2024-04-21 06:59:36
For scientists, theirs 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 a series of insights started. Their DNA came under the microscope and studying them helped a group of researchers acquire new knowledge that could be strategic for advancing the search for new treatments for type 1 diabetes, a lifelong disease in which the cells The patient’s immune system mistakenly destroys 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 without a known genetic explanation. Additionally, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors — which target the same pathway where the sibling mutation was found — are prone to developing autoimmune diabetes. Why this category of cancer immunotherapy alone can trigger 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 the UK 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 a 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 encodes PD-L1. The scientists hypothesized that this might be responsible for their very early-onset autoimmune diabetes. As far as we know, study author Matthew Johnson of the University of Exeter says, “no one has ever found humans with a disease-causing mutation in the gene that encodes PD-L1. We searched all over the world, looking at all sets of large-scale data that we are aware of, and we have not been able to find another family.”
These siblings, Johnson continues, “therefore offer us 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 is expressed exclusively on immune cells. When the two proteins bind together this provides 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 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 family doctor in Morocco, the children’s country of origin, the Exeter team visited the brothers and collected the samples, returning them to King’s College London, within the crucial ten-hour window for analysis while the immune cells they were still alive. The teams in London and New York then performed in-depth analyzes on 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 avoiding autoimmune diabetes, but is not essential for ‘everyday’ immune function. This discovery increases the 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.” .
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