@article{Zhang2026, 
author = {Yuemiao Zhang and Lan Wang and Junze Wu and Na Wan and Xingzi Liu and Miaomiao Lin and Jingmei Li and Jingyu Wang and Jingyi Wu and Jiawen Peng and Shaoqing Dang and Tong Xie and Hongyu Yang and Xin Zhang and Yang Li and Xujie Zhou and Lijun Liu and Sufang Shi and Timothy T. Lu and Peter K. Wung and David James Haddon and Yanni Jiang and Naren Gaowa and Jicheng Lv and Zijie Zhang and Chunmei Li and Rui Cheng and Hong Zhang},
title = {Single-cell transcriptomic analysis of the terminal ileum identifies BCMA as a therapeutic target in IgA nephropathy},
year = {2026},
journal = {hLife},
volume = {4},
number = {4},
pages = {233-248},
keywords = {IgA nephropathy, mucosal immunity, plasma cell, IgA production, B-cell maturation antigen (BCMA)},
url = {https://www.sciopen.com/article/10.1016/j.hlife.2025.12.010},
doi = {10.1016/j.hlife.2025.12.010},
abstract = {Aberrant mucosal immune responses drive IgA nephropathy (IgAN), yet the cellular drivers of pathogenic IgA production remain undefined. We performed single-cell RNA sequencing (scRNA-seq) and bioinformatic profiling of paired terminal ileal biopsies and blood samples from IgAN patients and healthy controls (HCs) (n = 5 each). Key features identified by scRNA-seq were validated using flow cytometry with circulating samples from an independent group (IgAN = 30, HCs = 30, disease controls [DCs] = 10). Transcriptomic comparison between IgA+ and IgG+ plasma cells identified key regulatory genes further validated in another group (IgAN = 23, HCs = 14, DCs = 24). Finally, we evaluated the therapeutic potency of the CD3 × B-cell maturation antigen (BCMA) T-cell engager cizutamig (EMB-06) in cynomolgus monkeys (0, 1.5, 5, or 15 mg/kg, n = 10 per group) by quantifying B cells and serum immunoglobulins (IgA, IgG, and IgM). We found that intestinal IgA+ plasma cells exhibited a marked expansion in IgAN patients, unlike IgG+ plasma cells, preferentially expressing the receptor BCMA. We validated the high BCMA expression on IgA+ plasmablasts in IgAN patients, which positively correlated with 24 h proteinuria and mesangial hypercellularity degree, while negatively correlating with the estimated glomerular filtration rate. In cynomolgus monkeys, targeting BCMA+ plasmablasts with cizutamig selectively reduced serum immunoglobulins, with a disproportionately greater reduction in IgA than in IgG and IgM. Together, these data identify BCMA as a promising therapeutic target in IgAN and support further clinical evaluation of BCMA-directed therapies.}
}