A Feed-Forward Loop Between Extrafollicular B Cell Differentiation and the Inflammatory Milieu Governs Remission and Relapse in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is driven by pathogenic B cells. Yet, why some patients receiving B cell depletion achieve durable remission, whilst others fail remains unclear. Here we use CD19-directed chimeric antigen receptor (CAR) T cell therapy as a mechanistic probe in 18 patients with refractory SLE ^1,2 , with longitudinal follow-up extending up to 40 months. We show that durable, drug-free remission is defined not by the depth of B cell depletion alone, but by the elimination of the extrafollicular (EF) B cell differentiation trajectory – specifically, activated naïve B cell precursors and CD11c ⁺ T-bet ⁺ double-negative type 2 B cells. In long-term responders, B cell reconstitution recapitulated healthy ontogeny, while the EF pathway remained truncated, coinciding with collapse of the interferon-rich milieu and contraction of PD1 ^hi T peripheral helper cells. In contrast, in relapse, persistently elevated CXCL13, interferons and expanded PD1 ^hi T cells preceded the B cell return, and nascent B cells immediately followed the EF differentiation trajectory in the confirmed absence of germinal centers in the lymph node, shortly followed by clinical symptoms. These findings indicate that CAR-T cell therapy achieves remission by breaking a feed-forward loop between the systemic inflammatory environment and extrafollicular B cell differentiation.