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article imageSuspected Cause of Type 1 Diabetes Caught

By Bob Ewing     May 9, 2008 in Health
Scientists at Washington University School of Medicine in St. Louis working with diabetic mice have examined in unprecedented detail the immune cells long thought to be responsible for type 1 diabetes.
Diabetic mice provided the scientists at Washington University School of Medicine in St. Louis the opportunity to examine in unprecedented detail the immune cells long thought to be responsible for type 1 diabetes.
The researchers were able to examine the immune cells from isolated insulin-making structures in the pancreas known as the islets of Langerhans. The result of this examination was that the scientists caught the immune cells, known as dendritic cells, "red-handed" carrying insulin and fragments of insulin-producing cells known as beta cells.
This can be the first step toward starting a misdirected immune system attack that destroys the beta cells, preventing the body from making insulin and causing type 1 diabetes.
The results were reported online in The Proceedings of the National Academy of Sciences, and will push scientists a step closer to finding ways to treat this condition.
"Now that we've isolated dendritic cells from the pancreas, we can look at why they get into the pancreas and determine which of the materials that they pick up are most critical to causing this form of diabetes," says senior author Emil R. Unanue, M.D., the Paul and Ellen Lacy Professor of Pathology. "That may allow us to find ways to inhibit dendritic cell function in order to block the disorder."
Insulin injections are essential to survival because the immune system has destroyed the islets of Langerhans, which contain the body's only beta cells. The insulin these cells make is required for the critical task of regulating blood sugar levels.
Dendritic cells in the islets were found years ago. Dendritic and other antigen-presenting cells are the sentinels of the immune system: their job is to pick up bits of protein from around the body and present them to lymphocytes to initiate an immune system reaction.
The lymphocytes lead immune attacks against foreign invaders like bacteria and viruses and eliminate them, clearing infections. But when interaction between an antigen-presenting cell and a lymphocyte leads to a part of the body being mistakenly identified as alien, the resulting attack harms the body, causing autoimmune diseases.
The presence of dendritic cells' in the islets and their ability to summon immune attacks made them likely suspects in type 1 diabetes, however, it was to isolate from the pancreas for closer examination.
"They're very tiny and there are only about 5 to 10 of them per islet, each of which contains approximately a thousand cells," explains Unanue. "So the senior postdoctoral researcher in the lab, who did this work, Boris Calderon, had to develop some sophisticated cellular assays to pick them up."
Indications that the cells were carrying granules of insulin and pieces of proteins from beta cells on their cell surfaces were found. In order to be able to test whether this cargo carried by the dendritic cells had the potential to trigger an immune attack on beta cells, Calderon exposed the dendritic cells to lymphocytes taken from diabetic mice.
The lymphocytes were activated by the dendritic cells of the islets and went on the offensive.
While following another line of research, Unanue's lab has discovered that dendritic cells in the pancreas may normally have beneficial effects on the health of beta cells. They've shown that when dendritic cells are absent from the pancreas, the beta cells are smaller, an indication that they're not as healthy.
"We think these dendritic cells aren't in the pancreas by accident," says Unanue. "We believe that in the normal individual they help maintain the health of beta cells. But in a person with autoimmune diabetes, they appear to start the problems that destroy beta cells."
The key distinction likely lies in a group of proteins called the major histocompatibility complex (MHC). Twenty years ago, Unanue and Paul Allen, Ph.D., the Robert L. Kroc Professor of Pathology and Immunology, demonstrated that the MHC provides the stage on which antigen-presenting cells show bits of protein or peptides to other immune system cells.
Scientists believe autoimmune conditions like type 1 diabetes are caused by differences in what the MHC binds to and how it presents that material to immune attack cells. In support of this theory, Unanue's laboratory and that of Michael Gross, Ph.D., Washington University professor of chemistry, have both shown that the genes that encode the MHC proteins in the diabetic mouse are unique and bind to a set of very characteristic peptides.
Unanue and others are also working to learn how genetic variations in the MHC alter the chances that the immune system will mistakenly attack the body.
More about Type diabetes, Insulin, Immune cells
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