Siblings with unique genetic mutation help scientists advance drug research 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 discovered, are susceptible to developing autoimmune diabetes.

Why only this type of cancer immunotherapy induces autoimmune diabetes is unclear. Like type 1 diabetes, genetic or immunotherapy-related autoimmune diabetes requires lifelong insulin replacement therapy and currently has no cure.

The new research is published in journal of 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 paper is titled “Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency.”

The University of Exeter offers free genetic testing worldwide 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 involvement in cancer immunotherapy,” said study author Matthew Johnson, Ph.D., of the University of Exeter, UK. Related.

“We’ve searched the world and looked at every large-scale data set we know of, and we haven’t found another family. So these siblings provide us with a unique and extremely important opportunity to study when this gene changes What happens when.

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 from the Rockefeller Institute in New York and King’s College London teamed up with the University of Exeter to study the siblings. 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 the critical 10-hour window while immune cells were still Survive. The research team in London and New York then conducted an extensive analysis of the siblings’ cells.

“We first showed that this mutation completely disabled the function of the PD-L1 protein,” said study co-author Dr. Masato Ogishi of The Rockefeller University in New York. “We then studied the siblings’ immune systems to look for immune abnormalities. ” This may be the reason for their very early onset of diabetes.

“As we previously described two other PD-1-deficient siblings, both of whom suffered from multi-organ autoimmunity, including autoimmune diabetes and widespread dysregulation of immune cells, we expected to find that patients with PD-L1-deficient immunity There is a serious imbalance in the system.

“To our great surprise, their immune systems looked perfectly normal in almost every aspect throughout the study. So PD-L1 is certainly ‘essential’ for preventing autoimmune diabetes, but it is not essential for human immunity.” Many other aspects of the system are ‘optional’.

“We believe that PD-L2 is an alternative ligand for PD-1 that, although less well studied than PD-L1, may serve as a backup system when PD-L1 is unavailable. This concept requires further study to artificially block PD-L1. L1 as a context for cancer immunotherapy.

Study co-author Timothy Tree, Professor at King’s College London, said: “By studying this unique pair of siblings, we found that the PD-L1 gene is crucial for avoiding autoimmune diabetes, but not for autoimmune diabetes. ‘Everyday immune function.

“This brings us to a big question: ‘What role does PD-L1 play in our pancreas that makes it critical for preventing our immune cells from destroying our beta cells?’ We know that in certain conditions Under normal circumstances, 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 important for preventing autoimmune diabetes. It’s important.

“This 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 uniquely provides new insights into the field of cancer immunotherapy. knowledge. Help accelerate this research.

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 as a treatment for type 1 diabetes and is awaiting approval in the UK.

“By focusing on the precise role of important players in the immune attack of type 1 diabetes, this exciting discovery may lead to more effective, targeted and transformative therapies for patients with or at risk of type 1 diabetes. Treatment paves the way.

“New drug development often fails because scientific discoveries made in animal models do not translate to humans,” said Ben Williams, a program officer at Helmsley. “Therefore, there is a strong preference for drug developers to develop human genetic evidence to support New drugs for drug targets.”