salivary glands

Receptors Found to Help Patients with Sjögren’s Disease

April 13, 2022 By Balslew, Karly (MU-Student) in Research Tags: salivary glands, Sjögren’s Disease

The Baker lab poses for a group photograph. The lab has been working with specialized pro-resolving lipid mediators in efforts to help patients with Sjögren’s Disease. Photo by Karly Balslew, Bond LSC

By Karly Balslew | Bond LSC

Saliva is probably not the first thing that comes to mind when we think about eating our favorite foods. The clear liquid washes away food debris and bacteria, and it plays a vital role in maintaining our dental hygiene and oral health.

You may take it for granted, but for patients with Sjögren’s disease, life without saliva is challenging.

“We’ve seen firsthand how patients suffer from Sjögren’s disease and what the consequences are in the oral cavity,” said Olga Baker, a Bond Life Sciences Center principal investigator studying the syndrome.

The autoimmune disease causes our body to attack the glands that produce tears and saliva. This destruction at the hands of our immune system causes dry mouth and dry eyes as it eventually kills the cells that perform this valuable service to our bodies. Without saliva, tooth decay and painful diseases like gingivitis are almost inevitable.

Sjögren’s disease affects approximately 4 million people in the United States. The severity of the disease varies in patients, but it destroys all exocrine glands and there is currently no cure. While the cause of the disease is still unknown, researchers are turning efforts to alleviate patient discomfort.

The Baker lab focuses on a class of drugs called specialized pro-resolving lipid mediators. These medications are derived from essential fatty acids and play an important role in decreasing inflammation and recovering salivary function.

Harim Tavares Dos Santos — a post-doctoral fellow in the Baker lab and lead author on a recent study of this drug —has seen success with restoring salivary functions with the specialized pro-resolving lipid mediator drug resolvin D1 (RvD1). Resolvins act as anti-inflammatory mediators and restores saliva flow rates. The lab will test a variety of drugs from the specialized pro-resolving lipid mediators’ class to see which one would yield the best results, but some receptors they affect within the salivary glands are unknown.

“The first step is to see if we know all the receptors for other drugs,” Tavares Dos Santos said. “Then, we test the different drugs to see which ones activate the receptor to possibly decrease inflammation and reach the goal of getting the saliva back.”

RvD1 activates the receptor ALX/FPR2 Tavares Dos Santos explains. This then triggers a signaling mechanism that promotes the survival of salivary gland cells and protects the cells tight junctions while increasing saliva secretion. Researchers used six human minor salivary from female subjects in this experiment to determine the expression of pro-resolving lipid mediators in patients with and without Sjögren’s syndrome.

Previously, the lab tested these drugs on mice models with Sjögren’s-like features and saw they can recover salivary function. However, researchers need more data to find other receptors that can maximize the positive response from the drug.

But mice aren’t the same as humans, and even when researchers test on humans it can be difficult to find patients with Sjögren’s disease willing to participate in the research.

“We don’t have a lot of literature in salivary glands to look for. Basically, what is known about resolvins and salivary glands is generated here in the lab,” Tavares Dos Santos said.

“Another challenge is that no one knows what causes the disease, so the research is mainly trial and error,” Baker said.

Baker explains that studies show people with Sjögren’s disease could have a genetic predisposition for it, but there are also environmental factors like viruses that could trigger the genetic components that lead to Sjögren’s disease.

“In the end, we want to create a drug that has all those properties to cure the patient so hopefully in the future, we can get a product on the market,” Baker said.

The Baker lab will present their progress with Sjögren’s syndrome at the 2023 Gordon Research Conference in Ventura, California. Both Baker and Tavares Dos Santos will co-chair the international conference that attracts researchers studying salivary glands and exocrine biology.

“This is a very important conference that will elevate Missouri,” Baker said. “The whole thing is really exciting.”

Olga Baker is a professor of Otolaryngology-Head and Neck Surgery and Biochemistry as well as a Bond Life Sciences Center principal investigator. Harim Tavares Dos Santos is a Bond Life Sciences Center post-doctoral fellow.

Standing out through saliva

August 4, 2016 By Roger Meissen in Research Tags: Bond LSC, extracellular ATP, salivary glands, Sjogren's syndrome

Bond LSC scientist internationally recognized for work on salivary glands and autoimmune disorders

By Phillip Sitter | Bond LSC

You might not think too highly of spit, but you would quickly regret not having any.

