Good Cellular Defense May Be Best Offense Against Type1 Diabetes
A group of scientists at The Scripps Research Institute (TSRI) have shown that if a certain type of cell in the pancreas can defend itself against one particular virus, the owner of that pancreas will not get diabetes.
Infection and loss of such insulin-producing "beta cells," residing in the Islets of Langerhans of the pancreas, is the cause of the chronic autoimmune disease Type 1 diabetes.
"Our goal is to understand the causes of Type 1 diabetes," says TSRI Professor of Immunology Nora Sarvetnick, who led the study. "The idea is that we might be able to go on and design preventative therapies."
What Sarvetnick's team has now shown at TSRI, which is home to one of the largest basic Type 1 diabetes research programs in the world, is that the antiviral defenses undertaken by beta cells is critical for the survival of this cell type even after the body survives a viral infection.
Type-1 (insulin-dependent) diabetes mellitus is a chronic metabolic disease that occurs when beta cells in the pancreas, the body's source of insulin, are destroyed. The insulin produced by these cells is responsible for regulating blood glucose levels, which cells normally ingest to provide energy for metabolic processes.
The therapy of choice for the disease is to inject insulin, and before the discovery and isolation of insulin in the 1920s, having this type of diabetes meant certain death. Though insulin is a reasonable treatment, Type 1 diabetes is still a chronic infection for which there is no prevention and no cure. It, along with the more common Type 2 diabetes, is one of the leading causes of blindness and kidney disease in the world and one of the most costly health problems in the United States.
The agent that triggers the onset of Type 1 diabetes is believed to be a common virus that infects cells in the pancreas, since patients who have recently developed the disease often have antibodies against this virus. And there are also genetic and other environmental factors, only some of which are known, that contribute to the development of Type 1 diabetes.
During the viral infection, the body makes an adaptive immune response, and cytotoxic T lymphocytes selectively target and eliminate cells that are infected with the virus.
Diabetes develops when the killing proceeds out of control, and the T cells become autoreactivetargeting the person's own insulin-producing b cells. In Type 1 diabetes, T cells attack and kill all the insulin-producing cells in the body, causing a depletion of these cells in the pancreas and of insulin in the bloodsteam.
Without insulin, the glucose in the bloodstream increases and is maintained at levels much greater than normal. Over time, this can lead to nerve and kidney damage, reduced eyesight, and an increased risk of developing heart disease and vascular degeneration.
Sarvetnick's group has shown that the beta cells play a role in their own destinythey can survive the infection if they are able to detect soluble proteins called Type1 interferons.
"When you get infected with the virus, the body reacts by producing Type1 interferons," says Research Associate Malin Flodström, who is first author on the paper.
"And," she says, "that should signal the b cells to respond."
During this response, the beta cells in the pancreas start producing proteins that send the cells into an antiviral state. Flodström, Sarvetnick, and their colleagues showed that if the cells lose the ability to make this response, they disappear from the body once they are infected.
In transgenic "knockout" models the team developed, which cannot detect the signal from the interferons, an infection with the virus causes diabetes 95 percent of the time. In normal models, the virus alone does not cause disease because the cells are able to respond to the interferons and protect themselves against the virus.
Similarly, most individuals' beta cells are able to sense interferons and protect themselves against the virus.
If a way can be found to provide people who are at risk of developing diabetes with the tools that will enable their pancreatic beta cells to defend themselves during a viral infection, the team believes Type1 diabetes may become a preventable disease.
The article, "Target cell defense prevents the development of diabetes after viral infection" is authored by Malin Flodström, Amy Maday, Deepika Balakrishna, Mary Malo Cleary, Akihiko Yoshimura, and Nora Sarvetnick and appears in the April 2002 issue of the journal Nature Immunology.
The article and a separate commentary are available online at http://www.nature.com/ni/. The research was funded by the National Institutes of Health and the Juvenile Diabetes Research Foundation.