Clinical Relevance of Domain-Specific Phospholipase A2 Receptor 1 Antibody Levels in Patients with Membranous Nephropathy

<jats:sec> <jats:title>Significance Statement</jats:title> <jats:p>Phospholipase A<jats:sub>2</jats:sub> receptor 1 (PLA<jats:sub>2</jats:sub>R1) is the major target of autoimmunity in membranous nephropathy. Anti-PLA<jats:sub>2</jats:sub>R1 antibody levels predict treatment response and outcome in this disease. Earlier studies identified three target epitope regions in the PLA<jats:sub>2</jats:sub>R1 and proposed that having antibodies against more than one PLA<jats:sub>2</jats:sub>R1 epitope region had prognostic relevance. In this prospective study of a cohort of 150 patients with newly diagnosed membranous nephropathy, the authors identified a fourth epitope region targeted by anti-PLA<jats:sub>2</jats:sub>R1 antibodies. They also found that all sera recognized at least two distinct PLA<jats:sub>2</jats:sub>R1 domains at the time of diagnosis. Detection of domain-specific antibodies was highly dependent on total anti-PLA<jats:sub>2</jats:sub>R1 antibody levels. Anti-PLA<jats:sub>2</jats:sub>R1 antibody levels, but not PLA<jats:sub>2</jats:sub>R1 epitope-recognition patterns or domain-specific PLA<jats:sub>2</jats:sub>R1 antibody levels, predict treatment response and outcome (remission of proteinuria) in membranous nephropathy.</jats:p> </jats:sec> <jats:sec> <jats:title>Background</jats:title> <jats:p>Antibodies against phospholipase A<jats:sub>2</jats:sub> receptor 1 (PLA<jats:sub>2</jats:sub>R1) are found in 80% of patients with membranous nephropathy, and previous studies described three autoantibody-targeted PLA<jats:sub>2</jats:sub>R1 epitope regions. Although anti-PLA<jats:sub>2</jats:sub>R1 antibody levels are closely associated with treatment response and disease prognosis, the clinical role of epitope regions targeted by autoantibodies is unclear.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>In a prospective cohort of 150 patients with newly diagnosed PLA<jats:sub>2</jats:sub>R1-associated membranous nephropathy, we investigated the clinical role of epitope-recognition patterns and domain-specific PLA<jats:sub>2</jats:sub>R1 antibody levels by western blot and ELISA.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We identified a fourth epitope region in the CTLD8 domain of PLA<jats:sub>2</jats:sub>R1, which was recognized by anti-PLA<jats:sub>2</jats:sub>R1 antibodies in 24 (16.0%) patients. In all study patients, anti-PLA<jats:sub>2</jats:sub>R1 antibodies bound both the N-terminal (CysR-FnII-CTLD1) region and the C-terminal (CTLD7-CTLD8) region of PLA<jats:sub>2</jats:sub>R1 at study enrollment. The total anti-PLA<jats:sub>2</jats:sub>R1 antibody levels of patients determined detection of domain-specific PLA<jats:sub>2</jats:sub>R1 antibodies, and thereby epitope-recognition patterns. A remission of proteinuria occurred in 133 (89%) patients and was not dependent on the domain-recognition profiles. A newly developed ELISA showed that domain-specific PLA<jats:sub>2</jats:sub>R1 antibody levels targeting CysR, CTLD1, and CTLD7 strongly correlate with the total anti-PLA<jats:sub>2</jats:sub>R1 antibody level (Spearman’s rho, 0.95, 0.64, and 0.40; <jats:italic toggle="yes">P</jats:italic><0.001, <jats:italic toggle="yes">P</jats:italic><0.001, and <jats:italic toggle="yes">P</jats:italic>=0.002, respectively) but do not predict disease outcome independently of total anti-PLA<jats:sub>2</jats:sub>R1 antibody levels.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>All patients with PLA<jats:sub>2</jats:sub>R1-associated membranous nephropathy recognize at least two epitope regions in the N- and C-terminals of PLA<jats:sub>2</jats:sub>R1 at diagnosis, contradicting the hypothesis that PLA<jats:sub>2</jats:sub>R1 “epitope spreading” determines the prognosis of membranous nephropathy. Total anti-PLA<jats:sub>2</jats:sub>R1 antibody levels, but not the epitope-recognition profiles at the time of diagnosis, are relevant for the clinical outcome of patients with this disease.</jats:p> </jats:sec>