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Background: Primary membranous nephropathy (PMN) is an autoimmune kidney disease. Despite the identification of certain autoantigens, the etiology and pathophysiology of PMN are still largely unknown., Methods: Five patients with biopsy-proven PMN were enrolled in this study. Their blood, kidney and urine samples were collected respectively to profile cellular, molecular and immunological alterations by using single-cell RNA sequencing (scRNA-seq). Experimental verifications were also implemented in kidney tissue., Results: In the peripheral blood mononuclear cell (PBMC) samples, portions of B cells and plasma cells were increased in PMN patients. Cell-cell communication analysis suggests that APRIL (a proliferation-inducing ligand from B cells) might be a potential molecule that regulates the activity of plasma cells. In the kidney samples, scRNA-seq analysis showed that the infiltration of T cells, as well as the myeloid cells, appears abundant compared with healthy controls, suggesting that immune cells are actively recruited to kidney. Furthermore, we observed an enhanced interaction between inflammatory cells and podocytes, which might contribute to kidney injury. Accordingly, scRNA-seq analysis of urinary samples is partially reminiscent of the kidney cell landscape, especially T cells and myeloid cells, suggesting monitoring urinary samples is a promising method to monitor PMN development. Additionally, integrative analysis across the blood, kidney and urine identified LTB, HERP1, ANXA1, IL1RN and ICAM1 as common regulators of PMN. Finally, immune repertoire in PBMC also showed an elevated diversity of clonal type, implying the existence of autoreactive T-cell receptor/B-cell receptor., Conclusion: Our study comprehensively profiled the transcriptomic landscapes of blood, kidney and urine in patients with PMN using scRNA-seq. We depicted the alterations including cell compositions and cell-cell communication in PMN. These results offer important clues with regard to the diagnosis and pathogenesis of PMN and potential intervention of PMN progression., Competing Interests: Z.C. is a scientific advisor to Beijing SeekGene BioSciences Co. Ltd. The other authors declare no potential conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Chimeric antigen receptor T (CAR-T) cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies. However, there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T (CAR-T) cell therapy, as well as the optimal timing for CAR-T cell infusion post-chemotherapy., Materials and Methods: We employed cell-derived tumor xenograft (CDX) murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment. Furthermore, transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen., Results: Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine, followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy, exerts the most efficacious therapeutic effect in B-cell hematological malignancies. Concurrently, RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism, primarily through the inhibition of key mitochondrial targets, such as C-Jun Kinase enzyme (C-JUN)., Conclusion: In summary, the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies., Competing Interests: The authors declare no conflicts of interest., (© 2024 Xia et al.)