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Joslin Diabetes Center scientists find genetic defects

ustain 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."

What if the safeguard mechanism is defective? Left unchecked, the self-destructive T-cells can roam throughout the body and wreak havoc. This is the process behind many autoimmune, or "self-immune," diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis and others.

To understand what happens in type 1 diabetes, the researchers combined a unique set of cutting-edge technologies, using cultures of thymus cells from transgenic mice, together with DNA chips and "genome scans." They compared non-obese diabetic (NOD) mice, which researchers elsewhere had shown to have the tolerance defect, with diabetes-resistant controls. They looked for regions where the data from the DNA chips and the genome scan converged. Overlap would indicate the regions and genes that affect tolerance.

In the mice with diabetes, two findings emerged -- a distinct decrease of activity in regions that governed the elimination of errant T-cells, and an increase of activity promoting their survival. The safeguard system was broken. The T-cells were alive and able to leave the thymus and attack beta cells.

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Contact: Marjorie Dwyer
marjorie.dwyer@joslin.harvard.edu
617-732-2415
Joslin Diabetes Center
22-Mar-2005


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