Rare genetic mutation in sibling holds clues to treatment for type 1 diabetes

Two siblings who share the world’s only known key genetic mutation are helping scientists gain new insights that could help advance the search for new treatments for type 1 diabetes.

Type 1 diabetes (also called autoimmune diabetes) is a devastating, lifelong disease in which a person’s immune cells mistakenly destroy insulin-producing beta cells in the pancreas. People with autoimmune diabetes need to test their blood sugar and inject insulin throughout their lives to control blood sugar and prevent complications.

Autoimmune diabetes with clinical onset in early childhood is rare and may be caused by multiple genetic variants. However, there are many cases of early-onset diabetes with no known genetic explanation. Additionally, some cancer patients treated with a class of immunotherapy called immune checkpoint inhibitors, which target the same pathways as the mutations, are susceptible to developing autoimmune diabetes. Why only this type of cancer immunotherapy induces autoimmune diabetes is unclear. Like type 1 diabetes, autoimmune diabetes related to genetics or immunotherapy requires lifelong insulin replacement therapy and currently has no cure.

The new research is published in Magazine experimental medicine, began when researchers studied two siblings 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 globally to babies diagnosed with diabetes before the age of nine months. For most babies, the service provides a genetic diagnosis, and for about half of them, it allows for a change in treatment.

When the researchers tested the two siblings in the study, no mutations with known causes were found. The Exeter team then performed whole-genome sequencing to search for the previously unknown cause of autoimmune diabetes. Through sequencing, they discovered that the siblings had mutations in the gene encoding PD-L1 and realized that this might be the cause of their early-onset autoimmune diabetes.

“PD-L1 has been particularly well-studied in animal models because of its important role in sending stop signals to the immune system and its relevance to cancer immunotherapy,” said study author Matthew Johnson, Ph.D., of the University of Exeter, UK. . However, to our knowledge, no pathogenic mutations in the human PD-L1 encoding gene have been found. We’ve scoured the globe and looked at every large dataset we know of, but we haven’t been able to find another family. Therefore, these siblings provide us with a unique and critically important opportunity to study what happens when the gene is disabled in humans.

The PD-L1 protein is expressed on many different cell types. Its receptor, PD-1, is expressed only on immune cells. When the two proteins bind together, it sends a stop signal to the immune system, preventing collateral damage to body tissues and organs.

Researchers at the Rockefeller Institute in New York and King’s College London teamed up with the University of Exeter to study the siblings, with funding from Wellcome, the Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK and the National Institutes of Health. Institute. After contacting the family’s clinicians in Morocco, the Exeter team visited the siblings where they lived, collected samples and sent them back to King’s College London for analysis within a critical ten-hour window while immune cells alive. The team in London and New York then conducted extensive analysis of the sibling cells.

Study co-author Dr. Masato Ogishi of The Rockefeller University in New York said: “We first demonstrated that this mutation completely renders the PD-L1 protein nonfunctional. We then studied the siblings’ immune systems to look for immune abnormalities that might have contributed to their very early onset of diabetes. As we previously described two other siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity, including autoimmune diabetes and widespread dysregulation of immune cells, we expected that in the PD-L1-deficient siblings Severe immune system disorders are found in . To our surprise, their immune systems looked perfectly normal in almost every way throughout the study.Therefore, PD-L1 is definitely indispensable Used to prevent autoimmune diabetes, but dispensable Used in many other aspects of the human immune system. We believe that PD-L2 (another ligand of PD-1), although less well studied than PD-L1, may serve as a backup system when PD-L1 is unavailable. This concept requires further investigation in the context of artificial blockade of PD-L1 as cancer immunotherapy.

Study co-author Professor Timothy Tree from King’s College London said: “By studying this unique pair of siblings in the world, we found that the PD-L1 gene is essential for avoiding autoimmune diabetes, but it is not necessary for the prevention of autoimmune diabetes. of. This raises a big question: What role does PD-L1 play in our pancreas, making it essential for preventing our immune cells from destroying our beta cells? We know 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 figure out the communication between different cell types, which is critical to preventing autoimmune diabetes.

The discovery increases our understanding of how autoimmune diabetes, such as type 1 diabetes, develops. It opens up a new potential target for future treatments to prevent diabetes. At the same time, it provides new knowledge to the field of cancer immunotherapy by uniquely delivering the result of completely disabling PD-L1 in humans, something you can never manipulate in research. Reducing PD-L1 is already effective in cancer treatment, while enhancing PD-L1 is currently being studied as a treatment for type 1 diabetes, and our findings will help accelerate the search for new and better drugs.

Dr Lucy Chambers, director of research communications at Diabetes UK, said: A pioneering treatment that changes the behavior of the immune system to block its attack on the pancreas is already advancing in the treatment of type 1 diabetes and is awaiting US approval.

By focusing on the precise role of an important player in the immune attack of type 1 diabetes, this exciting discovery may lead to more effective, targeted and transformative treatments for people with or at risk of type 1 diabetes Pave the way.

Helmsley program officer Ben Williams said: New drug development often fails because scientific discoveries made in animal models cannot be translated to humans. Therefore, there is a strong preference among drug developers to develop new drugs for which human genetic evidence supports the drug target. This study provides compelling evidence that PD-L1 is a high-priority target for the treatment of T1D and should be investigated with the goal of ultimately reducing the burden of this difficult-to-control disease.

refer to: Johnson MB, Ogishi M, Domingo-Vila C, et al. Inherited PD-L1 deficiency in humans is clinically and immunologically less severe than PD-1 deficiency. journal of experimental medicine. 2024;221(6):e20231704. Doi: 10.1084/jem.20231704

This article is reproduced from the following information. NOTE: Material may have been edited for length and content. For more information, please contact the cited source.Our press release distribution policy can be accessed here.