In an important advance in diabetes research, Yale Medical School scientists have identified insulin proteins as the targets of aggressive attacks by cells that cause diabetes, clearing the way for further research into diverting these attacks and preventing the disease.
Published in the September issue of Nature Medicine magazine, the study is the first to identify the autoantigen recognized by diabetes-causing CD8 T cells (T lymphocytes) in the Non-Obese Diabetic Mouse, one of the best animal models for research of human diabetes.
These findings should make it easier to discover the genetic and environmental influences that allow autoreactive clones—cells that react to the body’s own proteins—to emerge and thrive in people with diabetes, according to F. Susan Wong, M.D., Ph.D., Associate Research Scientist, Section of Immunobiology at Yale University School of Medicine.
“This is the first time that the target of CD8 cells that cause Type 1 diabetes has been recognized,” said Dr. Wong. “Now that we know that insulin is an important autoantigenic target, we can use this knowledge to find out how to prevent the attacks.”
Type 1 diabetes is an autoimmune disease in which CD4 and CD8 immune system T cells destroy the insulin-producing beta cells in the pancreas. This kind of diabetes mainly affects children and unlike Type 2 diabetes, which affects a larger number of people, is not considered hereditary. Although there is a genetic susceptibility, only 10 percent of people with Type 1 diabetes have a family history of the disease. Many researchers believe the disease is triggered by environmental conditions that have not yet been identified.
The immune system has many different types of cells, but it is widely believed that the T cells play a major role in diabetes. There are 2 subsets of T cells: CD4, which are helper cells and CD8, which are cytotoxic cells—a type of killing cell that normally rids the immune system of viruses. In type 1 diabetes however, these cells that normally do a great job of protecting us recognize molecules and proteins within the insulin-producing cells that they attack as if it were something foreign.
Out of the many genes involved in determining whether or not diabetes develops in certain people, one of the most significant is the major histocompatability complex (MHC). T cells can’t directly recognize their targets without the help of MHC genes. The T cells are able to see bits of protein with MHC molecules that they would otherwise miss in the absence of MHC, according to Dr. Wong.
“Our results reaffirm the importance of insulin as an autoantigen in diabetes,” said Dr. Wong, whose co-investigators at Yale School of Medicine included Charles A. Janeway, Jr. , also of Howard Hughes Medical Institute; Jaana Karttunen; Caroline Dumont; Li Wen; Irene Visintin; Ingrid Pilip and Erica G. Palmer. Nilabh Shastri of University of California, Berkeley, was also a member of the research team. The National Institutes of Health and the Juvenile Diabetes Foundation International funded this study.
