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.”
“Aire controls the development and function of iNKT cells,” says Drs. 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, 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.
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 development of 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 says. “By understanding more, we are better able to come up with better targets,” he says.
“iNKT development is still the big question,” says Dr. Mi. “Not only how they develop, but how they develop properly.”
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.
Other researchers recently confirmed that the Aire gene is involved in negative selection by controlling some protein expression in the thymus, Dr. Mi says. The thymus is supposed to express most body proteins so any T cells that would react to them can be eliminated through negative selection, he says. “But Aire’s role in protein expression is not sufficient to explain all the clinical symptoms of patients with APS1,” Dr. Mi says. “The Aire gene must have other immune functions.”
iNKT cells also go through a development process but via a somewhat 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 disrupts this natural nurturing 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 says. “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 include 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.
Toni Baker | EurekAlert!
Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München
Second research flight into zero gravity
21.10.2016 | Universität Zürich
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
21.10.2016 | Health and Medicine
21.10.2016 | Information Technology
21.10.2016 | Materials Sciences