Researchers from The University of Colorado (USA), in collaboration with St Vincent’s Institute of Medical Research (SVI) in Melbourne, have identified what may be the initial target of the immune response that causes type 1 diabetes.
The discovery provides a plausible explanation for why the immune system mistakenly destroys the body’s cells in type 1 diabetes.
When our immune system is functioning properly, it protects us against “invaders” that might make us sick, such as bacteria and viruses. But in people with autoimmune diseases, the immune system attacks healthy parts of the body.
In type 1 diabetes, the cells that secrete insulin, called beta cells, are the target of the immune system’s attack. Beta cells live in small clumps of cells called islets, within the pancreas.
In research published in the journal Science today, the American-Australian team has shown that fragments of two different beta-cell proteins, called peptides, join together to create a hybrid peptide. This hybrid is recognised as foreign by the immune system’s T cells, and may be one of the early steps in the immune cascade that eventually destroys the beta cells and causes type 1 diabetes.
University of Colorado researchers Professor Kathryn Haskins and Assistant Professor Thomas Delong identified the hybrid peptides in a type of mouse that develops type 1 diabetes. However, they needed to determine if their findings held true in humans.
They turned to SVI’s Dr Stuart Mannering for help. Stuart’s team was the first in the world to isolate human T cells from the pancreas of organ donors who had type 1 diabetes. He says that his group has been using these T cells as a tool to dissect what they recognise and respond to within the human beta cells.
“When we tested the hybrid peptide identified by the American group with T cells from human islets from organ donors who had type 1 diabetes, some of the T cells responded vigorously. It is like a police line-up. The T cells only recognise hybrid peptides that they have met before. The fact that the T cells reacted to the hybrid peptide meant that we were on the right track.”
Stuart says that the work provides a new paradigm for understanding how the immune system might be mistakenly destroying the body’s cells in type 1 diabetes. If the hybrid peptides turn out to be the targets of the initial immune response the researchers will be able to start working on strategies to use them to halt the disease.
“We may have found one of the early steps in the development of type 1 diabetes. This seemingly innocuous event – two peptide fragments joining together within the beta cell – gives us new avenues to pursue in order to find ways to combat type 1 diabetes.”
Professor Tom Kay, Director of St Vincent’s Institute says, “This is a remarkable discovery. It confirms that insulin itself is likely to be the main target of the immune system in type 1 diabetes, but in an unexpected way. This work opens up an exciting new line of research that could lead to practical application in both early diagnosis and treatment.”
Funding for the research was provided by the National Institutes of Health, an American Diabetes Association Pathway to Stop Diabetes Grant, the Australian National Health and Medical Research Council, the Juvenile Diabetes Research Foundation, the Diabetes Australia Research Trust and the Helmsley Charitable Trust.
Read the research article, entitled ‘Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion’, in Science.