A rare genetic defect that can trigger a host of diseases from type 1 diabetes to alopecia has helped explain the imbalance of immune regulator and killer cells in autoimmune disease.

Mutation in the Aire gene causes APS1, a disease causing two out of three problems - an underactive parathyroid, yeast infection of the skin and/or mucous membrane and adrenal gland insufficiency - by age 5 and up to 16 autoimmune diseases over a lifetime.

The same mutation causes a defect in iNKT cells, a type of regulatory cell that helps the immune system fight infections while suppressing errant T cells bent on attacking the body, Medical College of Georgia researchers say.

This finding opens new pathways for treating or preventing APS1, or autoimmune polyglandular syndrome type 1, and potentially other autoimmune diseases as well, researchers report in the June issue of Nature Medicine.

"The body should maintain a balance between killing and suppression," says Dr. Qing-Sheng Mi, immunologist and lead and co-senior author. "If you are killing too hard, it can induce autoimmune disease. If you regulate suppression too hard, you can get cancer. iNKT cells help maintain a healthy balance. But patients with autoimmune disease may not have enough functional iNKT cells," he added.

"Aire controls the development and function of iNKT cells," Drs. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and co-senior author said adding, "This relationship means that iNKT cells are critical to most autoimmune diseases and manipulating the iNKT cell population is one possible way to cure autoimmune disease."

A lipid purified from sea plants, called alpha-GalCer, is already under study as a way to boost iNKT cell numbers and fight autoimmune disease as well as cancer. iNKT cells' reactivity to alpha-GalCer, prompted the scientists to use it as a marker to examine the status of these cells in a mouse missing the Aire gene. That Aire knockout is a good model for humans with APS1.

They found significantly fewer iNKT cells in the thymus, spleen, liver and bone marrow and severely impaired maturation of those cells in mice missing the Aire gene. And the mice given alpha-GalCer had significantly reduced autoantibody production.

But Drs. Mi and She say new iNKT boosters likely are needed because the action of alpha-GalCer somehow depends on individual genetic architecture as well as other factors. Under certain conditions, the drug can help or worsen an autoimmune disease by producing good or bad cytokines. That's why it also has worked for some cancers and why a modified version of the glycolipid or totally different drugs may work better, Dr. She says. "By understanding more, we are better able to come up with better targets," he says.

The researchers watched the key regulatory cells come out of the bone marrow and go to the thymus where all T cells go for a process of positive and negative selection and maturation. Positive selection eliminates cells that are dysfunctional. Negative selection is eliminating T-cells that recognize the body's own proteins, Dr. She says.

The research was supported by the American Diabetes Association, the Juvenile Diabetes Research Foundation, the National Institutes of Health and the Canadian Institutes of Health Research.