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Objectives: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue depletion of B cells; however, such effect has not been proven in humans in vivo., Methods: Sequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as well the number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells and macrophages., Results: Sequential lymph node biopsies were analysed from five patients with AID before and after CD19-CAR T-cell therapy and from five patients with AID after RTX treatment. In addition, non-lymphoid organ biopsies (colon, kidney and gallbladder) from three additional patients with AID after CD19-CAR T-cell therapy were analysed. CD19 + and CD20 + B cells were completely depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX treatment. Plasma cells, T cells and macrophages in the lymph nodes remained unchanged. Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX. Non-lymphoid organs were completely depleted of B cells., Discussion: This study demonstrates complete B-cell depletion in secondary lymphoid tissues of patients with AIDs following CD19-CAR T-cell therapy combined with standard lymphodepleting therapy., Competing Interests: Competing interests: GS has received speaker honoraria from BMS, Cabaletta, Janssen, Kyverna, Miltenyi and Novartis. AM has received speaker honoraria and consulting fees from BMS/Celgene, Kite/Gilead, Novartis, BioNTech, Miltenyi Biomedicine, Century Therapeutics. MADA has received grants or contracts from Amgen, Abbvie, UCB, Pfizer, J&J and Galapagos and speaker honoraria and consulting fees from Abbvie, Amgen, Novartis, BMS, UCB, J&J, Biogen, MSD, Lilly and Galapagos. FM has received speaker honoraria and consulting fees from AstraZeneca, Kite/Gilead, Novartis, Sobi, BMS, Miltenyi, Janssen, BNT., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)