Background: Membranous nephropathy (MN), an autoimmune disease, has not yet been fully elucidated regarding its relationship with immune cells. Methods: As a primary method in this Mendelian randomization (MR) analysis, we employed the Inverse Variance Weighted (IVW)， Wald Ratio (WR), Steiger filtering, Weighted Median, Weighted mode, MR-Egger, Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) and Leave-one-out sensitivity test. Reverse MR analysis was utilized to investigate whether MN affects immune cells. Results： After False Discovery Rate multiple correction (threshold was 10%), it was determined that CD45RA+ CD8+ T cell (IVW OR=1.074, 95%CI: 1.034-1.114, P=0.0001, PFDR=0.036), Effector Memory CD8+ T cell (IVW OR=0.929, 95%CI: 0.895-0.964, P=0.0001, PFDR=0.036), HLA DR+ CD8+ T cell (IVW OR=0.921, 95%CI: 0.884-0.960, P=0.0001, PFDR=0.036) are significantly affected by MN. CD28+ CD45RA- CD8+ T cell (WR OR=0.513, 95%CI: 0.357-0.793, P=0.0003, PFDR=0.061), CD8 on Terminally Differentiated CD8+ T cell (WR OR=0.378, 95%CI: 0.219-0.652, P=0.0005, PFDR=0.061), and HVEM on Effector Memory CD4+ T cell (WR OR=0.378, 95%CI: 0.219-0.652, P=0.0005, PFDR=0.065), among others, are considered immune cells that possess protective factors against MN. However, HLA DR on CD33+ HLA DR+ CD14- (WR OR=1.910, 95%CI: 1.269-2.876, P=0.002, PFDR=0.065), CD80 on granulocyte (WR OR=2.606, 95%CI: 1.417-4.792, P=0.002, PFDR=0.065), and CD62L- plasmacytoid Dendritic Cell (WR OR=1.508, 95%CI: 1.138-1.998, P=0.004, PFDR=0.071) pose a risk to MN. When increased by one standard deviation in peripheral blood, these immune cells positively or negatively impact the risk of MN with an odds ratio (OR). Conclusions: The MR analysis unveiled the association between immune cells and MN. We have deepened our understanding of the pathogenic mechanisms linking MN and immune cells and also identified new targets for immunotherapy in MN.

The authors have declared no competing interest.

Shenzhen Key Medical Discipline Construction Fund (SZXK009).

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Source data were openly available before the initiation of the study.The datasets (analyzed) for this study can be found in the supplementary document. The datasets (generated) for this study can be found in the address as follow: Membranous nephropathy data can be obtained from: https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST010005/ . Immune cell data can be obtained from: https://www.ebi.ac.uk/gwas/publications/32929287. Peripheral blood cell data can be obtained from: https://gwas.mrcieu.ac.uk/datasets/ieu-b-29/ , https://gwas.mrcieu.ac.uk/datasets/ieu-b-30/ , https://gwas.mrcieu.ac.uk/datasets/ieu-b-31/, https://gwas.mrcieu.ac.uk/datasets/ieu-b-32/, https://gwas.mrcieu.ac.uk/datasets/ieu-b-33/, https://gwas.mrcieu.ac.uk/datasets/ieu-b-34/ .

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