Lu, L., Chan, C. Y., Than, M., Teo, S., Lau, P. Y., Lam, K.-P., Ng, K. H., & Yap, H. K. (2026). B-cell activation underpins Rituximab response in focal segmental glomerulosclerosis. Translational Research. https://doi.org/10.1016/j.trsl.2026.01.002
Abstract:
The pathogenesis of primary focal segmental glomerulosclerosis (FSGS) is incompletely understood, and outcomes remain poor. Some patients respond to Rituximab, especially patients who have hyporesponsive T-cells, but the underlying mechanism is unknown. This study aimed to investigate the association between B-cell activation and T-cell hypo-responsiveness as well as Rituximab response. A cohort of 33 patients with childhood-onset FSGS receiving Rituximab were recruited. T-cell hypo-responsiveness was defined as stimulated T-cell IFNγ <2.5%, and B-cell activation was characterized by CD80 expression and cytokine production. T-cell hypo-responsiveness was associated with Rituximab response (OR: 5.4 (95% CI: 1.2-25), p=0.028). Compared to T-cell normo-responsive patients, T-cell hypo-responsive patients had elevated activated CD19+CD80+ B-cells (16% (IQR 6-25) vs 5% (IQR: 1-9), p=0.009), and upregulation in resting B-cell cytokine production (15/27 cytokines, p<0.05). Rituximab selectively restored T-cell responsiveness and abolished elevated B-cell CD80 expression and resting cytokine production in these patients, although nascent B-cell activation could still be detected on in vitro stimulation (6/27 cytokines, p<0.05). Resting B-cell culture supernatants from patients with hypo-responsive T-cells (p=0.02) but not normo-responsive T-cells were able to induce cytoskeletal rearrangements in cultured podocytes. Together with T-cell responsiveness, resting B-cell cytokine production was able to strongly predict Rituximab response (AUC 0.922±0.077, p=0.002), and also the duration of Rituximab response (AUC 0.958±0.062, p=0.019). Rituximab response in childhood-onset FSGS occurs in a subgroup of patients with B-cell mediated disease characterized by B-cell activation and the production of podocyte damaging factors. Resting B-cell cytokine production can predict Rituximab response, and if it will be long-lasting.
License type:
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Funding Info:
This research / project is supported by the National Medical Research Council - Enterprise Development Grant, Clinician Scientist Research Grant
Grant Reference no. : NMRC/EDG/0026/2008, NMRC/CIRG/1376/2013 and NMRC/CIRG/1447/2016