New
pathways for autoimmune treatment identified
by Toni Baker
A rare genetic defect helps 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 attacking the body, MCG 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,” said Dr. Qing-Sheng Mi, immunologist and lead and co-senior author. “Excess cell death 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.”
“Aire controls the development and function of iNKT cells,” said Dr. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and co-senior author. “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, alpha-GalCer, is already under study to boost iNKT cell numbers and fight autoimmune disease and cancer. iNKT cells’ reactivity to alpha-GalCer prompted the scientists to use it as a marker to examine these cells in a mouse missing the Aire gene, 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.
In 2001, Dr. Terry L. Delovitch and his colleagues at Canada’s Robarts Research Institute, including Dr. Mi, reported in Nature Medicine that using alpha-GalCer to boost iNKT cells and re-establish a healthy balance of good and bad immune cells prevented type 1 diabetes in an animal model for the disease.
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 said. “By understanding more, we are better able to come up with better targets.”
“iNKT development is still the big question,” said Dr. Mi, “not only how they develop, but how they develop properly.”
The researchers watched key regulatory cells travel from the bone marrow to the thymus, where all T cells go for positive and negative selection and maturation. Positive selection eliminates dysfunctional cells. Negative selection eliminates T cells that recognize the body’s own proteins.
Other researchers recently confirmed that the Aire gene is involved in negative selection by controlling some protein expression in the thymus. The thymus is supposed to express most body proteins so any T cells that would react to them can be eliminated through negative selection. “But Aire’s role in protein expression is not sufficient to explain all the clinical symptoms of patients with APS1,” Dr. Mi said. “The Aire gene must have other immune functions.”
iNKT cells also develop, but via a different path than that of other T cells. MCG researchers have learned medullary epithelial cells in the thymus are critical to proper iNKT cell development. A defective Aire gene interrupts this relationship by disrupting medullary epithelial cell function, leading to insufficient numbers of iNKT cells.
“Whether or not you develop autoimmune disease to a large degree depends on the balance of these bad T cells that recognize the body’s own protein and regulatory T cells,” Dr. She said. “It’s all about balance.”
Dr. Mi received a Junior Faculty Travel Award from the American Association of Immunologists for the iNKT research during the association’s annual meeting in May.
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.
Co-authors were Drs. Zhong-Bin Deng, Sunil K. Jushi, Zai-Zhai Wang, Li Zhou, Sarah Eckenrode, Ratnmani Joshi as well as Bing Yi from MCG and Dr. Delovitch and Ph.D. candidate Dalam Ly from the Robarts Research Institute and the University of Western Ontario.