Researchers at National Jewish Health and the University of Colorado Anschutz Medical Campus have identified the precise protein fragment, or peptide, that can trigger diabetes in mice. The finding, published in the June 15, 2010, issue of the Proceedings of the National Academy of Sciences, supports an emerging theory about the origins of autoimmunity, and may lead to new diagnostic and therapeutic strategies in humans.
"Our findings contradict conventional wisdom, which suggests that insulin peptides that are well presented to the immune system trigger diabetes," said John Kappler, PhD, Professor of Immunology at National Jewish Health. "We believe, however, that the peptide we identified triggers diabetes precisely because it is so poorly presented to the immune system."
The immune system tries to delete all T cells that might cause autoimmune disease. During development in the thymus, immature T cells are exposed to "self" protein fragments, which are part of the organism. T cells that recognize and bind to them are destroyed. This process, however, is not foolproof, and autoimmune T cells do occasionally escape.
The development of type I diabetes in mice is associated with one form of MHCII, the molecule that holds and presents peptides to the immune system. Previous research had identified a specific fragment of insulin, consisting of 12 linked amino acids, as the target of the autoimmune attack in type I diabetes. The MHCII molecule, which has a binding pocket only 9 amino acids long, can bind to and present that insulin fragment in at least four different ways, known as registers. Peptides bound in register present different subsets of amino acids to the T cells that cause diabetes.
Contrary to conventional wisdom, the research team found that the peptide presented in the register that binds most weakly to the MHCII molecule stimulated four different T cells associated with diabetes. Peptides bound in the other registers did not stimulate those T cells.
"Although scientists have been closing in on the cause of type I diabetes, this is the first time that anyone has identified exactly what T cells recognize when they initiate an autoimmune attack in diabetes," said co-author George Eisenbarth, MD, Professor of Immunology at the University of Colorado Anschutz Medical Campus and executive director of the Barbara Davis Center for Childhood Diabetes at the university.