DNA Mutations In Immune Cells May Be Driving Autoimmune Diseases, Study Finds

Autoimmune diseases could be driven by DNA mutations in immune cells that remove natural brakes on the immune system, according to a new study that used advanced DNA sequencing methods. Findings published in the journal Nature reveal a previously hidden role for somatic mutations. DNA changes acquired throughout life -- in diseases beyond cancer. The mutations, arising from environmental factors such as smoking or ultraviolet radiation, have been shown to typically target genes that drive cancer development. Andrew Lawson, co-first author from the Wellcome Sanger Institute at the University of Cambridge, UK, 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."

Since the 1950s, 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 in autoimmunity. Researchers developed a method called 'NanoSeq', which allows detecting rare mutations invisible to traditional DNA sequencing methods, to look for genetic changes that may drive the disease.

The team studied thyroid autoimmune disease, including samples from consenting patients with Hashimoto's and Graves' disease, which are the leading causes of thyroid dysfunction. They found that many B cells -- a type of white blood cell -- had developed inactivating mutations in key genes that normally control the immune system.

"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," Lawson said.

The researchers then used additional methods to look at the DNA of individual cells and microscopic areas of tissue. Many B cells in each patient were found to carry 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 a patient -- some 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, the researchers said.

Studies have shown that an artificial inactivation of the genes -- through experiments or during cancer immunotherapy -- can cause thyroid autoimmunity. The team has now shown frequent mutations in the genes occurring in autoimmune patients.

The study 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, the researchers said. However, further research is required to confirm if the mutations are the root cause of autoimmune disease or perhaps just contribute to its exacerbation over time, they said.

Pantelis Nicola, co-first author and a clinical lecturer at The Christie NHS Foundation Trust in Manchester, UK, 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," Nicola said.

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