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IntroductionSystemic lupus erythematosus (SLE) is characterized by dysregulated humoral immunity, leading to the generation of autoreactive B cells that can differentiate both within and outside of lymph node (LN) follicles.MethodsHere, we employed spatial transcriptomics and multiplex imaging to investigate the follicular immune landscaping and the in situ transcriptomic profile in LNs from SLE individuals.ResultsOur spatial transcriptomic analysis revealed robust type I IFN and plasma cell signatures in SLE compared to reactive, control follicles. Cell deconvolution revealed that follicular T cell subsets are mainly affected by the type I IFN fingerprint of SLE follicles. Dysregulation of TFH differentiation was documented by i) the significant reduction of Bcl6hi TFH cells, ii) the reduced cell density of potential IL-4 producing TFH cell subsets associated with the impaired transcriptomic signature of follicular IL-4 signaling and iii) the loss of their correlation with GC-B cells. This profile was accompanied by a marked reduction of Bcl6hi B cells and an enrichment of extrafollicular CD19hiCD11chiTbethi, age-associated B cells (ABCs), known for their autoreactive potential. The increased prevalence of follicular IL-21hi cells further reveals a hyperactive microenvironment in SLE compared to control.DiscussionTaken together, our findings highlight the altered immunological landscape of SLE follicles, likely fueled by potent inflammatory signals such as sustained type I IFN and/or IL-21 signaling. Our work provides novel insights into the spatial molecular and cellular signatures of SLE follicular B and TFH cell dynamics, and points to druggable targets to restore immune tolerance and enhance vaccine responses in SLE patients.