Researchers Uncover Self-Reinforcing Immune Loop Driving Sjögren's Disease Progression
Key Insights
Researchers at Keio University identified disease-associated CD4+ T cells that recognize the same Ro60 (search) protein targeted by autoreactive B cells in Sjögren's disease (search), revealing a self-reinforcing immune loop.
The team used single-cell RNA sequencing and TCR analysis to identify 13 T-cell receptors that specifically recognized Ro60 (search)-derived peptides, with findings consistent across Japanese and Caucasian patients.
Anti-Ro60 (search) antibodies form immune complexes that are taken up by antigen-presenting cells, which then activate Ro60-reactive CD4+ T cells, promoting further antibody production and sustaining chronic autoimmunity.
A team of researchers led by Assistant Professor Masaru Takeshita from the Division of Rheumatology at Keio University School of Medicine has identified a previously unrecognized self-reinforcing immune loop that sustains autoimmune responses in patients with Sjögren's disease (search). The findings, published online in Science Advances on June 3, 2026, represent the first identification of disease-associated CD4+ T cells that recognize the same Ro60 (search) protein targeted by autoreactive B cells, opening new avenues for safer and more targeted therapies.
Sjögren's disease (search) is a chronic autoimmune disorder affecting millions worldwide, in which the immune system attacks the body's exocrine glands — particularly the salivary and lacrimal glands — causing persistent dry mouth and dry eyes. The disease can progress to involve the skin, lungs, kidneys, and peripheral nerves. Despite its prevalence, no curative treatment exists; patients currently rely on broad immunosuppressive drugs that dampen the entire immune system rather than addressing the underlying cause.
Unmasking Pathogenic T Cells in Diseased Tissue
A hallmark of Sjögren's disease (search) is the presence of anti-Ro60 (search) autoantibodies, which mistakenly target the body's own Ro60 protein. While B cells have been extensively studied in this context, far less is known about the role of CD4+ T cells, which coordinate immune responses and help activate other immune cells. Scientists have long suspected that these T cells cooperate with B cells to sustain autoimmune reactions, but identifying the molecules recognized by pathogenic T cells has remained difficult.
To bridge this knowledge gap, Takeshita and colleagues analyzed immune cells isolated from the salivary glands of patients with Sjögren's disease (search). The team combined single-cell RNA sequencing with T-cell receptor (TCR) analysis, identifying more than 200 TCRs from immune cells infiltrating diseased salivary glands. Using engineered reporter cells and artificial antigen-presenting systems, they identified 13 TCRs that specifically recognized Ro60 (search)-derived peptides presented by patient HLA molecules.
A Self-Reinforcing Loop Sustains Chronic Disease
Through further analysis, the researchers uncovered a cyclical pathogenic process. Many of the Ro60 (search)-reactive T cells belonged to specialized subsets of CD4+ T cells known to stimulate antibody-producing B cells. The team 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," explained Dr. Takeshita.
Notably, the results were consistent across both Japanese and Caucasian patients, suggesting this mechanism is a general feature of anti-Ro60 (search)-positive Sjögren's disease (search) regardless of genetic background.
Toward Selective Immunotherapy
The discovery carries significant therapeutic implications. Current therapies for Sjögren's disease (search) suppress immune responses broadly, affecting both harmful and protective immune functions. Interrupting the identified pathogenic loop could enable a more precise approach.
"Currently, therapies for Sjögren's disease (search) 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," remarked 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 mechanisms and translate their findings into effective therapies for Sjögren's disease (search) and other autoimmune disorders, with the ultimate goal of improving patients' quality of life.