Autoantibodies targeting CRB2 and Nephrin correlate with extrafollicular B cells in idiopathic podocytopathies
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.