Prof. Yuval Dor and Dr. Anaïs Kloshandler are investigating whether disruption of RNA editing in pancreatic beta cells causes them to behave as if they were infected with a virus, triggering an immune response that leads to cell destruction and diabetes.
Type 1 diabetes is one of the best-known autoimmune diseases, but even today a very basic question about it is still open: What is the first signal that begins the immune attack on beta cells? These cells are located in the islets of Langerhans – clusters of endocrine cells in the pancreas – and they produce the hormone insulin, which regulates blood sugar levels. When beta cells are destroyed, blood sugar levels rise and diabetes develops.
It has been suggested for decades that viral infection may trigger the development of the disease. This hypothesis is supported, among other things, by the fact that the early stages of type 1 diabetes are characterized by an interferon response, a response that is activated when cells sense the presence of viruses. However, to date, a causal relationship between viral infection and the onset of the disease has not been proven.
“What drives the development of the disease? That’s exactly the question,” says Prof. Dor. “What is very clear is that the cells behave as if they have been infected with a virus.”
In a study by Prof. Yuval Dor and Dr. Agnes Klosshandler from the Faculty of Medicine of the Hebrew University, conducted with the support of a grant from the "Healer" program from the National Science Foundation, a new possibility is examined: It is possible that the initial trigger for the disease is not an external virus, but rather an internal disruption in the molecular mechanism of the cell.
What is the question? What is the first signal that begins the immune attack on beta cells?
Antiviral response
In the early stages of the disease, beta cells activate an interferon response, a classic antiviral response. Such a response is usually triggered when the cell detects double-stranded RNA, a molecular signature often associated with a viral infection. But another possibility has emerged in Dor and Kloschandler's lab. Perhaps the source of the double-stranded RNA is not external at all, but internal? It turns out that our body's cells produce many "dangerous" RNA molecules that organize themselves to form a double-stranded structure. To prevent the interferon response from being incorrectly activated due to the presence of such molecules, they undergo "editing" that changes their sequence and disrupts the double-stranded structure. The research hypothesis is that in the event of a disruption in the RNA editing process, endogenous double-stranded RNA molecules accumulate in the cell, and the cell mistakenly triggers an antiviral alarm. This could start a chain of events that leads to inflammation in the pancreatic islets, with inflammatory cells specifically attacking the beta cells, killing them, and eventually developing diabetes. The process would appear to be triggered by a viral infection, but in fact there is no virus involved.
In both images, you can see images of the islets of Langerhans in the mouse pancreas taken with a confocal microscope. In the upper image: green GFP (a marker for mutant beta cells lacking the ADAR gene), white IBA1 (a marker for macrophages), red CD3 (a marker for T cells), blue DNA. In the lower image: green insulin, white glucagon (alpha cells), red laminin (a blood vessel stain in the islets of Langerhans), blue DNA.
To test this idea, the researchers developed a mouse model in which they genetically engineered the gene responsible for the RNA editing mechanism in beta cells. The result was clear: the beta cells activated a strong interferon response, inflammation appeared around the islets, and the mice developed diabetes. According to them, the model surprisingly reproduced a number of key features of type 1 diabetes in humans. Dor and Kloschandler's group was the first to present this direction, and published it about three years ago in the journal Cell metabolism Since then, other groups around the world have begun to examine the link between RNA editing and the risk of type 1 diabetes.
The early stages of type 1 diabetes are characterized by an interferon response, a response triggered when cells sense the presence of viruses. However, to date, a causal link between viral infection and the onset of the disease has not been proven.
One island was destroyed, a neighboring island remained intact.
But perhaps the most important contribution of the model is not just in proposing a new mechanism, but in that it allows us to study a particularly mysterious phenomenon: the heterogeneity of inflammation in pancreatic islets. In the pancreas of patients in the early stages of the disease, one can sometimes see an islet of Langerhans (a small group of cells within the pancreas) that is under severe immune attack, and next to it an islet that appears to be completely intact. “In our model, too, in the same section of the pancreas, we see an islet with inflammation and a strong interferon response, and next to it an islet in which almost nothing happens,” says Dr. Klosshandler. “In this study, we mainly want to focus on the heterogeneity of inflammation.”
The hypothesis is that the heterogeneity of inflammation stems from differences between islets in interferon response and beta cell metabolic activity, creating an “all or nothing” response in each individual islet. To test this, the researchers will use genetically engineered mice, human material, and spatial omics methods that will allow for the examination of inflammation at high spatial resolution.
Why is the disease more severe in children?
The model also opens the door to other fundamental questions. One of them is the connection to age: Type 1 diabetes tends to be more severe in children, compared to a mild and slow onset in adults – a distinct phenomenon that is not understood. The researchers also saw a similar pattern in the model mice. Another question is why the beta cells are damaged, while the neighboring alpha cells, which are very similar to them but produce glucagon, remain unharmed – both in human type 1 diabetes and in the mouse model developed here. “For the first time, we have an experimental system that allows us to gain insights,” says Dor, because the model allows us to study not only the onset of the disease, but also its dynamics and the differences between different cells and islets.
Ultimately, this is basic research in the deepest sense of the word: not an immediate attempt to develop a cure, but an effort to understand exactly what happens in the cell, in the tissue, and at the interface between them and the immune system. If the hypothesis proves correct, it could change the way we understand the onset of disease, and perhaps also point to future ways to inhibit inflammation, protect certain islets, or delay the onset of diabetes.
Short FAQ:
What is type 1 diabetes?
Type 1 diabetes is an autoimmune disease in which the immune system attacks the beta cells in the pancreas, which produce insulin.
What does the new study test?
The study examines whether disruption of RNA editing in beta cells causes them to mount an incorrect antiviral response, as if they were infected with a virus.
Why is the research important?
If this turns out to be a central mechanism in the onset of the disease, it may be possible in the future to develop ways to inhibit inflammation or protect some of the pancreatic islets.
More of the topic in Hayadan:
