By Stephen Beech via SWNS
Two siblings who have the only known mutations in a key gene anywhere in the world could hold the key to treating diabetes.
They have helped scientists gain vital insights that could help progress the search for new treatments for type 1 diabetes.
Also known as autoimmune diabetes, it is a life-long disease in which the patient’s immune cells wrongly destroy the insulin-producing beta cells in the pancreas.
People living with type 1 diabetes (T1D) need to test their blood sugar and inject insulin to control their blood sugar and prevent complications.
Scientists say that T1D in very early childhood is rare and can result from a variety of genetic variants.
However, there are multiple cases of early-onset diabetes without known genetic explanation.
Some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors – which target the same pathway that the mutation was found in – are prone to developing autoimmune diabetes.
The reason why only that category of cancer immunotherapy can trigger autoimmune diabetes is not properly understood.
Like T1D, genetic or immunotherapy-associated autoimmune diabetes requires life-long insulin replacement therapy – and there is currently no cure.
The new research, published in the Journal of Experimental Medicine, began when the University of Exeter 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 worldwide for babies diagnosed with diabetes before they are nine months old.
When researchers tested the siblings, no mutation in any of the known causes was identified.
The Exeter team then performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes.
Through the sequencing, they found a mutation in the gene encoding PD-L1 in the siblings and realized it could be responsible for their very-early-onset autoimmune diabetes.
Study author Dr Matthew Johnson, of the University of Exeter, said: “PD-L1 has been particularly well studied in animal models because of its crucial function in sending a stop signal to the immune system and its relevance to cancer immunotherapy.
“But, to our knowledge, nobody has ever found humans with a disease-causing mutation in the gene encoding PD-L1.
“We searched the globe, looking at all the large-scale datasets that we know of, and we haven’t been able to find another family.
“These siblings therefore provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans.”
Researchers from the Rockefeller Institute in New York and King’s College London linked up with the Exeter team to study the siblings.
After contacting the family’s clinician in Morocco, the Exeter researchers visited the siblings where they were living to collect samples and return them to King’s College London, within the “crucial” 10-hour window for analysis while the immune cells were still alive.
The London and New York teams then performed extensive analysis on the siblings’ cells.
Study co-author Dr. Masato Ogishi, of Rockefeller University in New York, said: “We first showed that the mutation completely disabled the function of PD-L1 protein.
“We then studied the immune system of the siblings to look for immunological abnormalities that could account for their extremely early-onset diabetes.
“As we previously described another two siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity including autoimmune diabetes and extensive dysregulation in their immune cells, we expected to find severe dysregulation of the immune system in the PD-L1-deficient siblings.
“To our great surprise, their immune systems looked pretty much normal in almost all aspects throughout the study.
“Therefore, PD-L1 is certainly indispensable for preventing autoimmune diabetes but is dispensable for many other aspects of the human immune system.
“We think that PD-L2, another ligand of PD-1, albeit less well-studied than PD-L1, may be serving as a backup system when PD-L1 is not available.”
Dr. Ogishi added: “This concept needs to be further investigated in the context of artificial blockade for PD-L1 as cancer immunotherapy.”
Co-author Professor Timothy Tree, of King’s College London, said: “Through studying this one set of siblings – unique in the world to our knowledge – we have found that the PD-L1 gene is essential for avoiding autoimmune diabetes, but is not essential for ‘everyday’ immune function.
“This leads us to the grand question; ‘what is the role of PD-L1 in our pancreas making it critical 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 work out the “communication” between different cell types that is critical for preventing autoimmune diabetes.”
He added: “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.
“Simultaneously, it gives new knowledge to the cancer immunotherapy field by uniquely providing the results of completely disabling PD-L1 in a person, something you could never manipulate in studies.”
Dr. Lucy Chambers, Head of Research Communications at Diabetes UK, said: “Pioneering treatments that alter the behavior of the immune system to hold off its attack on the pancreas are already advancing type 1 diabetes treatment in the USA, and are awaiting approval here in the UK.
“By zeroing in on the precise role of an important player in the type 1 diabetes immune attack, this exciting discovery could pave the way for treatments that are more effective, more targeted and more transformational for people with or at risk of type 1 diabetes.”
