers, that only kill the “rogue” mutated cells while leaving your healthy immune system intact.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Genetics research news
Author: Susannah Young
Source: Wellcome Trust Sanger Institute
Contact: Susannah Young – Wellcome Trust Sanger Institute
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity” by Pantelis A. Nicola, Andrew R. J. Lawson, Alexandra Tidd, Juliette Imbert, Yoshihiro Ishida, Luke A. Wylie, Paul A. Scott, Kenny Roberts, Luke M. R. Harvey, Stefanie V. Lensing, Wei Cheng, Federico Abascal, Daniel Leongamornlert, Yvette Hooks, Matthew Mayho, Nicole Müller-Sienerth, Sara Widaa, Laura Mincarelli, James Illing, Flavia Peci, Bee Ling Ng, Georgeina L. Jarman, Andrew J. C. Russell, Krishnaa T. A. Mahbubani, Kourosh Saeb-Parsy, Anna L. Paterson, Krishna Chatterjee, Raheleh Rahbari, Omer Ali Bayraktar, Michael R. Stratton, Peter J. Campbell, John A. Tadross, Nadia Schoenmakers & Iñigo Martincorena. Nature
DOI:10.1038/s41586-026-10493-9
Abstract
Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity
Our immune system contains multiple checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood.
A long-standing hypothesis posits that somatic mutations in immune-regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints1–3, but testing this has been challenging due to technical limitations.
Here, we use whole-exome and targeted NanoSeq4,5, an accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease.
This revealed many B cell clones convergently acquiring loss-of-function mutations in the key immune checkpoint genes TNFRSF14 (HVEM) and CD274 (PD-L1), as well as less frequent mutations in other immune genes.
In highly inflamed biopsies, we detected tens to hundreds of independent immune checkpoint mutant clones.
Laser microdissection, methylation sequencing, spatial transcriptomics, immunostaining, single-nucleus DNA sequencing, and antibody synthesis localised these mutations to B cells, confirmed some to be self-reactive, and identified clones carrying multiple hits.
We found widespread TNFRSF14 biallelic loss, and clones with as many as 4-6 driver mutations.
Whilst each clone accounts for a small fraction of cells (typically <1%), the myriad mutant clones in each donor amounted to a substantial fraction of B cells harbouring driver mutations.
Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution, providing new insights into the molecular basis of autoimmune disease.
