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,1,2 however their molecular basis remains poorly understood. Somatic mutations are changes in DNA that occur in our cells over time and are not inherited.3 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,4,5 which are leading causes of thyroid dysfunction in the population. The researchers used several advanced DNA analysis techniques.6 Firstly, they used a method called NanoSeq, which they recently developed7,8,9 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." |
