New antigens involved in membranous nephropathy beyond phospholipase A2 receptor

Abstract

When the physiopathology of membranous nephropathy was first described, almost 30% of cases were recognized to be secondary to well-known diseases such as autoimmune diseases, tumors or infections. The remaining 70% cases were called primary membranous nephropathy as the exact mechanism or pathogenic factor involved was unknown. The discovery of the M type phospholipase A2 receptor and thrombospondin type 1 domain containing 7A as causative antigens in these “so called” primary membranous nephropathies provided new insights into the effective causes of a large proportion of these cases. Novel techniques such as laser microdissection and tandem mass spectrometry as well as immunochemistry with antibodies directed against novel proteins allowed the confirmation of new involved antigens. Finally, using confocal microscopy to localize these new antigens and immunoglobulin G and Western blot analysis of serum samples, these new antigens were detected on the glomerular membrane, and the related antibodies were detected in serum samples. The same antigens have been recognized in some cases of secondary membranous disease due to autoimmune diseases, tumors and infections. This has allowed examination of the relationship between antigens in primary membranous nephropathy and their presence in some secondary nephropathies. The aim of this study is to describe the characteristics of the new antigens discovered and their association with other diseases.

The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis

“…In approximately 80% of patients, MN has no root cause (primary MN), and 20% of cases are related to drugs or other diseases, such as malignancy, hepatitis virus infection, or systemic lupus erythematosus ( Ronco et al, 2021 ; Zhao et al, 2023 ). MN patients are diagnosed by the presence of the phospholipase A 2 receptor before they progress to renal failure ( Wang et al, 2022b ; Salvadori and Tsalouchos, 2022 ). However, the subepithelium-like immunocomplex deposit-mediated downstream molecular pathways are poorly understood ( Miao et al, 2023a ; Miao et al, 2023b ).…”

“…In the clinical setting, treatments for renal fibrosis are ineffective or unsafe ( Breyer and Susztak, 2016 ). Although numerous therapeutic strategies to prevent and treat renal fibrosis have been explored, the prognosis of patients is still poor ( Salvadori and Tsalouchos, 2022 ). Thus, there is an urgent need for the development of specific and efficacious antifibrotic drugs to improve AKI and CKD ( Tanemoto and Mimura, 2022 ; Allinson et al, 2023 ; Habshi et al, 2023 ; Song and Gong, 2023 ).…”

Membranous nephropathy: Systems biology-based novel mechanism and traditional Chinese medicine therapy

“…The first new proteins and antigens were exostosin1/exostosin2 (EXT1/EXT2). EXT1/EXT2 were the most common among the unique proteins in patients with PLA 2 R-negative MN and are present in patients with secondary MN ( Sethi et al, 2019 ; Salvadori and Tsalouchos., 2022 ). In patients with EXT1/EXT2-positive antigens compared to patients with EXT1/EXT2-negative antigens; nephrotic proteinuria is found more often in patients with membranous lupus nephritis, than in patients with decreasing glomerulosclerosis and renal fibrosis.…”

Lipoic Acid as a Trigger for NELL-1 Positive Membranous Nephropathy

“…Membranous nephropathy (MN) occurs when antibodies target an antigen in the glomerular basement membrane (GBM). Primary membranous nephropathy (PMN) represents 70% of MN cases, 1 with M-Type Phospholipase A2 Receptor (PLA2R) being the target antigen in about 70% of cases, Thrombospondin type-1 domain-containing 7A (THSD7A) in about 1-5% of cases, and about 25% of cases having an unknown target antigen. 2 Recently, nerve epidermal growth factorlike 1 (NELL-1) antigen-antibody has been identified as a rare cause of PMN in PLA2R-negative cases.…”