Unlocking the secrets of Graves’ disease

Our immune and endocrine systems typically keep us healthy, fending off pathogens and regulating our hormones, respectively. But in Graves’ disease, the immune system’s antibodies provoke the thyroid gland to unleash a constant stream of thyroid hormones, leading to chronic jitteriness, fatigue, and for some, bulging eyeballs.

In findings published on August 8 in Nature, a team led by UCSF pharmaceutical chemist Aashish Manglik, MD, PhD, and biochemist Yifan Cheng, PhD, showed how these autoantibodies—antibodies that target the body itself—activate the thyroid gland during Graves’ disease. The findings pave the way for a new generation of therapies for the condition, which is the most common autoimmune disorder.

“The medications that we give for people with Graves’ disease haven't changed for several decades,” said Manglik, faculty member in the UCSF School of Pharmacy’s Department of Pharmaceutical Chemistry and co-senior author on the findings. “We need to make headway for patients.”

Treatments for Graves’ disease range from drugs that block the thyroid gland all the way to its surgical removal. But the body still needs the thyroid’s hormones on occasion, so patients must take replacement hormones for the rest of their lives. And the treatments for those with Graves’ eye disease—30% of patients with Graves’ disease—are particularly lacking, according to Manglik.

Manglik first learned about the condition in medical school, where it was presented both as an example of a disease affecting millions of patients, including former president George Bush, Sr., and his wife, Barbara Bush, and as a medical mystery.

In Graves’ disease, autoantibodies behave like hormones, disrupting the balance of signals that keep the thyroid gland in check. Manglik wanted to observe the molecular interaction between thyroid stimulating hormone (TSH) and the TSH receptor, which, based on how hormones often work, he expected to resemble how a key opens a lock. Then he would compare this with how the autoantibody “key” opened the TSH receptor “lock.”

“The notion that two different keys could fit the same lock is a great little puzzle,” he said. “Thanks to advances in techniques like cryo-electron microscopy, we could now visualize, at a very precise atomic level, how one of these keys, when it fits into this lock, opens it up, and what is changing about the lock’s shape.”

Manglik partnered with Cheng, an expert with the ultra-cold microscopy that could reveal snapshots of molecular keys opening molecular locks. The two brought together colleagues from their respective labs as well as Stanford University, the Salk Institute, and industry to carry the work across the finish line. Particularly crucial were former UCSF graduate student, Bryan Faust, PhD, who was mentored by both Manglik and Cheng, and Manglik lab postdoctoral fellow Christian Billesbølle, PhD.

“With the right tools and the right people, the time was ripe for us to work out the mechanics of this disease,” said Cheng.

A model of the findings from Manglik and Cheng’s recent work. Both thyroid stimulating hormone (TSH) and a Graves' disease autoantibody (M22) activate the thyroid stimulating hormone receptor (TSHR) (green), while another antibody, CS-17, deactivates TSHR (red).

The group found that the way that TSH normally activated the TSH receptor was “unusual.” Rather than lining up perfectly in a small pocket of the receptor, like a key fitting into a keyhole, TSH fits around a large portion of the TSH receptor, forcing the receptor to bend and “turn on.” The autoantibody, itself a large molecule, happened to similarly hug the same portion of the receptor, turning it on and sending the thyroid gland into overdrive.

In other words, because the TSH receptor didn’t behave like a typical molecular lock, it was vulnerable to being opened by an autoantibody with just the right shape.

Manglik and Cheng are ready to extend the finding toward solutions for patients. They are working with clinicians to determine whether the autoantibodies present in many patients behave the same as the autoantibody used in this study, which came from a single patient.

And with the knowledge of just how the autoantibody fits onto the TSH receptor, there’s opportunity to develop a drug that would specifically block the autoantibody without blocking TSH itself, enabling the thyroid gland to resume its normal function.

“This is a great example of UCSF’s strengths,” said Manglik. “It’s a story where mechanistic science gives us deep insight into human biology and leads to something with near-term impact for a relatively common human disease.”

Additional authors on the paper were Carl-Mikael Suomivuori, Isha Singh, Kaihua Zhang, Nicholas Hoppe, Antonio F.M. Pinto, Jolene K. Diedrich, Yagmur Muftuoglu, Mariusz W. Szkudlinski, Alan Saghatelian, and Ron O. Dror.