Two siblings who have the only known mutations in a key gene have helped scientists find potential type 1 diabetes treatments.
The new research, published in the 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 University of Exeter offers free genetic testing worldwide for babies diagnosed with diabetes before they are nine months old.
The services provide a genetic diagnosis for most of the babies. In half of these babies, a change of treatment is allowed.
When the team tested two siblings in the study, no mutation in any of the known causes was identified.
Then, the researchers performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes.
Through this, they found a mutation in the gene encoding PD-L1 in the siblings. This could be responsible for very-early onset autoimmune diabetes.
Impacts of type 1 diabetes
Type 1 diabetes is a devastating and life-long disease. The patient’s immune cells wrong destroy the insulin-producing beta cells in the pancreas.
People living with type 1 diabetes need to test their blood sugar and inject insulin throughout their lives to control their blood sugar levels.
There is currently no cure for autoimmune diabetes
Autoimmune diabetes with clinical onset in very early childhood is rare and can result from different genetic variants.
However, there are many cases of early-onset diabetes without known genetic explanation.
Further to this, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors (which target the same pathway the PD-L1 mutation was found in) are prone to developing autoimmune diabetes.
Why this category of cancer immunotherapy can trigger autoimmune diabetes is not well understood.
The PD-L1 protein
The PD-L1 protein is expressed in many different cell types. Its receptor, PD-1, is only expressed in immune cells.
When the two proteins bind together, it provides a stop signal to the immune system, preventing collateral damage to the body’s tissues and organs.
Study author Dr Matthew Johnson, from the University of Exeter, UK, 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.”
Analysis of the siblings’ cells
Scientists from the Rockefeller Institute in New York and King’s College London collaborated with Exeter to investigate the siblings, supported by funding from Wellcome, The Leona M and Harry B Helmsley Charitable Trust, Diabetes UK, and the US National Institutes for Health.
After contacting the family’s clinician, the team collected samples from where they were living in Morocco and returned them to King’s College London within the crucial ten-hour window for analysis while the cells were still alive.
The teams then performed an extensive analysis of the cells.
Johnson continued: “These siblings, therefore, provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans.”
The gene should be studied as a potential treatment for type 1 diabetes
Study co-author Dr Masato Ogishi, from the 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 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 back-up system when PD-L1 is not available. This concept needs to be further investigated in the context of artificial blockade for PD-L1 as cancer immunotherapy.”
Increasing knowledge of how type 1 diabetes develops
The finding increases knowledge of how autoimmune forms of diabetes develop. It opens up a new potential target for treatment that could prevent diabetes in the future.
Dr Lucy Chambers, Head of Research Communications at Diabetes UK, said: “Pioneering treatments that alter the behaviour of the immune system to hold off its attack on the pancreas are already advancing type 1 diabetes treatment in the US, 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.”
