Science + Technology

UCLA Study Uncovers Clues About Why Graves’ Disease Attacks the Eyes; Discovery Suggests New Target for Treating the Disorder

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UCLA researchers have uncovered new clues that may explainwhy Graves' disease attacks the muscle tissue behind the eyes, often causingthem to bulge painfully from their sockets, as in the case of the late actorMarty Feldman.

Scientists at UCLA's Jules Stein Eye Institute and Harbor–UCLA Medical Centerdiscovered defects in the infection-fighting T-cells of Graves' diseasepatients' immune systems. The study, reported March 1 in the Journal ofImmunology, may deepen understanding of how the autoimmune disorder damages thebody and offer a new target for treating the disfiguring disease.

Earlier research found that the immune systemsof patients with Graves' disease produce an antibody not found in healthypeople. This antibody fails to recognize patients' thyroid gland as "self"and mistakenly mounts an attack against the organ. Thethyroid then goes into overdrive, producing excess levels of hormone that cancause inflammation and damage to the body and attack the tissue behind the eyes,causing them to protrude. In extreme cases, patients experience trouble closingtheir eyelids, severe doublevision, corneal scarring, optic nerve damage and even blindness.

In the current study, UCLAresearchers discovered that T-cells taken from patients with Graves' diseasecontain an abnormal surplus of the receptor targeted by this antibody. Anantibody must latch to a specific receptor — like a key into a lock — in orderto elicit a cellular response. These receptors mobbed the patients' immunesystems, even appearing on T-cells that normally would not produce them.

"We didn't know why Graves' disease patients' cells createda new antibody but had a hunch that that it sprang from an immune abnormality,"explained Dr. Raymond Douglas, assistant professor of ophthalmology at theJules Stein Eye Institute and first author of the study. "Because T-cells are the generals of theimmune system and lead the attack in any immune response, we assumed that theyplayed a key role in this antibody's development."

The team tested patients' bloodfor the antibody and compared their findings to samples from healthy people,with about 100 subjects in each group. The new antibody was found in almost allof the Graves' disease patients' blood.

The new antibody binds to theexcess receptors on the T-cells, mimicking the actions of a hormone calledIGF-1, or insulin-likegrowth factor 1. Similar to insulin, IGF-1 stimulates cell growth while suppressing normal celldeath. The team suspects that this mechanism prolongs the survival ofolder T-cells, causing a cascade of autoimmune problems that spur the body toattack its own tissue.

"We think that the extra receptors allow the new antibodyand IGF-1 to disrupt the programming of the T-cells," said principalinvestigator Dr. Terry Smith, professor of medicine at the David Geffen Schoolof Medicine at UCLA and chief of molecular medicine at Harbor–UCLA Medical Center.

"Theantibody provokes the receptor to signal the T-cell to grow and multiply — longafter the cell was programmed to die," Smith said. "After two or threegenerations of this process, we suspect that the hijacked T-cells mutiny overthe normal T-cells, sparking the body's immune reaction against itself."

The next step is to identify what the T-cells are reactingto and how the receptor enables the cells to survive beyond their normallifespan. The team plans to develop an antibody drug to block the receptorfrom interacting with the T-cells and slow down the disease. 

Graves' disease isnine times more common in women than men. The disorder most often strikesduring the childbearing years and runs an average course of one to two years.No cure exists, though surgery can be performed at the end stage to correctdisfigurement.

Dr. Andrew Gianoukakis,assistant professor-in-residence of endocrinology at Harbor–UCLA Medical Center, was a co-authorof the study, which received funding from the National Eye Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the AmericanThyroid Association and the Bell CharitableFoundation.

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