I have read with keen interest the article by Cumpelik et al. (1), which presents a pioneering investigation into a novel T cell–independent pathway of B1 cell activation through anaphylatoxin-mediated secretion of BAFF by neutrophils. This compelling work has stimulated my curiosity, because I believe its implications may extend beyond the confines explored within the paper.
The pathogenesis of idiopathic nephrotic syndrome (INS) has remained an enigma for more than seven decades. Despite the description of numerous molecular mechanisms associated with INS pathogenesis, these findings remain fragmented and challenging to integrate into a cohesive framework.
A well-established facet of INS involves the dysregulated maturation and activation of B cells, characterized by the expansion of specific cellular subpopulations and the production of autoantibodies targeting the podocyte in some patients (2). Nowadays, the main proof supporting the involvement of B cells in the pathogenesis of INS is provided by the demonstrated effectiveness of the treatment with chimeric and human anti-CD20 mAbs that selectively deplete B cells, in patients with either steroid- and calcineurin inhibitor–dependent or –resistant INS (3, 4).
Notably, recent attention has been drawn to the potential role of BAFF in such dysregulation. BAFF has been described as a potential pathogenetic “circulating factor” in INS, with certain studies suggesting its involvement in disease development and progression (5, 6). Although promising, further research is necessary to confirm these claims.
Furthermore, the activation of the complement system has been firmly established in both animal models and INS patients (7, 8); however, investigations into the role of anaphylatoxins in the pathogenesis of the disease remain limited.
Considering the interconnected nature of these observations and their alignment with the mechanisms elucidated by Cumpelik et al. (1), I conjecture that their findings may hold implications for the pathogenetic model of INS. My speculation posits that the pathogenetic mechanisms of INS may primarily involve complement system activation and anaphylatoxins synthesis, thereby triggering excessive BAFF secretion and ultimately contributing to B cell–mediated damage to the glomerular barrier. Moreover, these findings find reinforcement in the work of Paiano et al. (9), which demonstrated that signaling through C3aR1/C5aR1 is crucial for B2 cell responsiveness to BAFF and plays a pivotal role in multiple stages of B2 cell activation needed for class-switch recombination and affinity maturation. Such a comprehensive perspective would provide a unifying theory, capable of encompassing all known alterations in the context of INS and consolidating them into a coherent framework.
Nevertheless, I acknowledge that this hypothesis requires meticulous exploration and rigorous validation. Therefore, I advocate for further investigation into this promising avenue, with particular emphasis on the role of neutrophils and BAFF secretion in the pathogenesis of INS.
In conclusion, the newfound study by Cumpelik et al. (1) has instigated a captivating inquiry into a novel pathway, and I propose its potential extension to address the complex pathogenesis of INS. Such an advancement would provide profound insights and open new horizons for therapeutic interventions in this enigmatic disorder.
