On Assignment for Mayo's Clinic's Discovery's Edge magazine, reposted with permission.
Summary: In almost half of all patients with Graves’ Disease, a form of hyperthyroidism, the antibodies that attack the thyroid gland also attack the eyes, causing changes known as Graves’ Ophthalmopathy. A team headed by Mayo Clinic investigator, Rebecca Bahn, M.D., discovered that a specific protein in the thyroid that is attacked by the antibody is also present in the cells behind the eyes. Their discovery may lead to new therapies that prevent the disease from developing.
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Unlocking the Mysteries of Graves’ Ophthalmopathy
By Nikolas Charles
December 2008
Every good mystery has an evil villain and a charming protagonist that saves the day. This mystery is no different. However, our villain isn’t a serial killer hiding in the shadows, it is an antibody that has cleverly eluded researchers for decades.
That was the case until clinician investigator Rebecca Bahn, M.D. entered the story. At that time, in the late 80s, the mystery wasn’t what causes Graves’ Disease—a type of hyperthyroidism or overactive thyroid. The real mystery was what was the connection between Graves’ Disease and Graves’ Ophthalmopathy, the eye problems that are associated with Graves’ Disease.
“The basic question at that time was ‘what do the eyes have to do with the thyroid?” says Dr. Bahn. “It was totally unknown. Why would they both be involved in the same disease?”
Like the heroes in mystery stories—and even more importantly in real life—Dr. Bahn decided to dedicate her career to not only treating patients with Graves’ Ophthalmopathy, but to research work that would lead to a greater understanding of its causes and developing effective treatment options.
“Current treatments have significant side effects and are often ineffective or reserved for patients with the most severe disease,” says Dr. Bahn.
Clinicians currently treat Graves’ Ophthalmopathy with prednisone, orbital radiation, or by waiting and watching until it either improves or progresses to the point where surgery becomes an option. Although invasive, the surgery is effective for severely affected patients.
When antibodies attack
Graves’ Disease is caused when antibodies attack the thyroid gland but instead of destroying the thyroid, they stimulate the thyroid cells to make too much of the thyroid hormone thyroxine, sometimes referred to as T4. This increases the body’s metabolic rate and causes several health problems, including anxiety, difficulty sleeping, fatigue, irregular heartbeat, weight loss, and frequent bowel movements.
“If you carefully examine the eyes of all patients with Graves’ Disease, you will see that about half have something wrong with their eyes, including eye irritation and redness” says Dr. Bahn. “They will say ‘I think I have an allergy. I keep scratching my eyes.’ This half of Graves’ Disease patients have Graves’ Ophthalmopathy. About 20 percent have more severe eye problems including pain, swelling, double vision and forward protrusion of the eyes. Sometimes these symptoms can be troublesome enough to interfere with working or driving.
“The course of the disease is that it starts mild and then may gradually worsen for perhaps three years,” says Dr. Bahn. “Then there’s usually a plateau followed by gradual improvement. Our concern is how severe it may become before it plateaus and improves on its own. Will it stop at eye irritation or double vision, or will it compress the optic nerve until the patient needs emergency surgery?
Rather than being the result of too much thyroid hormone, an important cause of the changes in the eyes is that the same antibody attacks the tissues behind the eyes,” says Dr. Bahn “That’s confusing to patients. They say ‘I’ve already had my thyroid destroyed but my eyes are getting worse. I thought this was going to fix my eyes.’ What we need is a way to stop the antibodies from attacking.”
Solving the mystery
It took a deeper understanding of what the antibodies were really attacking to solve the mystery regarding the connection between the thyroid and the eyes. They are not really attacking the entire thyroid or eye. They are not even attacking all of the cells within those tissues. They are attacking a specific part of a protein on the cells.
“We asked ourselves ‘why do these antibodies attack both the thyroid cells and the cells behind the eyes, and occasionally the skin, but no other part of the body?’ They don’t attack the liver or the heart. There must be something unique to the areas that they attack. There must be a protein that’s found essentially only in these areas, or is found in greater amounts in these areas.”
Nearly 10 years before Dr. Bahn began her research, other laboratories had a general idea that Graves’ Disease was caused by antibodies attacking a part of the thyroid stimulating hormone receptor (TSHR). The TSHR is a protein shaped a certain way so that only this particular hormone fits into it, locking in to signal thyroid cells to produce thyroid hormone.
The actual structure of the TSHR wasn’t completely clear until about ten years after Bahn’s research began. The biological connection between the thyroid and the eyes was then also completely unknown. Although Bahn and others wondered whether there might be TSHR in tissues besides the thyroid, there was at first no good way to find out.
“Once the TSHR was cloned, we were able to study its RNA (ribonucleic acid) and find out where else in the body the protein can be found. We were especially interested in cells from behind the eyes and found that the protein was indeed there and that levels were increased in eye tissue from patients with the disease.”
The specific cells that are being attacked are called orbital preadipocytes. These are cells behind the eye that are capable of turning into fat cells when stimulated by the antibodies. Since fat cells are larger than preadipocytes, the increase in tissue volume behind the eyes sometimes causes them to protrude forward. In addition, fat and other cells make chemicals that inflame the eyes and cause the pain and swelling experienced by patients with Graves’ Ophthalmopathy.
Testing a potential treatment
Since the antibodies are causing damage, one of the goals of Bahn’s research is to decrease their production. That has to be done early in the antibody’s lifecycle. Antibodies are produced when B-lymphocytes (also known as B-cells) mature. Since immature lymphocytes cannot make antibodies, the goal is to decrease the number of newly produced cells so they never reach the age when they can make antibodies that attack the TSHR.
Dr. Bahn, the principal investigator, and her co-investigators, James Garrity, M.D., Elizabeth Bradley, M.D., and Marius Stan, M.D., are currently recruiting patients for a clinical trial with the drug Rituximab. Rituximab destroys pre-antibody producing cells, thus eliminating the attacking antibodies, and also blocks early activation of the immune system. Rituximab is used to treat autoimmune diseases such as rheumatoid arthritis and lupus.
Dr. Bahn credits her longstanding relationship with Drs. Garrity and Bradley, both orbital surgeons; as well as her lab team and Mayo’s philosophy of collaboration with advances she has made in lab studies. She conducts a myriad of studies on fat tissue that is removed during surgery from behind the eyes of severely affected patients—research that she hopes will produce clinical advances as it furthers the understanding of involved cells.
Body of evidence
To an experienced researcher, the human body is filled with evidence and information—something Dr. Bahn learned very early from her father, Robert Bahn, a Mayo Clinic pathologist.
“I grew up going into his lab on weekends,” she says.
Both she and her brother, Mark Bahn, M.D., a Mayo Clinic neuroradiologist, followed in their father’s footsteps by becoming physicians.
Dr. Bahn began her research at Mayo 20 years ago with a Rappaport Fellowship grant before receiving a grant from the National Institutes of Health. Since then, her research has not only begun to solve the mystery of Graves’ Ophthalmopathy and identified the attacker, but also begun to attack back.