Abstract: FR-PO792
Selective B Cell Expansion Occurs in a Subset of Patients with Idiopathic Nephrotic Syndrome and Is Associated with Rituximab Response
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Chan, Chang-Yien, National University of Singapore, Singapore, Singapore
- Lin, Chenshi, National University of Singapore, Singapore, Singapore
- Cui, Jian-Zhou, National University of Singapore, Singapore, Singapore
- Chen, Jinmiao, Agency for Science Technology and Research, Singapore, Singapore, Singapore
- Yap, Hui Kim, National University of Singapore, Singapore, Singapore
- Lu, Liangjian, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore, Singapore
Background
Rituximab response in idiopathic nephrotic syndrome (INS) is highly heterogenous. This may be because only a sub-group of patients have B-cell driven disease, while others have T-cell driven disease. We aimed to investigate the extent of B-cell dysregulation in INS, and correlate this with Rituximab response.
Methods
11 patients with relapsed steroid-sensitive INS were recruited together with 16 healthy controls, and B-cell subsets enumerated by flow cytometry. Single-cell RNA sequencing (scRNA-seq) was used to further characterize baseline B-cells in 4 patients with bifurcated Rituximab response (2 early relapse by 7 months, 2 sustained remission).
Results
INS patients had elevated CD27-IgD+ naïve B-cells (14±1.8% lymphocytes vs 8.1±0.7%, p=0.002) as well as elevated CD27+IgD- switched memory B-cells (2.8±0.7% vs 1.6±0.2%, p=0.05). K-means clustering of the cohort into 2 groups using these 2 parameters resulted in 7 patients clustering with all controls, and the remaining 4 patients with marked naïve and switched memory B-cell expansion forming a separate cluster (p=0.019). Detailed B-cell subclustering utilizing scRNA-seq revealed sustained Rituximab response was associated with expansion of an atypical B-cell cluster (2.4±1.9 vs 0.2±0.09% B-cells) that was IgD+CD27+/-CD24+CD38- and expressed PAX5 and elevated IL15. Furthermore, differentially expressed genes in B-cells showed that poor Rituximab response was strongly associated with upregulated “positive regulation of T-cell activation” (p<0.00002) and “Th17 cell differentiation” (p<0.0001), suggesting a primarily T-cell driven disease in these patients.
Conclusion
INS patients who demonstrate a good response to Rituximab likely have B-cell driven disease characterized by expansion of specific B-cell subsets.