Researchers have made significant progress in understanding the causes behind the autoimmune disorder Sjögren’s disease, thanks to recent findings related to calcium signaling, regulatory T cells, and interferon. A new study indicates that the dysfunction of regulatory T cells plays a crucial role in both mice and humans with Sjögren’s disease, and it has identified an existing rheumatology medication as a potential treatment option for this condition.
Researchers at NYU College of Dentistry and NYU Grossman School of Medicine have advanced our knowledge about Sjögren’s disease, an autoimmune disorder, through new insights into calcium signaling, regulatory T cells, and interferon.
Their recent study, featured in Science Translational Medicine, reveals that faulty regulatory T cells are a significant factor in the development of Sjögren’s disease in both mice and humans. Additionally, they highlight a currently used rheumatology drug as a promising treatment avenue.
Sjögren’s disease occurs when the immune system erroneously attacks the glands that produce saliva and tears, leading to symptoms like dry mouth and eyes. It may also affect other areas of the body, with patients sometimes experiencing exhaustion, joint and muscle discomfort, skin rashes, and inflammation in the lungs.
“The inability to produce tears or saliva can profoundly affect a person’s quality of life,” stated Rodrigo Lacruz, a professor of molecular pathobiology at NYU College of Dentistry. “Without saliva, communication and the ability to digest food become difficult, increasing the likelihood of cavities and negatively impacting overall health.”
Key indicators of Sjögren’s disease, which assist in diagnosis, include the presence of autoantibodies in the bloodstream and lymphocytes found in the salivary glands. While there is no definitive cure for Sjögren’s disease, some treatments can help alleviate symptoms, although they may not offer complete relief.
“Sjögren’s disease is driven by inflammation,” emphasized Stefan Feske, the Jeffrey Bergstein Professor of Medicine at NYU Grossman School of Medicine. “Current treatments that target B cells with antibodies have yielded mixed results in clinical settings.”
Feske and Lacruz conducted two studies examining different tissues — salivary gland and immune cells — to better comprehend the cellular mechanisms involved in Sjögren’s disease. They specifically targeted cells that lacked the genes Stim1 and Stim2, which are crucial for calcium signaling, the body’s most abundant mineral.
Understanding Calcium’s Role
Lacruz and Feske are investigating how calcium signaling relates to human diseases, including immune system disorders and conditions affecting oral health. While calcium signaling is vital for saliva production, its precise role in the onset of Sjögren’s disease is not fully understood.
In a study published in the journal Function, the researchers examined mice that lacked the Stim1 and Stim2 genes in their salivary glands, leading to decreased calcium absorption. They discovered that these mice produced less saliva because of reduced calcium levels and signaling. Interestingly, these mice did not exhibit salivary gland inflammation or heightened levels of autoantibodies commonly seen in humans with Sjögren’s disease, indicating that a loss of calcium signaling might suppress inflammatory responses rather than make the mice more susceptible.
“We identified that a specific calcium channel, activated by STIM1 and STIM2 proteins, known as the ORAI1 channel, is crucial for saliva secretion. This is a vital finding. Reduced calcium signals not only hinder function but may also diminish the impact of inflammatory molecules linked to Sjögren’s disease,” remarked Lacruz, who led the Function study.
Impact of Regulatory T Cells
Earlier research showed that genetically modified mice, which lacked calcium signaling in their immune system’s T cells, faced issues within regulatory T cells that led to increased inflammation and autoimmune conditions. Regulatory T cells are essential for regulating immune responses, and when they fail to function correctly, autoimmune diseases can arise. Given the inconsistent results from prior studies on regulatory T cells and Sjögren’s disease, these cells became a focal point in Feske’s and Lacruz’s research.
In the Science Translational Medicine study, spearheaded by Feske, the researchers again studied mice lacking Stim1 and Stim2 genes, this time concentrating on regulatory T cells. The issues with these cells led to notable inflammation in the mice that matched the diagnostic criteria for Sjögren’s disease: dry mouth, dry eyes, autoantibodies, and lymphocytes in the salivary glands. Several mice also showed signs of lung inflammation, which can be a symptom of Sjögren’s disease.
“Removing these two genes triggered a cascade of immune problems,” said Feske.
The question arose: Did the lack of calcium signaling drive the autoimmune response similar to Sjögren’s disease in the mice? Further investigations involving both mice and human blood cells led researchers to conclude that the main issue was the dysfunction of regulatory T cells, which can fail through various mechanisms, not solely due to calcium signaling.
A significant factor contributing to Sjögren’s disease symptoms in the mice was identified as interferon gamma.
“The problem boiled down to defective regulatory T cells and an overactivation of cells that secrete an inflammatory cytokine known as interferon gamma,” noted Feske. “Interferon gamma was crucial in causing dysfunction in the salivary glands in our mouse model.”
Regulatory T cells usually inhibit other immune cells, including those that produce interferon gamma. By eliminating calcium signaling in regulatory T cells, these cells became overactive, leading to increased production of the cytokine. The researchers observed that genetically removing interferon gamma from the T cells in the mice improved salivary gland function.
Could a medication replicate this effect? To explore this possibility, the researchers investigated an existing drug named baricitinib, which is currently used for treating rheumatoid arthritis, alopecia, and, more recently, in hospitalized COVID-19 patients. Baricitinib acts as a JAK (Janus kinase) inhibitor, reducing inflammation by blocking signals downstream from the interferon receptor.
When the researchers treated mice with baricitinib, they noted a reduction in salivary gland dysfunction and inflammation. Given the positive results observed in mice displaying Sjögren’s symptoms, the researchers believe that baricitinib may be a viable treatment option for Sjögren’s disease.
To see if their mouse study findings were applicable to humans, the researchers also analyzed blood samples from individuals with Sjögren’s disease. By utilizing single-cell RNA sequencing to investigate white blood cells, they revealed a strong connection between gene expression patterns in both mice and humans affected by Sjögren’s disease.
“We not only identified the underlying mechanisms causing Sjögren’s disease in our mouse model, but we also correlated our findings with the disease’s classification and gene patterns in humans,” Feske commented. “Additionally, I believe that baricitinib shows great potential for treating Sjögren’s disease in the future.”
Other contributors to the Science Translational Medicine study include 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 from NYU Grossman School of Medicine, and Ga-Yeon Son from NYU College of Dentistry. The research was funded by the National Institutes of Health (R01DE027981, EY030917, U01DE028891, AI164803), the Colton Center for Autoimmunity at NYU, and a research initiative from China’s Central South University.
Co-authors of the Function study include Ga-Yeon Son and Anna Zou from NYU College of Dentistry; Amanda Wahl, Kai Ting Huang, Larry Wagner, and David I. Yule from the University of Rochester; as well as Saruul Zorgit, Manikandan Vinu, and Youssef Idaghdour from NYU Abu Dhabi. The study also received support from the National Institutes of Health (R01DE027981, DE014756, U01DE028891, P30CA016087).
