Study Identifies Hidden B-Cell Mutations in Autoimmune Disease

Common examples include rheumatoid arthritis, multiple sclerosis, lupus, and type 1 diabetes. Although these disorders affect an estimated 5% to 10% of the global population, their molecular underpinnings remain poorly understood.

Somatic mutations, which are DNA changes that arise in cells over time and are not inherited, are well established in cancer and have long been suspected to contribute to other diseases, yet they have been difficult to study outside oncology. Recent advances in DNA sequencing methods now enable their investigation across a broader range of conditions. New findings show that previously undetected B-cell mutations can accumulate for years before thyroid autoimmunity becomes clinically apparent.

Wellcome Sanger Institute researchers, together with Cambridge University Hospitals NHS Foundation Trust (CUH), the University of Cambridge, and collaborators, investigated whether somatic mutations in lymphocytes contribute to autoimmune thyroid disease. The work, published on April 14 in Nature, centers on NanoSeq, an ultra‑accurate sequencing approach the team recently developed to detect rare mutations that are invisible to standard DNA sequencing. Using this and complementary analyses, the investigators probed the genetic landscape of immune cells involved in thyroid autoimmunity.

The study assessed samples from consenting patients with Hashimoto's and Graves' disease, two leading causes of thyroid dysfunction. With NanoSeq, the team identified previously unseen, inactivating mutations in key immune-regulatory genes in many B cells. Additional single‑cell and spatially targeted DNA analyses showed that numerous B‑cell clones within each patient carried multiple mutations.

Loss‑of‑function changes in two immune‑checkpoint genes, TNFRSF14 and CD274 (PD-L1), were found repeatedly and independently across multiple B‑cell clones in each patient. Some clones had accrued as many as six driver mutations over many years, silently building genetic alterations long before symptoms appeared. Artificial inactivation of these checkpoint genes in experimental studies or during cancer immunotherapy is known to cause thyroid autoimmunity, and the researchers observed frequent mutations in these genes among the autoimmune cohorts studied.

Collectively, the findings reveal a hidden layer of somatic evolution in B cells during autoimmunity and provide strong evidence that such mutations play an important role in a common autoimmune disease. The authors note that further research is needed to determine whether these mutations initiate disease or exacerbate it over time. Similar mutational patterns are beginning to surface in other autoimmune conditions, though these observations are preliminary and require additional validation.

"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," said Dr. Pantelis Nicola, co-first author formerly of the Wellcome Ph.D. Program for Clinicians in Cambridge, and currently an NIHR clinical lecturer at The Christie in Manchester.

“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,” said Dr. Iñigo Martincorena, senior author at the Wellcome Sanger Institute.

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