Two siblings with unique mutations in a crucial gene are providing valuable insights that could advance the search for type 1 diabetes treatments.
Type 1 diabetes, also known as autoimmune diabetes, is a serious and lifelong illness. The patient’s immune cells mistakenly attack the insulin-producing beta cells in the pancreas.
Increas. People with autoimmune diabetes must regularly monitor their blood sugar levels and administer insulin for the rest of their lives to manage their blood sugar and avoid complications.
Autoimmune diabetes that starts in early childhood is uncommon and can be caused by various genetic variations. However, there are numerous instances of early-onset diabetes without a known genetic cause. Furthermore, some cancer patients undergoing immunotherapy with immune checkpoint inhibitors are at risk of developing autoimmune diabetes, as these drugs target the same pathway associated with the mutation found in diabetes. The cause of autoimmune diabetes triggered by cancer immunotherapy is not well understood and requires lifelong insulin replacement therapy. There is currently no cure for this type of diabetes, similar to type 1 diabetes. A recent study published in the Journal of Experimental Medicine, focused on two siblings who were diagnosed with a rare genetic form of autoimmune diabetes in their first weeks of life. The University of Exeter provides free genetic testing for infants diagnosed with diabetes before they are nine months old. This service is available worldwide.It is estimated that one in every 300,000 babies is born with diabetes caused by a genetic mutation, and for about half of these babies, having a genetic diagnosis can lead to a change in treatment. Researchers conducted tests on two siblings who were part of the study, but they did not find any mutations in the known causes of autoimmune diabetes. The team then utilized whole genome sequencing to search for previously unidentified causes of autoimmune diabetes. This led them to discover a mutation in the gene that encodes PD-L1 in the siblings, indicating that it could be the cause of their autoimmune diabetes at such a young age. Dr. Matthew Johnson, one of the authors of the study from the University of Exeter in the UK, highlighted that PD-L1 has been extensively studied in animal models due to its involvement in regulating the immune system.
The researchers highlighted the crucial role of PD-L1 in signaling the immune system to stop, especially in the context of cancer immunotherapy. However, they noted that no humans with a disease-causing mutation in the gene encoding PD-L1 have been found to date. Despite searching through large-scale datasets worldwide, no other families with such mutations have been identified. The researchers emphasized that studying these siblings provides a unique and highly valuable opportunity to understand the effects of disabling this gene in humans.”
PD-L1 is expressed on various cell types, while its receptor, PD-1, is exclusively expressed on immune cells. This interaction is important in regulating the immune response.When two proteins come together, they signal the immune system to stop, which helps prevent damage to the body’s tissues and organs. Researchers from the Rockefeller Institute in New York and King’s College London, in collaboration with Exeter, studied siblings with funding from Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK, and the US National Institutes for Health. The Exeter team visited the siblings in Morocco, collected samples, and returned them to King’s College London within a ten-hour window.The immune cells were analyzed while they were still alive. The London and New York teams conducted thorough analysis on the siblings’ cells.
Dr. Masato Ogishi, a study co-author from the Rockefeller University in New York, stated: “We demonstrated that the mutation completely deactivated the PD-L1 protein’s function. We then examined the siblings’ immune system to identify any immunological abnormalities that could explain their extremely early-onset diabetes. As we previously reported, we also found two other siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity, including autoimmune diabetes, and extensive dysregulation in the immune system.The researchers originally believed that the PD-L1-deficient siblings would have major issues with their immune system due to a lack of immune cells. However, they were shocked to find that their immune systems were mostly normal in all aspects throughout the study. The researchers concluded that while PD-L1 is crucial for preventing autoimmune diabetes, it is not necessary for many other aspects of the human immune system. They theorize that PD-L2, another ligand of PD-1, may act as a backup system when PD-L1 is not present. This theory needs to be further investigated, especially in the context of using PD-L1 blockade for cancer immunotherapy.
According to a study co-author Professor Timothy Tree from King’s College London, the PD-L1 gene is crucial for preventing autoimmune diabetes but is not necessary for everyday immune function. The study focused on a unique set of siblings, and their findings raised the question of the role of PD-L1 in the pancreas. They discovered that under specific conditions, beta cells express PD-L1, and certain types of immune cells in the pancreas also express this gene. Further research is needed to understand the communication between these cells and the role of PD-L1 in preventing immune cells from attacking beta cells.
The discovery enhances our understanding of the development of autoimmune diabetes, such as type 1 diabetes. It also identifies a potential new target for preventing diabetes in the future. Additionally, it offers valuable insights for cancer immunotherapy, as it presents results of completely disabling PD-L1 in a person, which is not feasible in studies. This is significant as reducing PD-L1 has proven effective for cancer treatment, and increasing it is now being explored as a treatment for type 1 diabetes. Our findings will contribute to accelerating this research.The search for new and improved drugs is being evaluated. Dr. Lucy Chambers, who is the Head of Research Communications at Diabetes UK, mentioned that innovative treatments are being developed in the USA to change the way the immune system behaves in order to delay its attack on the pancreas. These treatments are currently awaiting approval in the UK. Dr. Chambers also stated that by focusing on the specific role of a key player in the immune attack associated with type 1 diabetes, this groundbreaking discovery could lead to more effective and targeted treatments that could significantly impact people with type 1 diabetes or those at risk. Ben Williams, a Helmsley Program Officer, also commented on this topic.The researchers stated that many new drugs fail during the development process because the findings from animal models do not necessarily apply to humans. Because of this, drug developers prefer to focus on developing drugs that are supported by human genetic evidence. The study provides strong evidence that PD-L1 is a high-priority target for treating T1D, and the researchers recommend pursuing this target in order to ultimately reduce the burden of this challenging disease. The paper, titled ‘Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency’, has been published in the Journal of Experimental Medicine.The study received funding from the National Institute of Health and Care Research (NIHR) Exeter Biomedical Research Centre and The NIHR Exeter Clinical Research Facility.
