This study investigates the deep tissue depletion of B cells following CD19-targeting chimeric antigen receptor (CAR) T-cell therapy in patients with autoimmune diseases (AIDs). Sequential ultrasound-guided lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in five patients with AIDs, and results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients. Conventional and immunohistochemistry staining were used to assess the architecture and number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells, and macrophages in the lymph nodes. The results showed that 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 remained unchanged in the lymph nodes after CD19-CAR T-cell therapy. 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, including the colon, kidney, and gallbladder, were also completely depleted of B cells after CD19-CAR T-cell therapy. The study demonstrates that CD19-CAR T-cell therapy induces deep B-cell depletion in secondary lymphoid tissues of patients with AIDs, which may contribute to the long-term drug-free remission observed in these patients. This effect is more pronounced than that achieved by RTX treatment, which only partially depletes B cells in lymph nodes. The findings highlight the importance of tissue analysis in evaluating the depth of treatment effect in B-cell depleting therapies.This study investigates the deep tissue depletion of B cells following CD19-targeting chimeric antigen receptor (CAR) T-cell therapy in patients with autoimmune diseases (AIDs). Sequential ultrasound-guided lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in five patients with AIDs, and results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients. Conventional and immunohistochemistry staining were used to assess the architecture and number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells, and macrophages in the lymph nodes. The results showed that 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 remained unchanged in the lymph nodes after CD19-CAR T-cell therapy. 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, including the colon, kidney, and gallbladder, were also completely depleted of B cells after CD19-CAR T-cell therapy. The study demonstrates that CD19-CAR T-cell therapy induces deep B-cell depletion in secondary lymphoid tissues of patients with AIDs, which may contribute to the long-term drug-free remission observed in these patients. This effect is more pronounced than that achieved by RTX treatment, which only partially depletes B cells in lymph nodes. The findings highlight the importance of tissue analysis in evaluating the depth of treatment effect in B-cell depleting therapies.