Insulin attracts immune wrath in diabetes.

In juvenile diabetes, immune cells attack a person's own pancreas. They single out pancreatic cell clusters called the islets of Langerhans and destroy the tiny insulin factories within, called beta cells. How beta cells invite such immune damage is a long-running mystery.

Recently, several discoveries have shed light on the biological mechanism behind this carnage. A study in mice now points to a fragment of the insulin protein itself as the target that draws friendly fire from immune-system warriors called CD8 T cells, researchers report in the September NATURE MEDICINE.

In mice and people prone to juvenile diabetes, these cells become rogues, killing off beta cells as if they were invaders. In neither species do beta cells grow back once destroyed.

Microbes or compounds that initiate immune responses are called antigens. Because part of the insulin protein draws an assault to the body's own tissues, researchers consider it an autoantigen. The immune system programs T cells to destroy anything carrying a specific antigen or autoantigen. Once created, that's all CD8 T cells do.

The new study is the first to finger an autoantigen for CD8 T cells, says study coauthor Charles A. Janeway Jr., an immunobiologist at the Howard Hughes Medical Institute at Yale University. Earlier research had identified the same area of the insulin molecule as an autoantigen for CD4 T cells, which also play a role in the attack on beta cells.

"To find what these [T cells] are actually targeting is very important," says endocrinologist George S. Eisenbarth, director of the Barbara Davis Center for Childhood Diabetes in Denver "It's coming out that insulin ... might be a primary or dominant autoantigen" for juvenile, or type 1, diabetes, he says.

Insulin is necessary for the proper metabolism of carbohydrates. In less than 1 percent of the population, beta cells are absent or fail to make enough insulin resulting in juvenile diabetes. Genetic flaws--many details of which remain hidden--predispose the T cells to incite an immune attack on beta cells, Janeway says.

Mice make a useful, though not perfect, model of human diabetes. The mice used in this experiment came from a strain that frequently gets diabetes after 12 weeks of age. Janeway's group modified CD8 T cells so that they would change color when they come into contact with their activating antigen. The researchers were then able to identify the antigen as a stretch of nine ammo acids on the insulin molecules B chain.

Janeway's team now is looking for means to stimulate immune responses that turn off the rogue T cells. Scientists have been able to flood the bodies of mice with insulin fragments, preventing diabetes, Eisenbarth says. They suspect that T cells lock onto the insulin fragments instead of attacking the pancreas.

Indeed, Eisenbarth and other researchers are giving insulin or its derivatives to children at genetic risk of type 1 diabetes in hopes of inoculating them against beta-cell destruction.