Summary: A major new study provides the strongest evidence yet for a long-standing theory: somatic mutations—DNA changes acquired during life—can drive common autoimmune diseases. The team found that B cells in patients with thyroid autoimmunity (Hashimoto’s and Graves’ disease) frequently accumulate mutations that disable key immune checkpoints, effectively removing the brakes on the immune system and enabling it to attack healthy thyroid tissue.
Key Facts
- New paradigm: The work offers compelling support for the idea that somatic mutations, previously associated mainly with cancer, are also a core mechanism in some autoimmune diseases.
- Thyroid focus: The study examined Hashimoto’s and Graves’ disease, the most common causes of autoimmune thyroid dysfunction, and observed patterns that may extend to other autoimmune conditions.
- Precision medicine potential: Current therapies broadly suppress the immune system. Identifying specific mutated B cell clones opens a path toward targeted treatments that spare healthy immunity.
- Historical validation: The concept of “forbidden” or self-reactive clones driven by acquired mutations dates back to the 1950s; modern sequencing now makes testing that idea possible.
- Public health relevance: Autoimmune diseases affect an estimated 5–10% of people worldwide, making improved diagnostics and therapies a major priority.
Source: Wellcome Sanger Institute
New research reveals a previously hidden layer of biological change within the immune system: somatic evolution of B cells. Using ultra-accurate DNA sequencing and multiple complementary molecular methods, researchers detected numerous independent B cell clones in patients with thyroid autoimmunity that carry loss-of-function mutations in genes that normally restrain immune responses.
Autoimmune diseases occur when the immune system mistakenly attacks the body’s own tissues. Conditions such as rheumatoid arthritis, multiple sclerosis, lupus and type 1 diabetes are well-known examples. Despite their prevalence, the molecular triggers that allow self-reactive immune cells to escape normal tolerance checkpoints have been difficult to define.
Somatic mutations are DNA changes that arise in individual cells during a person’s life rather than being inherited. They are well established as drivers of cancer, but their role in non-cancer conditions has been hard to study because many of these mutations are rare and technically challenging to detect. The Sanger Institute and collaborators applied recent advances in sequencing to search for such mutations in thyroid autoimmunity.
The team analyzed samples from consenting patients with Hashimoto’s and Graves’ disease using a suite of sensitive assays. Central to their approach was NanoSeq, a single-molecule sequencing method developed to detect ultra-rare mutations that conventional methods miss. NanoSeq and targeted whole-exome sequencing revealed that many B cells carried inactivating mutations in immune-checkpoint genes.
Two genes stood out: TNFRSF14 (also known as HVEM) and CD274 (PD-L1). The study found frequent, independent loss-of-function mutations of these checkpoint genes in multiple B cell clones within the same patient. Some clones carried several driver mutations—up to four to six—accumulating slowly over years before clinical symptoms appeared. This polyclonal pattern of somatic evolution resembles the early stages of cancer development but results in cells that promote autoimmunity rather than form tumours.
The researchers used laser microdissection, methylation sequencing, spatial transcriptomics, immunostaining and single-nucleus DNA sequencing to localize the mutations to B cells, demonstrate that some mutated clones are self-reactive, and establish that multiple independent clones can exist in highly inflamed thyroid tissue. While each clone typically represents a small fraction of total cells, together they can make up a substantial portion of B cells in affected tissue.
These findings show somatic mutation and selection operating within the immune system during autoimmunity and provide strong molecular evidence supporting the hypothesis that acquired mutations in lymphocytes can allow self-reactive cells to bypass tolerance mechanisms. The work does not yet prove that these mutations are the sole root cause of disease, but it establishes a plausible and testable mechanism that could exacerbate or initiate autoimmune responses.
Authors and co-first authors emphasize the clinical implications: if confirmed in larger studies and across additional autoimmune diseases, this mechanism could enable diagnostic tests that detect pathogenic mutant clones and therapies that selectively target them. That approach would be more precise than current broad immunosuppression and could reduce infection risk and other side effects.
Independent experts who have studied somatic mutations in autoimmunity welcome the results as an important advance that clarifies previously puzzling observations and opens new directions for research and treatment development.
Funding:
This research was supported in part by Wellcome. Full acknowledgements are listed in the publication.
Key Questions Answered:
A: In a limited sense. Both involve cells that acquire DNA mutations and evade normal biological controls. Unlike cancer, these mutated immune cells generally do not form tumours; instead, they persist in blood and tissues and drive immune attacks on healthy organs.
A: No. These are somatic mutations—changes that occur during life in individual cells. They are not inherited from parents and can arise even without a family history of autoimmunity.
A: Current treatments broadly suppress immunity. If these findings are validated, they could lead to targeted therapies that eliminate or modulate specific mutated clones, preserving overall immune function while treating the disease more precisely.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The full journal paper was reviewed for accuracy.
- Additional context was added by staff editors.
About this genetics research news
Author: Susannah Young
Source: Wellcome Sanger Institute
Contact: Susannah Young, Wellcome Sanger Institute
Image: Image credit: Neuroscience News
Original Research: Closed access.
Title: Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity
Authors: 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.
Journal: Nature
DOI: 10.1038/s41586-026-10493-9
Abstract
Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity
The immune system uses multiple checkpoints to prevent self-reactive lymphocytes from causing harm. How some lymphocytes bypass these tolerance mechanisms has been unclear. A longstanding hypothesis proposes that somatic mutations in immune-regulatory genes permit self-reactive cells to evade checkpoints, but detecting such mutations outside cancer has been technically difficult.
Using whole-exome sequencing and targeted NanoSeq, an ultra-accurate single-molecule DNA sequencing protocol, researchers searched for driver mutations in autoimmune thyroid disease. They discovered convergent loss-of-function mutations in the immune checkpoint genes TNFRSF14 (HVEM) and CD274 (PD-L1), along with less frequent mutations in other immune genes. Highly inflamed biopsies contained tens to hundreds of independent mutant clones.
Complementary techniques—laser microdissection, methylation sequencing, spatial transcriptomics, immunostaining, single-nucleus DNA sequencing and antibody synthesis—localized mutations to B cells, confirmed self-reactivity in some clones, and identified clones carrying multiple driver mutations. Widespread biallelic loss of TNFRSF14 and clones with up to four to six driver mutations were observed. Although individual clones were typically rare (<1% of cells), the combined burden of mutant clones represented a substantial fraction of the B cell population in each donor.
These results support the model that polyclonal somatic evolution in lymphocytes can enable escape from immune tolerance, offering new molecular insight into the origins of autoimmune disease.