IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. For decades, the "gut-kidney axis" hypothesis has suggested that the disease begins not in the kidneys, but in the gut mucosa, where an abnormal immune response produces pathogenic galactose-deficient IgA1 (Gd–IgA1). However, current treatments mostly focus on suppressing inflammation in the kidney, failing to stop the production of harmful antibodies at their source. The precise cellular mechanisms within the gut of IgAN patients have remained a black box due to the challenges of obtaining and analyzing intestinal tissue.
In a breakthrough study published in hLife, the research team led by Professor Hong Zhang and Professor Yuemiao Zhang from Peking University First Hospital and Professor Zijie Zhang from Yunnan University utilized single-cell RNA sequencing (scRNA-seq) to construct a high-resolution map of the immune microenvironment in the terminal ileum of IgAN patients.
The researchers compared biopsy samples from patients and healthy controls, revealing a distinct remodeling of the gut immune system. They found a significant expansion of plasma cells in the intestinal lamina propria of IgAN patients. More importantly, they identified that these expanded cells are primarily IgA‑producing plasma cells that preferentially express B‑cell maturation antigen (BCMA), a receptor critical for cell survival and antibody production.
"Current therapies often act like firefighters trying to put out the blaze in the kidney, while the spark continues to burn in the gut," said Professor Hong Zhang at Peking University First Hospital, the study's corresponding author. "By combining single-cell transcriptomics with clinical validation, we have not only confirmed that the gut is the production site of pathogenic IgA but also pinpointed BCMA as the key switch maintaining these harmful cells. This gives us a precise target to intercept the disease upstream."
The study went beyond observation to test the therapeutic potential of this target. The researchers found that the abundance of BCMA‑positive plasma cells in patients correlated with clinical severity, including proteinuria levels and kidney function decline. Furthermore, in a proof-of-concept study using cynomolgus monkeys, the team tested a bispecific antibody targeting BCMA (Cizutamig). The treatment effectively depleted B cells and led to a deep, sustained reduction in serum IgA levels, significantly outperforming its effect on other immunoglobulin types.
These findings provide a robust scientific rationale for repurposing BCMA‑targeted therapies for IgA nephropathy. The study supports the ongoing clinical evaluation of BCMA‑directed treatments (NCT07135219), offering hope for a new generation of precision medicines that can modify the underlying disease process of IgAN.
This work was conducted by researchers at the Renal Division of Peking University First Hospital and the School of Life Sciences at Yunnan University. The study was supported by the National Natural Science Foundation of China (Grant Nos. 82170711, 82070733, 92478202, 22321005, 32371000 and 32500588, etc.), the Beijing Nova Programme (20240484677), and other funding agencies.
About Author:
Dr. Yuemiao Zhang is a physician, researcher, and doctoral supervisor in the Department of Nephrology, Peking University First Hospital, China, and also serves as the Deputy Director of the Office of Scientific Research. Her research interests focus on the mucosal immune pathogenesis of IgA nephropathy and targeted diagnosis and treatment strategies. She has published more than 50 papers as first/corresponding author in Natl Sci Rev, Adv Mater, Cell Discov, eClinicalMedicine, eBioMedicine, Kidney Int, Int J Epidemiol, J Infect and other journals; participated in the compilation of 2 monographs, led over 19 national/provincial scientific research projects (including 3 NSFC projects and 4 Beijing municipal projects), and has been supported by talent programs such as the Beijing Nova Program and Peking University Clinical Scientist. Additionally, she successfully commercialized a non-invasive diagnostic kit for IgA nephropathy, with a licensing value of 18 million RMB.
