Germs: the cause of type 1 diabetes?
Bacteria could play a role in the development of type 1 diabetes, by triggering the immune system to destroy the cells that produce insulin. The new discovery, made using super powerful X-rays, could lead to new ways to diagnose, prevent, and possibly halt type 1 diabetes.
Unlike type 2 diabetes, which mainly affects older people, type 1 diabetes is prevalent in children and young adults, and is not connected with diet. At the moment there is no cure, and patients require life-long treatment. There is an urgent need to understand what lies at the heart of type I diabetes.
Scientists at Cardiff University have previously shown that killer T-cells, a type of white blood cell that normally protects us from germs, play a major part in type 1 diabetes by destroying insulin producing cells that they wrongly identify as being dangerous.
New research, led by Professor Andrew Sewell from the Division of Infection and Immunity, and the Systems Immunity Research Institute, at Cardiff University School of Medicine, shows that the same killer T-cells that can cause type 1 diabetes are strongly activated by some bacteria. This interaction could ‘wake-up’ harmless ‘sleeping’ killer T-cells, triggering them to cause type 1 diabetes.
Professor Sewell said: “Killer T-cells are extremely effective at killing off germs, but when they mistakenly attack our own tissues, the effects can be devastating. During type 1 diabetes, killer T-cells are thought to attack pancreatic beta cells. These cells make the insulin that is essential for control of blood sugar levels. When beta cells are destroyed, patients have to inject insulin every day to remain healthy.”
In a previous study, the Cardiff team isolated a killer T-cell from a patient with type 1 diabetes to view the unique interaction which kills the insulin-producing beta cells in the pancreas (Nature Immunology, 2012). They found that these killer T-cells were highly ‘cross-reactive’, meaning that they can react to lots of different triggers (Journal of Biological Chemistry, 2012), raising the possibility that a pathogen might stimulate the T-cells that initiate type I diabetes.
In this new study, the team used Diamond Light Source, the UK’s synchrotron science facility, to shine intense super powerful X-rays, similar to those used to take pictures of bones, into their samples to uncover how these killer T-cells could see beta cells as being a threat.
Dr David Cole, also of Cardiff University School of Medicine, and the lead author on the study said: “Killer T-cells sense their environment using cell surface receptors that act like highly sensitive fingertips, scanning for germs. However, sometimes these sensors recognise the wrong target, and the killer T-cells attack our own tissue. We, and others, have shown this is what happens during type 1 diabetes when killer T-cells target and destroy beta cells. In our present study, we wanted to find out what was causing these T-cells to kill beta cells. We identified part of a bug that turns on killer T-cells so they latch onto beta cells. This finding sheds new light on how these killer T-cells are turned into rogues, leading to the development of type 1 diabetes.”
The research, published in The Journal of Clinical Investigation, provides a first ever glimpse of how germs might trigger killer T-cells to cause type 1 diabetes, but also points towards a more general mechanism for the cause of all other autoimmune diseases.
The team hopes that by knowing more about this process will mean they can work out new ways to diagnose, prevent or even halt the type I diabetes. Showing what is possible with T-cells relevant to type 1 diabetes has led to new studies aimed at linking other autoimmune diseases to changes caused by germs.
Professor Melanie Welham, Chief Executive at Biotechnology and Biological Sciences Research Council (BBSRC), who co-funded the study, said: “This demonstrates the value of research that explores the fundamental cell biology of the immune system. Finding the cellular mechanisms behind the development of autoimmune diseases, such as type 1 diabetes, could lead to treatments that help us lead longer, healthier lives.”
Professor Matthias von Herrath, MD, Professor at La Jolla Institute for Allergy and Immunology and Vice President at NovoNordisk commented: “Type 1 diabetes is a very serious and hard to treat condition affecting mainly young people. This new finding, demonstrating how external factors may trigger T-cells to ‘wake-up’ and start attacking beta cells, helps to explain how this disease develops and could shape the future direction of new treatments and diagnostics.”
The Cardiff study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) UK, the Juvenile Diabetes Research Foundation (JDRF), and the Wellcome Trust, using facilities provided by Diamond Light Source.
Notes to editors
Reference: Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. David K. Cole et al. The Journal of Clinical Investigation (2016). doi: 10.1172/JCI85679.
“Structural basis of human β-cell killing by preproinsulin-specific CD8+ T-cells in type 1 diabetes” was published in the journal, Nature Immunology (15/01/12).
“A single autoimmune T-cell receptor recognises over a million different peptides” was published in the Journal of Biological Chemistry (06/01/12).
Copies of the papers are available on request.
About Cardiff University
Cardiff University is recognised in independent government assessments as one of Britain’s leading teaching and research universities and is a member of the Russell Group of the UK’s most research intensive universities. The 2014 Research Excellence Framework ranked the University 5th in the UK for research excellence. Among its academic staff are two Nobel Laureates, including the winner of the 2007 Nobel Prize for Medicine, University Chancellor Professor Sir Martin Evans. Founded by Royal Charter in 1883, today the University combines impressive modern facilities and a dynamic approach to teaching and research. The University’s breadth of expertise encompasses: the College of Arts, Humanities and Social Sciences; the College of Biomedical and Life Sciences; and the College of Physical Sciences and Engineering, along with a longstanding commitment to lifelong learning.
Cardiff’s flagship Research Institutes are offering radical new approaches to pressing global problems. www.cardiff.ac.uk
About King's College London
King's College London is one of the top 30 universities in the world (2011/12 QS World University Rankings), and the fourth oldest in England. A research-led university based in the heart of London, King's has nearly 23,500 students (of whom more than 9,000 are graduate students) from nearly 140 countries, and some 6,000 employees. King's is in the second phase of a £1Bn redevelopment programme which is transforming its estate.
King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10% in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450M.
King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe; no university has more Medical Research Council Centres.
King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King's Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: www.kingshealthpartners.org
About Diamond Light Source
Diamond Light Source is the UK’s national synchrotron facility, located at the Harwell Science and Innovation Campus in Oxfordshire. By accelerating electrons to near light-speed, Diamond generates brilliant beams of light from infra-red to X-rays which are used for academic and industry research. www.diamond.ac.uk
BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by Government, BBSRC invested over £509M in world-class bioscience in 2014-15. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
About The Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to improving health. We support bright minds in science, the humanities and the social sciences, as well as education, public engagement and the application of research to medicine. Our investment portfolio gives us the independence to support such transformative work as the sequencing and understanding of the human genome, research that established front-line drugs for malaria, and Wellcome Collection, our free venue for the incurably curious that explores medicine, life and art. www.wellcome.ac.uk