People with Sjögren’s syndrome suffer chronic dry mouth and eyes from an overzealous immune system that attacks salivary and tear ducts, causing serious health issues.

Gary Weisman’s research might hold the key to understanding and managing this immune response, leading to effective treatment or even prevention of this ailment.

For this, the International Association of Dental Research, or IADR, awarded him the 2016 Distinguished Scientist Award for Salivary Research. Weisman accepted the award in June at the opening ceremonies of the IADR conference in Seoul, Republic of Korea.

Gary Weisman stands in his lab in Bond LSC where he studies the cellular mechanisms of auto-immune disease, specifically how the release of ATP from damaged cells signals receptors that trigger an immune response. | Phillip Sitter, Bond LSC

“We want the good, but not the bad,” said Weisman, a Bond Life Sciences Center investigator, of what we ideally want from our immune system’s functions.

Mice with un-checked autoimmune disease of their salivary glands have their glands destroyed. The disease can spread to other secretory organs next. An over-reactive immune system on a civil war-path can extend its damage to cause pancreatic failure and death.

The destruction wrought by Sjögren’s syndrome is self-inflicted, caused by an overreaction of our bodies’ defenses against infection and injury. This is what an autoimmune disease is.

But, our bodies’ immune cellular response team is complicated. Weisman said dozens of different cell types have been isolated and identified as part of the immune system, and he likens the immune system to fire, police and construction services in human society all working together.

While firefighters are meant to prevent further damage from an inferno, sometimes our bodies’ first responders start doing the equivalent of using dynamite to stop the spread of a fire.

In chronic inflammation, that autoimmune response can mean a burning, throbbing, constant pain. The key to a healthy immune response is balance. The balance has to be between containment and repair of damage caused by infection or injury and damage caused by chronic inflammation if that emergency response continues unabated.

Weisman has spent almost 30 years studying how to prevent our bodies’ immune system from over-reacting to threats and causing further harm.

Earlier in his career, Weisman studied how extracellular ATP plays a critical role in immune responses, and how too much of it can cause the over-reaction that leads to tissue destruction in autoimmune diseases. ATP, or adenosine 5’-triphosphate, is the main molecule used for energy in cellular activities inside cells. Weisman was one of the first scientists to study how damaged cells release ATP as a distress signal.

The released ATP signals receptors that “send out the alarm to the fire station” — the body’s immune cells, he said.

Once he understood this, Weisman began to manipulate the actions of released ATP to see how that would affect an immune response.

Mice with salivary gland autoimmune disease got healthy when the released ATP was prevented from activating their receptors on the surface of cells. Preventing the ATP receptors from being activated slowed down and even stopped the advance of autimmune disease.

Conversely, if you prevent the activation of the ATP receptors in lab mice with Alzheimer’s disease they die much more rapidly from the disease, Weisman said, suggesting that activation of immune cells by ATP is beneficial in slowing the progression of this disease.

Alzheimer’s disease and autoimmune diseases such as Sjögren’s syndrome are only some of the inflammatory diseases that Weisman has studied. With each of these diseases, the role of ATP receptors has to be investigated individually, suggesting that Weisman’s work may extend beyond salivary glands and the brain to other parts of the body.

“Our [ATP] receptor is also involved in heart disease,” Weisman said, and he added that other diseases like cystic fibrosis, cancer, lupus and arthritis have inflammatory components, too.

For now, we all fight a losing battle when it comes to our bodies’ management of the immune system. As we and our immune system age, it has the potential to destroy more than it protects and “eventually you could slip over to the dark side and die,” Weisman said.

In the meantime, Weisman said that a better understanding of the immune system could lead to more effective, targeted treatments of chronic inflammation and other autoimmune disorders. This could provide a new approach to control undesirable activation of the immune system beyond the use of with anti-histamines, anti-cytokines and ibuprofen.

Weisman is a Curator’s Distinguished Professor of Biochemistry. He began his salivary gland research at MU 27 years ago with Professor John Turner, before Turner’s retirement. Since then, his research has been continuously funded by the National Institutes of Health, where one of his recent grants was well scored and will likely be extended for another five years.