Two brothers who have the only known mutations in a key gene anywhere in the world have helped scientists gain new insights that could help advance the search for new treatments for type 1 diabetes.
Type 1 diabetes (also known as autoimmune diabetes) is a devastating, lifelong disease in which the patient’s immune cells mistakenly destroy the insulin-producing beta cells in the pancreas. People living with autoimmune diabetes need to control their blood sugar and take insulin throughout their lives to control their blood sugar and prevent complications.
Autoimmune diabetes with clinical onset in early childhood is rare and may be due to a variety of genetic variants. However, there are many cases of early-onset diabetes with no known genetic explanation. Additionally, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors, which target the same pathway in which the mutation was found, are prone to developing autoimmune diabetes. The reason why only this category of cancer immunotherapy can trigger autoimmune diabetes is not well understood. Like type 1 diabetes, genetic or immunotherapy-associated autoimmune diabetes requires lifelong insulin replacement therapy; currently there is no cure.
The new research, published in the Diary of Experimental Medicine, began when researchers studied two brothers who were diagnosed with a rare genetic form of autoimmune diabetes in the first weeks of life. The University of Exeter offers free genetic testing worldwide for babies diagnosed with diabetes before nine months. For the majority of these babies, this service provides a genetic diagnosis and in about half of these babies it allows for a change in treatment.
When researchers examined the two brothers in the study, no mutation was identified in any of the known causes. The Exeter team then performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes. Through this sequencing, they found a mutation in the gene encoding PD-L1 in the brothers and realized that it could be responsible for their very early-onset autoimmune diabetes.
Study author Dr Matthew Johnson, from the University of Exeter, UK, said: “PD-L1 has been particularly well studied in animal models due to its crucial role in sending a stop signal to the immune system and its relevance to cancer immunotherapy. But, to our knowledge, no one has ever found humans with a disease-causing mutation in the gene encoding PD-L1. We searched the world, analyzing all large-scale data sets. that we know of, and we have not been able to find it in another family. Therefore, these siblings provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans.
The PD-L1 protein is expressed on many different cell types. Its receptor, PD-1, is expressed exclusively on immune cells. When the two proteins join together, they provide a stop signal to the immune system, preventing collateral damage to the body’s tissues and organs.
Researchers from the Rockefeller Institute in New York and King’s College London joined forces with Exeter to study the brothers, with funding from Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK and the US National Institutes of Health. After contacting the family’s doctor in Morocco, the Exeter team visited the brothers where they lived to collect samples and return them to King’s College London, within the crucial ten-hour period for analysis while the immune cells still remained. They were alive. The teams in London and New York then performed extensive analysis of the brothers’ cells.
Study co-author Dr Masato Ogishi, from Rockefeller University in New York, said: “We first showed that the mutation completely disabled the function of the PD-L1 protein. We then studied the brothers’ immune systems to look for immunological abnormalities. which could explain their extremely early onset diabetes. As we previously described two other brothers with PD-1 deficiency, who had multi-organ autoimmunity, including autoimmune diabetes and extensive dysregulation in their immune cells, we expected to find severe dysregulation of the disease. immune system in PD-L1 deficient siblings To our great surprise, their immune system seemed quite normal in almost all aspects throughout the study. So PD-L1 certainly is. indispensable to prevent autoimmune diabetes, but it is dispensable for many other aspects of the human immune system. We believe that PD-L2, another PD-1 ligand, although less studied than PD-L1, may be serving as a backup system when PD-L1 is not available. “This concept should be further investigated in the context of artificial PD-L1 blockade as cancer immunotherapy.”
Study co-author Professor Timothy Tree, from King’s College London, said: “By studying this group of siblings, unique in the world to our knowledge, we have discovered that the PD-L1 gene is essential for preventing autoimmune diabetes. but it is not essential for “everyday” immune function. This brings us to the big question: “what is the role of PD-L1 in our pancreas that makes it critical in preventing our immune cells from destroying our beta cells?” that under certain conditions beta cells express PD-L1. However, certain types of immune cells in the pancreas also express PD-L1. We now need to resolve the “communication” between different cell types that is critical to preventing autoimmune diabetes. .
“This finding increases our knowledge of how autoimmune forms of diabetes, such as type 1 diabetes, develop. It opens up a new potential target for treatments that could prevent diabetes in the future. At the same time, it brings new insights to the field of immunotherapy. against cancer by uniquely providing the results of completely turning off PD-L1 in a person, something that could never be manipulated in studies. Reducing PD-L1 is already effective for cancer treatment, and boosting it is now being investigated as a treatment. for type 1 diabetes; our findings will help accelerate the search for new and better drugs.”
Dr Lucy Chambers, Head of Research Communications at Diabetes UK, said: “Pioneering treatments that alter the behavior of the immune system to stop its attack on the pancreas are already advancing the treatment of type 1 diabetes in the US. .and are awaiting approval here in the UK.
“By focusing on the precise role of a major player in the immune attack of type 1 diabetes, this exciting discovery could pave the way for treatments that are more effective, more specific and more transformative for people with type 1 diabetes or at risk.” to suffer it.”
Ben Williams, head of the Helmsley programme, said: “New drugs often fail in development because scientific discoveries made in animal models do not translate to humans. As such, drug developers prefer to look for new drugs where human genetic evidence support the drug’s target. This study “Provides compelling evidence that PD-L1 is a high-priority target for treating Type 1 diabetes, and should be pursued with the ambition of eventually reducing the burden of this difficult-to-control disease.”
The article is titled “Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency” and is published in the journal Diary of Experimental Medicine. The research was supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Center and the NIHR Exeter Clinical Research Centre.