Estimates suggest that as many as 4 million Americans may have Sjögren’s disease, a chronic systemic autoimmune disease characterized by dry eyes and dry mouth, but which may also cause fatigue, joint pain, inflammation in the liver, kidney, lungs, blood vessels, nerves, and brain. Sjögren’s disease can lead to complications during pregnancy, as well as complications for the fetus during gestation and the newborn after delivery. Patients with certain types of Sjögren’s disease are also at risk for lymphoproliferative diseases including lymphoma. Like many autoimmune diseases, women are at higher risk of developing Sjögren’s disease than men. However, it should be noted that men who develop Sjögren’s disease have a higher risk of complications. Although doctors know that Sjögren’s disease occurs when the immune system attacks glands and epithelial tissues, what drives this condition or how to stop it is unclear. There is no cure for Sjögren’s disease, but people with the condition may take treatments to manage their symptoms.
A recent NIH-supported study in mouse models of Sjögren’s disease offers important insights into this condition, pointing to an important role for dysfunction in regulatory T cells that normally control immune responses to prevent autoimmune diseases. Although these cells have been linked to other autoimmune conditions, their role in Sjögren’s disease had been unclear. The findings also identify a drug already used to treat other conditions including rheumatoid arthritis as a potential therapy for Sjögren’s disease.
These new findings are reported in Science Translational Medicine by a team led by Stefan Feske, M.D., and Rodrigo Lacruz, M.Sc., Ph.D., of New York University’s Grossman School of Medicine and College of Dentistry. Although they knew Sjögren’s disease is driven by inflammation, they wanted to understand more about what happens in the disease at the cellular level in salivary glands and the immune system.
An earlier study by the researchers in mice linked changes in calcium uptake in salivary glands to reduced production of saliva. The mice lacked two genes, called Stim1 and Stim2, which encode proteins that act as calcium sensors to regulate calcium’s entry into cells. But there was no evidence of other characteristics of Sjögren’s disease, including inflammation or an increase in autoantibodies that attack the body’s own tissues in autoimmune conditions including Sjögren’s disease.
In the latest study, the researchers focused again on mice lacking calcium signals due to changes in Stim1 and Stim2. This time, they turned their attention to the regulatory T cells. Other research had suggested that abnormal calcium signaling could lead to dysfunction in this part of the immune system. Indeed, in the new study, the researchers found that dysfunction in regulatory T cells in mice leads to severe inflammation that closely resembles what is seen in Sjögren’s disease. The mice had dry eyes, dry mouth, autoantibodies, and lymphocytes in their salivary and tear glands. Mice also developed lung inflammation, which sometimes happens in people with Sjögren’s disease.
The researchers determined that the dysfunction of regulatory T cells resulted in the overproduction of an inflammatory signal called interferon gamma, which is made by other immune cells called T helper 1 cells. When they depleted the interferon gamma signal from mouse T cells, they found improvements in salivary and tear gland function. The findings point to interferon signals as a promising target for treating symptoms of Sjögren’s disease.
To put the idea to the test, the researchers turned to an existing drug called baricitinib that works by blocking interferons and other inflammatory signals. Clinicians already use baricitinib to treat other diseases and conditions such as rheumatoid arthritis, alopecia, and COVID-19. When given to the mice with symptoms like those of Sjögren’s disease, the treatment led to improved salivary and tear gland function and reduced inflammation.
How likely is this drug to work in people with Sjögren’s disease? To get more clues, the researchers used RNA sequencing to explore molecular-level changes in immune cells from the mice compared to those in people with Sjögren’s disease. Their studies reveal strong similarities between the two, which leads the researchers to think that baricitinib or other treatments that work in similar ways are promising candidates for treating people with Sjögren’s disease.
Although much more study is needed, these new findings suggest there may one day be more targeted and effective ways to treat Sjögren’s disease and improve the quality of life of millions of people around the world living with it.
References:
- Wang YH et al. IFN-γ-producing TH1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren's disease. Science Translational Medicine. DOI: 10.1126/scitranslmed.ado4856 (2024).
- Son GY et al. Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease. Function. DOI: 10.1093/function/zqae047 (2024).
- NIH Support: NIH Office of Autoimmune Disease Research/Office of Research on Women’s Health, National Institute of Dental and Craniofacial Research, National Eye Institute, National Institute of Allergy and Infectious Diseases