Could Somatic Mutations Help Drive Autoimmune Disease?
Scientists Revisit Decades-Old Autoimmune Theory With New DNA Technology
Researchers are uncovering new evidence that acquired mutations in immune cells may play a role in autoimmune disease, reviving a decades-old theory about how the immune system loses tolerance to the body’s own tissues.
In a new study published in Nature, researchers used an advanced ultra-sensitive DNA sequencing method called NanoSeq to analyze thyroid tissue from patients with autoimmune thyroid disease, including Hashimoto’s thyroiditis and Graves’ disease (1).
The team discovered large numbers of B-cell clones carrying somatic mutations, non-inherited genetic changes acquired over a person’s lifetime, in key immune checkpoint genes such as TNFRSF14 (HVEM) and CD274 (PD-L1).
Immune checkpoints normally help prevent excessive immune activation and autoimmunity. The researchers suggest that when self-reactive B cells acquire mutations that disable these checkpoints, the cells may gain a survival advantage and become more capable of evading normal immune suppression (2).
The findings support a long-standing “forbidden clone” hypothesis, first proposed in the 1950s, which suggested that autoimmune disease could arise when self-reactive immune cells acquire mutations that allow them to bypass tolerance mechanisms. The newer model described in the paper proposes that autoimmune disease may develop through a gradual, multi-step process in which multiple self-reactive immune cell clones independently accumulate mutations over time.
Importantly, the study did not identify a single dominant clone, as is often seen in cancer.
Instead, researchers found hundreds of separate mutated B-cell populations within inflamed thyroid tissue, with many converging on the same immune checkpoint pathways. While each clone represented only a small percentage of cells individually, together they made up a substantial portion of the infiltrating B cells. This finding supports the idea that autoimmune disease may involve widespread, polyclonal immune dysregulation rather than a single dominant abnormal clone.
The study also linked some of these mutated B cells directly to thyroid autoantibodies. Researchers synthesized antibodies predicted to be produced by certain mutated cells and found that several reacted to thyroid-associated antigens, including thyroid peroxidase and thyroglobulin. These findings suggest that some of the mutated B cells were not merely present in inflamed tissue but may have been directly involved in producing autoimmune responses.
The findings may also help explain why immune checkpoint inhibitor drugs used in cancer treatment can sometimes trigger thyroid inflammation and autoimmune complications.
Although the research does not prove that these mutations directly cause autoimmune disease, experts described the findings as some of the strongest evidence yet supporting a role for somatic evolution in common autoimmune disorders.
Future studies will be needed to determine whether similar mutation patterns occur across other autoimmune diseases and whether these processes could eventually become targets for diagnosis or treatment.
Citations
- 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
- Koralov, S. B., & Borbet, T. C. (2026). Hard-to-detect mutations explain how common autoimmune diseases arise. Nature, 10.1038/d41586-026-01415-w. Advance online publication. https://doi.org/10.1038/d41586-026-01415-w