Researchers uncover immune loop driving Sjögren's disease progression

Sjögren's disease is a widespread chronic autoimmune disorder that attacks the body's own glands, yet its underlying disease mechanisms remain poorly understood. In a recent study, researchers from Japan discovered a self-reinforcing loop between different immune cells that sustains autoimmune responses in patients with Sjögren's disease. Their findings pave the way for safer and more effective therapies.

Sjögren's disease is a chronic autoimmune disorder that affects millions of people worldwide. In patients with this disease, the immune system attacks the body's own exocrine glands, such as the salivary and lacrimal glands, causing persistent dry mouth and dry eyes. The disease can also progress to affect the skin, lungs, kidneys, and peripheral nerves. Despite its prevalence, no curative treatment exists yet; patients often rely on broad immunosuppressive drugs that dampen the entire immune system rather than addressing the underlying cause.

A hallmark of Sjögren's disease is the presence of anti-Ro60 autoantibodies, which mistakenly target the body's own Ro60 protein. While B cells, the immune cells that produce antibodies, have been extensively studied in Sjögren's disease, far less is known about the role of CD4⁺ T cells, which coordinate immune responses and help activate other immune cells. Scientists suspect that these T cells cooperate with B cells to sustain autoimmune reactions, but identifying the molecules recognized by pathogenic T cells has remained difficult.

In a recent study, a team of researchers led by Assistant Professor Masaru Takeshita from the Division of Rheumatology at the Department of Internal Medicine of Keio University School of Medicine, Japan, tackled this knowledge gap. As reported in their latest paper, which will be made available online in Science Advances on June 3, 2026, they analyzed immune cells isolated from the salivary glands of patients with Sjögren's disease and identified, for the first time, disease-associated CD4⁺ T cells that recognize the same Ro60 protein targeted by autoreactive B cells.

To investigate how these immune responses develop, the team combined single-cell RNA sequencing with T-cell receptor (TCR) analysis. T-cell receptors are molecules that allow each T cell to recognize a specific target. The researchers identified more than 200 TCRs from immune cells infiltrating diseased salivary glands and tested whether they reacted to fragments of the Ro60 protein presented by patient HLA molecules. Using engineered reporter cells and artificial antigen-presenting systems, the team identified 13 TCRs that specifically recognized Ro60-derived peptides.

Through further analysis, the researchers shed light on a previously unrecognized process. They found that many of the Ro60-reactive T cells belonged to specialized subsets of CD4⁺ T cells known to stimulate antibody-producing B cells. The researchers also demonstrated that anti-Ro60 antibodies produced by B cells can bind to Ro60 proteins released from damaged cells, forming immune complexes that are efficiently taken up by antigen-presenting cells. These cells then display Ro60-derived peptides to CD4⁺ T cells, activating them and promoting additional antibody production. "Simply put, this process forms a self-reinforcing loop, sustaining autoimmune responses and contributing to chronic disease," explains Dr. Takeshita. Notably, the results were consistent across both Japanese and Caucasian patients, suggesting this mechanism is a general feature of anti-Ro60-positive Sjögren's disease regardless of genetic background.

Overall, this study contributes to a deeper understanding of Sjögren's disease and could lead to the development of better treatment strategies. "Currently, therapies for Sjögren's disease suppress immune responses broadly, affecting both harmful and protective immune functions. If the pathogenic loop we identified can be interrupted, it may be possible to selectively suppress disease-causing autoimmune responses without impairing normal immune function," remarks Dr. Takeshita. "Such approaches could potentially reduce the risk of infections and other complications associated with systemic immunosuppression."

Going forward, researchers at Keio University aim to further explore these newfound mechanisms and translate their findings into effective therapies for Sjögren's disease and other autoimmune disorders, with the ultimate goal of improving patients' quality of life.