Distribution of circulating and glomerular IgG subclasses against full-length anti-phospholipase A2 receptor and its epitopes in primary membranous nephropathy
Li, Lee Chuan
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OBJECTIVE: Research towards understanding PLA2R, the human antigen of primary membranous nephropathy has steadily gained ground since its discovery in 2009. This autoimmune kidney disease features a unique immunological character of high IgG4 prevalence, both in circulation and as immune complexes deposited in tissue. We seek to characterize and better understand the distribution of all IgG subclasses between serum and glomerular deposits, as well as characterize IgG reactivity directed against both full-length PLA2R and its immunogenic components. METHODS: Using biopsy data obtained from renal pathology centers, we identified 13 patients with primary membranous nephropathy as well as biopsy immunofluorescence data for all IgG subclasses. We compared anti-PLA2R staining in glomeruli to serum anti-PLA2R using western blot, and analyzed concordance of subclass distribution between the two sets of data using Cohen's kappa score. We also studied and similarly analyzed, using western blot, subclass distribution of IgG against PLA2R epitopes CysR, CTLD1, and CTLD4-8. RESULTS: All 13/13 (100%) patient samples were positive for circulating anti-PLA2R IgG4 in western blot, with 11/13 (84.6%) positive for IgG3, 6/13 (46.2%) for IgG2, and 11/13 (84.6%) for IgG1. When compared with biopsy immunofluorescence these results exhibited fair agreement for IgG4, IgG3, and IgG1; IgG2 was discordant with corresponding biopsies. For reactivity against PLA2R epitopes, 11/12 (91.7%) samples were positive for anti-CysR IgG4, 5/12 (41.7%) positive for IgG3, 0/11 (0.0%) for IgG2, and 8/11 (72.7%) for IgG1. Reactivity against epitopes CTLD1 and CTLD4-8 was detected less frequently than against CysR, though IgG4 was still the predominant subclass in almost all cases. CONCLUSION: In general, levels of circulating IgG subclasses directed against PLA2R is concordant between serum and in biopsy, and as such serum anti-PLA2R can act as a good proxy for all IgG subclasses found in glomerular deposits. Furthermore, both full-length PLA2R and its extracellular domain containing the CysR epitope exhibit concordance between IgG3 and IgG4 levels, demonstrating potential for anti-CysR autoantibodies to be a good indicator for primary MN in addition to anti-PLA2R.