Extrafollicular B cell responses are associated with autoreactivity against the slit diaphragm in idiopathic podocytopathies

Abstract

Idiopathic podocytopathies lack mechanistic biomarkers and rely on empirical immunosuppression, yet the recent discovery of autoantibodies against slit diaphragm proteins implicates podocyte-directed autoimmunity as a driver of podocyte injury. However, the immune mechanisms underlying autoreactivity and phenotypic heterogeneity, particularly across age groups, remain unclear. Here, we identify expansion of CD21low T-bet+ atypical B cells (atBCs) in peripheral blood as a shared immunologic feature across idiopathic podocytopathies. In children, atBC accumulation was associated with heightened B cell activation, favoring extrafollicular responses and plasmablast differentiation. Serologic profiling revealed that autoantibodies against the slit diaphragm protein CRB2 are highly prevalent across disease phenotypes and frequently co-occur with anti-Nephrin antibodies, particularly in adults. Autoantibody abundance correlated with atBC expansion in affected children, implicating extrafollicular B cell responses as a key pathway for their generation, whereas adults showed additional involvement of follicular pathways. Complementary mouse modeling demonstrated intermolecular epitope spreading as a mechanism linking anti-CRB2 and anti-Nephrin autoreactivity. Together, these findings define a shared immune framework for idiopathic podocytopathies in which extrafollicular B cell responses drive autoreactivity to multiple slit diaphragm proteins, with implications for biomarker development and therapeutic stratification.