Researchers at NYU College of Dentistry and NYU Grossman School of Medicine are closer to understanding what drives the autoimmune disorder Sjögren's disease, thanks to new discoveries about the role of calcium signaling, regulatory T cells, and interferon.
Their latest study, published in Science Translational Medicine , finds that impaired regulatory T cells are a critical contributing factor to Sjögren's disease in both mice and humans, and identifies an existing rheumatology drug as a promising therapy for the disease.
In Sjögren's disease, the immune system attacks the glands that produce saliva and tears, resulting in dry mouth and eyes. It can also affect other parts of the body, with some patients experiencing fatigue, joint and muscle pain, rashes, and lung inflammation.
"Not being able to produce tears or saliva can have a great impact on one's life," said Rodrigo Lacruz , professor of molecular pathobiology at NYU College of Dentistry. "If you can't produce saliva, it may hamper your speech and your ability to process food, increases your risk for developing cavities, and overall worsens one's health."
In addition to low tear and saliva production, the hallmarks of Sjögren's disease—and factors that help clinicians diagnose it—are autoantibodies in the blood and lymphocytes in the salivary glands. While there is no cure for Sjögren's disease, some treatments alleviate symptoms but may not provide patients with full relief.
"Sjögren's disease is an inflammation-driven disease," said Stefan Feske , the Jeffrey Bergstein Professor of Medicine in the Department of Pathology at NYU Grossman School of Medicine. "There are therapies for Sjögren's that deplete B cells with antibodies, but they showed mixed results in clinical trials."
Feske and Lacruz undertook two studies focusing on different tissues—salivary gland cells and immune cells—to better understand what's happening at the cellular level to contribute to Sjögren's disease. They specifically looked at cells lacking the Stim1 and Stim2 genes, which interrupt the signaling of the most abundant mineral in the body: calcium .
The calcium connection
Lacruz and Feske study the role of calcium signaling in human diseases, including disorders of the immune system and those that affect the mouth. Calcium signaling is important for saliva production, but it is unclear to what extent it may be involved in the development of Sjögren's disease.
In a study recently published in the journal Function , the researchers studied mice without the Stim1 and Stim2 genes in salivary gland cells, which leads to a lack of a calcium uptake into these cells. They found that these mice had lower saliva production, which was a result of reduced calcium levels and signaling. However, the mice did not have salivary gland inflammation or increased levels of autoantibodies characteristic of Sjögren's disease in humans, suggesting that the loss of calcium signaling in salivary gland cells might actually suppress inflammatory responses rather than rendering these mice susceptible to inflammation and autoantibodies.
"We found that a specialized calcium channel activated by STIM1 and STIM2 proteins, the ORAI1 channel, is essential for driving saliva secretion, which is an important discovery. Lack of calcium signals not only impairs function, it may also decrease the effect of inflammatory molecules that have been associated with Sjögren's disease," said Lacruz, who led the study in Function.
The role of regulatory T cells
Previous studies revealed that genetically altering mice to lack calcium signaling in their immune system's T cells resulted in dysfunction in one particular type of T cell—regulatory T cells—which prompted inflammation and autoimmune disease in the mice. Regulatory T cells help control the immune system's response, but when they don't work as they should, they fail to prevent autoimmune disease. Because prior research on regulatory T cells and Sjögren's disease has yielded mixed results, these cells became another key focus of Feske's and Lacruz's work.
In the study in Science Translational Medicine, led by Feske, the researchers again studied mice that were lacking Stim1 and Stim2 genes and thus calcium signals, but this time, focused on regulatory T cells instead of salivary gland cells. The dysfunction in regulatory T cells resulted in severe inflammation in the mice that aligned with the classification criteria for Sjögren's disease: dry eyes, dry mouth, autoantibodies, and lymphocytes in the salivary glands. Some mice also developed lung inflammation, which can be a symptom of Sjögren's disease.
"Knocking out these two genes drove a cascade of immune dysfunction," said Feske.
Was it the impaired calcium signaling that prompted the autoimmune response akin to Sjögren's disease in mice? In further analyses in mice and human blood cells, the researchers concluded that the key issue was the dysfunction of regulatory T cells, which can occur through different pathways, not just calcium signaling.
A likely culprit causing Sjögren's disease symptoms in mice: interferon gamma.
"It came down to a defect in regulatory T cells and an overactivation of the cells that produce an inflammatory cytokine called interferon gamma," said Feske. "Interferon gamma was absolutely critical for causing dysfunction of salivary glands in our mouse model."
Regulatory T cells typically inhibit other immune cells, including those that produce interferon gamma. Knocking out calcium signaling in regulatory T cells unleashed the cells that produce interferon gamma, allowing them to produce more of the cytokine. However, when the researchers genetically depleted interferon gamma from the mice's T cells, it improved salivary gland function.
Could a drug do the same? To test this idea, the researchers turned to an existing drug called baricitinib that is currently used to treat rheumatoid arthritis, alopecia, and more recently, hospitalized COVID-19 patients. Baricitinib is a JAK (Janus kinase) inhibitor that reduces inflammation by suppressing signals downstream of the interferon receptor.
When the researchers gave mice baricitinib, it suppressed salivary gland dysfunction and inflammation. Given the success of the drug in mice with Sjögren's symptoms, both in this study and others, the researchers think that baricitinib could be a candidate for treating Sjögren's disease.
To determine if their findings in mice translated to humans, the researchers also examined blood samples from patients with Sjögren's disease. Using single-cell RNA sequencing to study white blood cells, they found a strong correlation between the gene expression in cells of mice and humans with Sjögren's disease.
"Not only did we dissect the underlying cause for Sjögren's disease in our mouse model, but we correlated these findings to the disease's classification criteria and genetic signatures in humans," said Feske. "Moreover, I think using baricitinib has great promise in the treatment of Sjögren's disease going forward."
Additional authors of the Science Translational Medicine study are Yin-Hu Wang, Wenyi Li, Maxwell McDermott, Fang Zhou, Anthony Tao, Dimitrius Raphael, Andre L. Moreira, Boheng Shen, George Maiti, Martin Vaeth, Bettina Nadorp, and Shukti Chakravarti of NYU Grossman School of Medicine and Ga-Yeon Son of NYU College of Dentistry. The study was supported by the National Institutes of Health (R01DE027981, EY030917, U01DE028891, AI164803), the Colton Center for Autoimmunity at NYU, and Hunan Province Graduate Student Research and Innovation Project CX20190160 from China's Central South University.
Additional authors of the Function study are Ga-Yeon Son and Anna Zou of NYU College of Dentistry; Amanda Wahl, Kai Ting Huang, Larry Wagner, and David I. Yule of the University of Rochester; and Saruul Zorgit, Manikandan Vinu, and Youssef Idaghdour of NYU Abu Dhabi. The study was also supported by the National Institutes of Health (R01DE027981, DE014756, U01DE028891, P30CA016087).
