Scientists at Joslin Diabetes Center have found genetic regions that, when defective, allow the immune system to attack the pancreas -- the first in a series of mis-steps that lead to type 1 diabetes. Armed with these findings, published yesterday, March 22, in the journal Immunity, the researchers are now trying to hone in on the exact genes involved, in mice and in human patients.
"The significance of this study is that we found the chromosomal regions involved and can now zero in on the precise genes," said Diane Mathis, Ph.D., the study's principal investigator along with Christophe Benoist, M.D., Ph.D. They head the Section on Immunology and Immunogenetics at Joslin, and hold joint William T. Young Chairs in Diabetes Research. They are also Professors of Medicine at Harvard Medical School. The work was spearheaded by a group of Joslin fellows, hailing from across the globe: Silvia Zucchelli, Ph.D., who has now returned to Italy; Phil Holler, Ph.D., from the U.S.; and Tetsuya Yamagata, M.D., Ph.D, from Japan.
The genetic defect keeps the body from properly dealing with "errant" immune cells that it normally eliminates by a process called immunological tolerance. These immune cells then attack the insulin-producing beta cells in the pancreas, mistaking them as foreign invaders.
"It's critical for the immune system to recognize and tolerate tissues that belong in the body, which immunologists call 'tolerance,'" said Dr. Zucchelli. "Previous studies have shown that when the T-cells don't learn this tolerance, they can infiltrate the pancreas and attack the insulin-producing beta cells." This first step in the onset of type 1 diabetes is called insulitis. Later in life, within weeks or even years, full-blown type 1 diabetes emerges.
An estimated 1 million people in the United States have type 1 diabetes. Their pancreatic beta cells can no longer make insulin. Without this crucial hormone, their body cannot convert food into energy. To sustain life, they must get insulin through injections. The disorder can emerge in childhood, adolescence and even appear in adulthood, but the genetic stage is set beforehand.
T-cells play a key role. They are part of the highly complex array of immune cells that normally work together to fight invaders such as bacteria or viruses, adapting specifically to each new invader. Formed in the thymus gland, T-cells begin as "precursor" cells and mature -- during this time, receptor sites on their outer membrane are shaped to dock with each invader and destroy it.
"As T-cells form, it is not uncommon for a few to randomly develop with the potential ability to attack the body's own cells," said Dr. Holler. "That's when a safeguard mechanism normally kicks in to eliminate these errant T-cells. Our team found the genetic regions that govern this safeguard."