Insights into the Genetic Makeup of Autoimmune Disease

Autoimmune diseases such as type 1 diabetes, lupus, and rheumatoid arthritis occur when the immune system fails to regulate itself. However, up until now, researchers have not known exactly where the molecular breakdowns responsible for such failures occur.

"This may shorten the path to new therapies for autoimmune disease,” said Dr. Richard Young, senior author on the study, and a researcher from the Whitehead Institute for Biomedical Research (Cambridge, MA, USA) and professor of biology at Massachusetts Institute of Technology (MIT; Cambridge, MA, USA). The study was published January 21, 2007, online in the journal Nature. "With this new list of genes, we can now look for possible therapies with far greater precision.”

The immune system is frequently described as a sort of military unit, a defense system that guards the body from invaders. Seen in this way, a group of white blood cells called T cells are frontline soldiers of immune defense, engaging invading pathogens right away. These T cells are controlled by a second group of cells called regulatory T cells. Regulatory T cells prevent biologic "friendly fire” by ensuring that the T cells do not attack the body's own tissues. Failure of the regulatory T cells to control the frontline soldiers leads to autoimmune disease.

Scientists earlier found that regulatory T cells are themselves controlled by a master gene regulator called Foxp3. Master gene regulators bind to specific genes and control their level of activity, which in turn affects the behavior of cells. When Foxp3 blocks functioning the body can no longer produce working regulatory T cells. When this occurs, the frontline T cells damage multiple organs and cause symptoms of type 1 diabetes and Crohn's disease. However, until now, scientists have understood little about how Foxp3 controls regulatory T cells because they knew almost nothing about the actual genes under Foxp3's control.

Researchers in Richard Young's Whitehead lab, working closely with immunologist Dr. Harald von Boehmer of the Dana-Farber Cancer Institute (Boston, MA, USA), utilized DNA microarray technology developed by Dr. Young to scan the entire genome of T cells and locate the genes controlled by Foxp3. There were approximately 30 genes found to be directly controlled by Foxp3 and one, called Ptpn22, showed a particularly strong affinity.

"This relation was striking because Ptpn22 is strongly associated with type 1 diabetes, rheumatoid arthritis, lupus and Graves' disease, but the gene had not been previously linked to regulatory T-cell function,” commented Alexander Marson, a M.D. Ph.D. student in the Young lab and lead investigator of the study. "Discovering this correlation was a big moment for us. It verified that we were on the right track for identifying autoimmune related genes.”

The researchers still cannot determine exactly how Foxp3 enables regulatory T cells to prevent autoimmunity. But the range of the genes that Foxp3 targets provides an initial map of the circuitry of these cells, which is critical for understanding how they control a healthy immune response.

"Autoimmune diseases take a tremendous toll on human health, but on a strictly molecular level, autoimmunity is a black box,” stated Dr. Young. "When we discover the molecular mechanisms that drive these conditions, we can migrate from treating symptoms to developing treatments for the disease itself.”





Related Links:
Whitehead Institute for Biomedical Research