B-cell activation underpins Rituximab response in focal segmental glomerulosclerosis.

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.