UCLA researchers have uncovered new clues that may explain why Graves' disease attacks the muscle tissue behind the eyes, often causing them to bulge painfully from their sockets, as in the case of the late actor Marty Feldman.
Scientists at UCLA's Jules Stein Eye Institute and Harbor–UCLA Medical Center discovered defects in the infection-fighting T-cells of Graves' disease patients' immune systems. The study, reported March 1 in the Journal of Immunology, may deepen understanding of how the autoimmune disorder damages the body and offer a new target for treating the disfiguring disease.
Earlier research found that the immune systems of patients with Graves' disease produce an antibody not found in healthy people. This antibody fails to recognize patients' thyroid gland as "self" and mistakenly mounts an attack against the organ. The thyroid then goes into overdrive, producing excess levels of hormone that can cause inflammation and damage to the body and attack the tissue behind the eyes, causing them to protrude. In extreme cases, patients experience trouble closing their eyelids, severe double vision, corneal scarring, optic nerve damage and even blindness.
In the current study, UCLA researchers discovered that T-cells taken from patients with Graves' disease contain an abnormal surplus of the receptor targeted by this antibody. An antibody must latch to a specific receptor — like a key into a lock — in order to elicit a cellular response. These receptors mobbed the patients' immune systems, even appearing on T-cells that normally would not produce them.
"We didn't know why Graves' disease patients' cells created a new antibody but had a hunch that that it sprang from an immune abnormality," explained Dr. Raymond Douglas, assistant professor of ophthalmology at the Jules Stein Eye Institute and first author of the study. "Because T-cells are the generals of the immune system and lead the attack in any immune response, we assumed that they played a key role in this antibody's development."
The team tested patients' blood for 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 all of the Graves' disease patients' blood.
The new antibody binds to the excess receptors on the T-cells, mimicking the actions of a hormone called IGF-1, or insulin-like growth factor 1. Similar to insulin, IGF-1 stimulates cell growth while suppressing normal cell death. The team suspects that this mechanism prolongs the survival of older T-cells, causing a cascade of autoimmune problems that spur the body to attack its own tissue.
"We think that the extra receptors allow the new antibody and IGF-1 to disrupt the programming of the T-cells," said principal investigator Dr. Terry Smith, professor of medicine at the David Geffen School of Medicine at UCLA and chief of molecular medicine at Harbor–UCLA Medical Center.
"The antibody provokes the receptor to signal the T-cell to grow and multiply — long after the cell was programmed to die," Smith said. "After two or three generations of this process, we suspect that the hijacked T-cells mutiny over the normal T-cells, sparking the body's immune reaction against itself."
The next step is to identify what the T-cells are reacting to and how the receptor enables the cells to survive beyond their normal lifespan. The team plans to develop an antibody drug to block the receptor from interacting with the T-cells and slow down the disease.
Graves' disease is nine times more common in women than men. The disorder most often strikes during 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 correct disfigurement.
Dr. Andrew Gianoukakis, assistant professor-in-residence of endocrinology at Harbor–UCLA Medical Center, was a co-author of the study, which received funding from the National Eye Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Thyroid Association and the Bell Charitable Foundation.