UB dental professor studying immune system’s role in Sjögren’s disease

BUFFALO, N.Y. — Sjögren’s disease affects about 4 million people in the United States, predominately women. Characterized by severely reduced tears and saliva, the autoimmune disease makes the sufferers’ mouths feel like they’re filled with cotton and often results in tooth decay and difficulty swallowing.

Jill M. Kramer, DDS, PhD, associate professor in the Department of Oral Biology at the University at Buffalo School of Dental Medicine, is looking at how targeting a key molecule in the immune system could lead to better therapies for this debilitating condition.

“There are no FDA-approved drugs for Sjögren’s other than those that reduce eye inflammation,” she said. “Unfortunately, we don’t have anything that prevents the loss of salivary flow or reverses it. As dentists, we just advise patients to drink lots of water, avoid sugary, sticky foods, brush their teeth often, and use high-fluoride products to manage the symptoms and try to prevent decay.”’

Second NIH award for study

Kramer, who has studied Sjögren’s disease for several years, hopes that more effective treatments will become available in the near future. She recently received a $2.1 million, five-year renewal grant from the National Institute of Dental and Craniofacial Research (NIDCR), which is part of the National Institutes of Health (NIH), to study the molecule MyD88 and how it is activated by various receptors. This study continues research that Kramer and her team began in 2017.

“We know that MyD88 plays a key role in the immune system by helping cells respond to the signals that trigger inflammation,” she said. “If you don’t have this molecule, you’re very susceptible to disease.”

In their initial study, MyD88 was genetically removed from mice that were prone to Sjögren’s, and they didn’t exhibit the typical dry mouth or inflamed organs.

“We knew that MyD88 was really important because if it was gone, a lot of the disease manifestations were completely abrogated,” Kramer said.

There is a huge caveat: the mice typically became very sick by six months of age. Thus, blocking MyD88 may not work as a therapeutic approach to combatting Sjögren’s because humans could become severely ill with other diseases.

Understanding exactly how MyD88 causes Sjögren’s, however, could lead to the development of new drugs that block these harmful pathways.

Connections to other autoimmune diseases

Kramer and her team are expanding their study of the specific receptors that activate MyD88 and how they communicate with each other. Kramer is collaborating with dental school colleague Rose-Anne Romano, PhD, who is also an associate professor in the Department of Oral Biology, to understand these interactions in patients and mice with Sjögren’s disease. Also, PhD student Sheta Biswas and master’s student Bayan Alhaddad are working on the project.

A group of molecules called toll-like receptors (TLRs) play a crucial role, acting like sensors on immune cells that help the body detect germs or danger. The researchers[investigators?] have discovered that two different receptors, TLR7 and TLR9, are especially important, and there is a sex bias in how they work.

For instance, female mice that didn’t have TLR7 had a lessened amount of Sjögren’s disease, while the male mice got sicker.

“It made us wonder: Should we be thinking about treating males and females differently?” Kramer said. “It raises some interesting questions for us to consider from a therapeutic perspective.”

Insights gained from studying Sjögren’s could potentially benefit patients with other autoimmune diseases, such as lupus and rheumatoid arthritis, she said.

It was actually literature on lupus, which has been studied much more extensively than Sjögren’s, that provided Kramer with ideas for the UB study.

“When TLR7 was knocked out in lupus mouse models, the animals were much healthier,” she said. “And when TLR7 is mutated in humans, it can become overactive and drive lupus. When scientists put that same mutated TLR7 into mice, the mice developed a lupus-like disease. Obviously, lupus is a different disease than Sjögren’s, but some of the molecular findings are similar.”

She noted that current work in the field focuses on understanding Sjögren’s disease from a molecular perspective, and such studies will likely inform treatments for Sjögren’s and similar diseases.

“We’re starting to appreciate the fact that even though patients may be diagnosed clinically with Sjögren’s disease, there can actually be distinct molecular variations within these patients,” she explained. “And if we can identify specific subsets of patients with particular variations, we may be able to predict which patients may respond well to a specific treatment. I think as our understanding grows, we will be able to group patients according to their molecular profiles and then treat them in a targeted way.”

While the team hasn’t performed clinical trials, it is working with Jennifer Frustino, DDS, PhD, the director of oncology research and the associate chief of service, dentistry/Division of Oral Oncology & Maxillofacial Prosthetics at Erie County Medical Center, to get healthy salivary gland tissues from patients. This helps them understand how MyD88 in salivary gland cells contributes to inflammation in salivary cells.

“Our hope is that as we gain a more sophisticated understanding of how the disease progresses,” Kramer said,  “and about the differences between males and females, and the way that these molecules talk to each other, we can effectively block key mediators of inflammation without making the patient immunocompromised.”