Immune Imbalance in Primary Membranous Nephropathy at Single-cell Resolution

Background: Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insufficiently understood. Methods: We developed a single-cell transcriptomic profile of peripheral blood mononuclear cells (PBMCs) from 11 newly-diagnosed pMN patients and 5 healthy donors. Through correlation analysis, we identified potential biomarkers for disease stratification and poor prognosis. Results: Expression levels of several proinflammatory factors were significantly increased in patients compared to healthy donors, such as interleukins (IL1B, IL8, and IL15) and interferon G (IFNG). Multiple pattern recognition receptors involved in proinflammatory signaling were also upregulated in patients, including NOD-like receptors (NLRs) (NLRP1, NLRP3, and NLRC5), RNA helicases (DDX58, IFIH1, DHX9, and DHX36), cGAS (cyclic GMP-AMP synthase) and IFI16 (interferon gamma inducible protein 16). Additionally, human leukocyte antigen molecules HLA-DQA1 and HLA-DRB1 enriched in memory B cells were upregulated in patients. More importantly, we found that the genes for antiviral defense response were significantly elevated in high-risk patients relative to the low-risk group. More than twenty genes were negatively correlated with estimated glomerular filtration rate (eGFR), such as BST2 (bone marrow stromal cell antigen 2) and SLC35F1 (solute carrier family 35 member F1). Their predicted values were confirmed in a larger population with nephrotic syndrome or other chronic kidney diseases from a public database. Furthermore, we developed a series of scoring systems for distinguishing high-risk patients from low- and moderate-risk individuals. Conclusions: Our study provides insight into the immunological mechanism of pMN and identifies numerous biomarkers and signaling pathways as potential therapeutic targets for managing the progression of high-risk pMN.