Serum PLA2R-IgG4/PLA2R-IgG ratio dynamics reveal pathogenic autoantibody subclass switch during progression of PLA2R-associated membranous nephropathy.

BACKGROUND: Pathogenic autoantibody subclass switch has been found in lots of autoimmune disease. However, the information on anti-phospholipase A2 receptor antibody subclass switch in membranous nephropathy (MN) is limited and controversial. Here, we aim to uncover the subclass change during the PLA2R-associated MN progression. METHODS: Biopsy-proven PLA2R-associated MN cases with sufficient tissue for light microscopy, immunofluorescence, and electron microscopy (October 2022 - March 2023) were included. Serum levels of PLA2R-IgG4 and PLA2R-IgG were measured by TRFIA. The correlation of the ratio with EM stage and other clinical parameters was analyzed. RESULTS: Among 116 enrolled patients, glomerular IgG1 (r = 0.15, p = .01; r = 0.18, p = .002) and IgG3 (r = 0.17, p = .005; r = 0.27, p < .001) intensities were positively correlated with C3 and C1q intensities, respectively. The PLA2R-IgG4/PLA2R-IgG ratio was significantly positively correlated with serum albumin (r = 0.26, p = .005) but inversely correlated with both the intensity of glomerular IgG1 (r = -0.20, p = .03) and IgG3 deposits (r = -0.24, p = .009), as well as with C1q staining intensity (r = -0.27, p = .004). The median PLA2R-IgG4/PLA2R-IgG ratio significantly increased with pathological stage (Stage I: 18.92%; Stage II: 39.74%; Stage III: 59.38%; Stage IV: 68.99%) and was strongly positively correlated with EM stage (r = 0.52, p < .001). Advanced EM stages were observed more frequently with higher PLA2R-IgG4/PLA2R-IgG ratio. CONCLUSIONS: During the disease progression, EM stages were correlated with altered autoantibody IgG subclass profiles: early stages featured IgG1 or IgG3 autoantibodies, while late EM stages shifted to IgG4 predominance.