Identification of antibodies against phospholipase A2 receptor peptides in PLA2R-associated membranous nephropathy with negative circulating anti-PLA2R antibodies.

BACKGROUND

About 30% of patients with phospholipase A2 receptor (PLA2R) associated membranous nephropathy (MN) have negative circulating anti-PLA2R antibodies. We investigated whether these patients harbor antibodies against linear PLA2R peptides, with the aim of improving serological detection.

METHODS

We synthesized 123 sequential overlapping linear peptides spanning the extracellular region of PLA2R across ten domains. Circulating IgG antibodies to these peptides were measured by ELISA in 42 biopsy-proven PLA2R-associated MN patients with negative circulating anti-PLA2R antibodies.

RESULTS

Twenty-six of 42 (61.9%) anti-PLA2R-negative MN patients reacted with at least one PLA2R peptide. Overall, 68 of 123 (55.3%) peptides were recognized, with the highest recognition frequencies for CysR-11 (21.4%), CTLD7-1 (14.3%) and CTLD7-2 (16.7%). Reactivity to these peptides was rare in patients with minimal change disease, focal segmental glomerulosclerosis, IgA nephropathy, hepatitis B virus-associated MN, or tumor-associated MN. Combined any positivity of antibodies to the three peptides yielded a sensitivity of 43.7% and a specificity of 81.3% for identifying PLA2R-associated MN in the absence of circulating anti-PLA2R antibodies. In inhibition assays, none of the three peptides detectably blocked binding of circulating anti-PLA2R antibodies to full-length PLA2R under the experimental conditions used. Among 32 anti-PLA2R-positive MN patients, 28 (87.5%) also reacted with PLA2R peptides, with frequent recognition of CysR-5, CTLD1-7, CTLD4-7, CTLD5-6, CTLD5-9, CTLD6-2, and CTLD7-2.

CONCLUSIONS

Antibodies to linear PLA2R peptides are detectable in a substantial proportion of PLA2R-associated MN patients who are seronegative by conventional anti-PLA2R assays. CysR-11, CTLD7-1, and CTLD7-2 may serve as exploratory candidate biomarkers, and their pathogenic relevance warrants further study.

Copyright © 2026 Wang, Chen, Yan, Wang, Liu, Cui and Zhao.