Abstract
Primary membranous nephropathy (MN) is a glomerular disease mediated by autoreactive antibodies, being the main cause of nephrotic syndrome among adult patients. While the pathogenesis of MN is still controversial, the detection of autoantibodies against two specific glomerular antigens, phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A), together with the beneficial effect of therapies targeting B cells, have highlighted the main role of autoreactive B cells driving this renal disease. In fact, the detection of PLA2R-specific IgG4 antibodies has resulted in a paradigm shift regarding the diagnosis as well as a better prediction of the progression and recurrence of primary MN. Nevertheless, some patients do not show remission of the nephrotic syndrome or do rapidly recur after immunosuppression withdrawal, regardless the absence of detectable anti-PLA2R antibodies, thus highlighting the need of other immune biomarkers for MN risk-stratification. Notably, the exclusive evaluation of circulating antibodies may significantly underestimate the magnitude of the global humoral memory immune response since it may exclude the role of antigen-specific memory B cells. Therefore, the assessment of PLA2R-specific B-cell immune responses using novel technologies in a functional manner may provide novel insight on the pathogenic mechanisms of B cells triggering MN as well as refine current immune-risk stratification solely based on circulating autoantibodies.
Highlights
Primary membranous nephropathy (MN) is an autoantibody-mediated glomerular disease that represents one of the leading causes of nephrotic syndrome in adults [1]
Discovery of target podocyte antigens and the development of commercial assays for the detection of serum anti-phospholipase A2 receptor (PLA2R) and anti-THSD7A autoantibodies has revolutionized the traditional algorithms for diagnosis and management of MN, due to their high specificity for disease diagnosis [26, 27]
Cui et al [62] genotyped HLA-DRB1, DQA1, DQB1, and DPB1 genes in 261 primary MN patients and in 599 healthy controls. These investigators confirmed that risk alleles of HLA-DQA1 and PLA2R are significantly associated with the susceptibility to MN
Summary
Primary membranous nephropathy (MN) is an autoantibody-mediated glomerular disease that represents one of the leading causes of nephrotic syndrome in adults [1]. Discovery of target podocyte antigens and the development of commercial assays for the detection of serum anti-PLA2R and anti-THSD7A autoantibodies has revolutionized the traditional algorithms for diagnosis and management of MN, due to their high specificity for disease diagnosis [26, 27] Such autoreactive antibodies recognize the target conformational epitopes on the membrane protein expressed on glomerular podocytes under non-reducing conditions and are predominantly of the IgG4 subclass. Stanescu et al [56] defined the association between HLADQA1 allele with MN in Caucasian individuals, suggesting that the interaction between sequence variations in immune-proteins and glomerular components may explain a trigger-target model in the disease development Such interaction between PLA2R and HLA-DQA1 variants was studied in an Asian cohort with similar results [57]. MN [20] - Patients were all treated with Rituximab - Creatinine clearance ≥30 ml/min/1.73
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