Researchers at Kyoto University have discovered that “immune hubs” in the kidney create a unique metabolic environment that could be targeted for new treatments. These clusters of immune cells, called tertiary lymphoid structures (TLSs), show high levels of oxidative stress but counter this by accumulating glutathione, a key antioxidant, maintaining a delicate balance. The study found that specific support cells produce and supply glutathione to sustain these immune hubs, and blocking this process prevents new TLSs from forming or causes existing TLSs to shrink. By analyzing mouse and human samples, the researchers also demonstrated that measuring glutathione levels in urine could provide a simple, non-invasive way to monitor TLS formation (patent pending). This discovery opens the door to “metabolic intervention-based immune regulation,” a promising new therapeutic concept that could improve treatment for kidney diseases and beyond.
This research was led by Professor Motoko Yanagita (Department of Nephrology, Graduate School of Medicine, Kyoto University; Principal Investigator and Deputy Director at WPI-ASHBi ), Associate Professor Yuki Sugiura (Multi-Omics Platform, Center for Cancer Immunotherapy and Immunobiology , Graduate School of Medicine, Kyoto University), and Dr. Hiroyuki Arai (former graduate student in Nephrology at Kyoto University, current Research Fellow in the Division of Nephrology, Washington University in St. Louis, USA). The findings were published online in the Journal of the American Society of Nephrology on August 8, 2025.
Background
Kidney disease affects more than 850 million people worldwide. Current treatments often rely on steroids or immunosuppressive drugs, which broadly suppress the immune system. While these medications can control inflammation, they also increase patients’ risk of infections and other complications. This has prompted researchers to search for safer, more targeted therapeutic approaches.
Tertiary lymphoid structures (TLSs) are clusters of immune cells that form in organs where they normally wouldn’t exist, such as the kidneys. These structures develop in response to inflammation, infection, or aging, acting as local hubs for immune activity. Previous research has shown that kidney TLSs can directly cause tissue damage by promoting inflammation, as seen in patients who have received kidney transplants.
In recent years, scientists have increasingly focused on the connection between metabolism and immunity, a rapidly expanding field known as immunometabolism. While metabolic processes and the balance between oxidative stress and antioxidants are known to be important for immune function, their roles in TLS formation have remained unclear. In this study, researchers examined kidney TLSs from a metabolic perspective to better understand how they are regulated in kidney disease.
Key Findings
Using advanced technology that combines imaging mass spectrometry with comprehensive metabolomics analysis, researchers discovered that TLSs create a unique metabolic environment. These structures accumulate high levels of glutathione, a key antioxidant, while showing reduced levels of cystine and cysteine, the materials needed to produce glutathione. At the same time, TLSs also showed elevated oxidative stress levels. Immune cells within TLSs experienced significantly higher oxidative stress than those found elsewhere in the body, highlighting the delicate balance between antioxidant protection and oxidative damage within these structures.
Further analysis revealed that specific cells within TLSs, namely dendritic cells and fibroblasts, are key to maintaining this metabolic balance. These cells actively produce glutathione and export it to nearby immune cells. When researchers blocked this process using a drug called sulfasalazine, TLS formation dropped significantly, and even existing TLSs shrank. This finding shows that dendritic cells and fibroblasts function as metabolic supporters, providing the glutathione essential for sustaining immune activity within TLSs.
Currently, detecting TLSs requires invasive kidney biopsies. These procedures involve inserting a needle into the kidney and can cause pain and bleeding, making them unsuitable for frequent monitoring. To find a less invasive alternative, researchers analyzed glutathione levels in urine samples from both mice and humans as potential biomarkers. They discovered that when TLSs were present, urinary glutathione levels were higher. When treatments successfully reduced TLSs, urinary glutathione levels dropped accordingly. The same pattern appeared in patients with IgA nephropathy. These findings suggest that a simple urine test measuring glutathione could be used to monitor TLSs and track disease progression, enabling earlier diagnosis and better treatment management.
Future Perspectives
“By examining TLS from a metabolic perspective, we uncovered an immune mechanism that hadn’t been recognized before,” said first author Dr. Hiroyuki Arai. “Glutathione proves essential for TLS formation and maintenance, and targeting this pathway could offer both a novel therapeutic approach and a new biomarker for kidney disease. With effective treatments for kidney disease still limited, we hope this discovery will help develop new therapies and diagnostic technologies.”
Looking ahead, researchers plan to map metabolic changes in these kidney immune hubs in greater detail. This could reveal additional therapeutic targets and ultimately improve outcomes for the millions of people living with kidney disease worldwide. Beyond kidney diseases, these findings point toward an innovative therapeutic approach: “metabolic intervention-based immune regulation” that specifically targets TLSs, which may also transform treatment for autoimmune disorders and advance cancer immunotherapy.
KYOTO, Japan – August 18, 2025
Glossary
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About Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University
What key biological traits make us ‘human’, and how can knowing these lead us to better cures for disease? ASHBi investigates the core concepts of human biology with a particular focus on genome regulation and disease modeling, creating a foundation of knowledge for developing innovative and unique human-centric therapies.
About the World Premier International Research Center Initiative (WPI)
The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).
Journal of the American Society of Nephrology
Experimental study
Human tissue samples
Glutathione Synthesis via the Cystine/Glutamate Transporter Promotes the Formation of Tertiary Lymphoid Structures in the Kidney
8-Aug-2025