UCLA researchers have uncovered new clues that may explain why Graves’ disease (GD) attacks the muscle tissue behind the eyes, often causing them to bulge painfully from their sockets, as in 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 GD patients’ immune systems. Reported March 1 in the Journal of Immunology, their study 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 GD patients’ immune systems produce an antibody that other people do not. Not recognizing the patient’s thyroid as "self," the antibody mistakenly mounts an attack against the organ, causing inflammation and damage to the body, including eye tissue.
In the current study, UCLA researchers discovered that T-cells taken from GD patients 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. The receptors mobbed the patients’ immune systems, even on T-cells that normally would not produce them.
"We didn’t know why GD patients’ cells created a new antibody, but had a hunch that that it sprang from an immune abnormality," explained Dr. Raymond Douglas, first author and assistant professor of ophthalmology at the Jules Stein Eye Institute. "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 GD 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 GD 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 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," he explained. "After two or three generations of this process, we suspect that the high-jacked 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.
In Graves’ disease, the thyroid gland goes into overdrive, producing excess levels of hormone that attack the tissue behind the eye, causing them to protrude. In extreme cases, patients experience trouble closing their eyelids, severe double vision, corneal scarring, optic nerve damage and even blindness.
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 done at the end stage to correct disfigurement.
Enrique Rivero | EurekAlert!
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