Type 1 diabetes at birth and unique mutation: the case of little brothers that science can help

For scientists, this is a special case: two little brothers who have a unique mutation in the world in a key gene. The little ones were diagnosed with a rare genetic form of autoimmune diabetes in the first weeks of life. And from there began a series of insights. Their DNA was scrutinized and studying it helped a group of researchers gain new knowledge that could be strategic in advancing the search for new treatments for type 1 diabetes, a lifelong disease that destroys the cells of the body’s immune system. accidentally destroying the patient’s insulin-producing beta. cells in the pancreas.

Autoimmune diabetes with clinical onset in early childhood is rare and can result from a variety of genetic variants. However, there are many cases with no known genetic explanation. In addition, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors – which target the same pathway where the little brother mutation was found – are prone to developing autoimmune diabetes. Why this category of cancer immunotherapy alone can cause autoimmune diabetes is not well understood. The new research, published in the ‘Journal of Experimental Medicine’, aims to shed light on these aspects.

The University of Exeter in Britain offers free genetic testing worldwide for children diagnosed with diabetes before the age of 9 months. When the researchers tested the two little brothers, protagonists of the study, no known mutation was identified as the cause of the disease. The team then performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes. And he found a mutation in the gene that codes for PD-L1. The scientists hypothesized that this could be responsible for their very early autoimmune diabetes. To our knowledge, says study author Matthew Johnson of the University of Exeter, “no one has ever found people with a disease-causing mutation in the gene encoding PD-L1. We’ve searched all over the world and looked at all the large-scale data we know of, but we haven’t been able to find another family.”

These siblings, Johnson continues, “therefore provide us with a unique and incredibly important opportunity to investigate what happens when this gene is turned off in humans.” The PD-L1 protein is expressed on many different cell types. The receptor is expressed exclusively on immune cells. When the two proteins bind together, it sends a stop signal to the immune system, preventing additional 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 little brothers, with funding from Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK and the US NIH (National Institutes for Health). ).

After contacting the GP in Morocco, the children’s country of origin, the Exeter team visited the brothers, collected the samples and sent them back to King’s College London, within the crucial ten-hour window for analysis while the immune cells were still alive. The teams in London and New York then carried out in-depth analyzes of the brothers’ cells. Through the study of these little brothers, concludes Timothy Tree of King’s College London, “we have discovered that the PD-L1 gene is essential for preventing autoimmune diabetes, but not essential for ‘everyday’ immune function. This discovery 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 provides new insights into the field of cancer immunotherapy.” .