Finally, we point out avenues to be explored, including the events that induce production of anti-PLA2R, their ability to cause podocyte injury, the role of complement, and the nature of the antibodies in secondary forms of MN.
The discovery of two major podocyte antigens, neutral endopeptidase (NEP), involved in rare cases of neonatal membranous nephropathy, and the M-type phospholipase A2 receptor 1 (PLA2R1), the first antigen discovered in adults, have been major 'breakthroughs' in our understanding of the pathogenesis of human membranous nephropathy.
This research led to the identification of neutral endopeptidase, the M-type receptor for secretory phospholipase A(2) (PLA(2)R1) and cationic bovine serum albumin as target antigens of circulating and deposited antibodies in alloimmune neonatal, adult 'idiopathic' and early-childhood membranous nephropathy, respectively.
Autoantibodies to PLA2R, usually of IgG4 subclass, are found in 70-80% of patients with primary membranous nephropathy, bind to conformational epitopes on PLA2R expressed in the glomerular podocyte, form immune complexes in situ and induce proteinuria, mostly likely via local activation of complement.
Thus, increased staining for PLA2R in glomeruli of renal biopsies tightly correlates with the presence of PLA2R autoantibodies in the serum and this may help discriminate between primary and secondary membranous nephropathy.
We discuss the diagnostic value of serological testing for anti-PLA2R and tissue staining for the redistributed antigen, and their utility for differentiating between primary and secondary MN, and between recurrent MN after kidney transplant and de novo MN.
A genome-wide association study further showed a highly significant association of the PLA2R1 and the HLA-DQA1 loci with idiopathic MN in patients of white ancestry.
Identification of target epitopes within PLA2R and the genetic association of primary MN with class II major histocompatibility and PLA2R1 variants are 2 additional examples of our evolving understanding of this disease.
The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN.
Furthermore, a number of signals that could differentiate the different forms of iMN that were positive to PLA2R or IgG4 were detected, as well as a further set of signals (m/z 1094, 1116, 1381 and 1459) that could distinguish these patients from those who were negative to both.
Prognostic value of PLA2R autoimmunity detected by measurement of anti-PLA2R antibodies combined with detection of PLA2R antigen in membranous nephropathy: A single-centre study over 14 years.
In all, 20 non-lupus FHN patients had idiopathic non-lupus FHN, and in 12 patients, secondary non-lupus FHN was considered due to membranous nephropathy (anti-PLA2R-positive, n = 1; cancer-associated, n = 3), IgA nephropathy ( n = 4), infection-related glomerulonephritis ( n = 2) or anti-neutrophil cytoplasmic antibody-associated glomerulonephritis ( n = 2).
A meta-analysis was performed for analysis of the diagnostic accuracy of histologic PLA2R and IgG4 deposition for differentiation of primary from secondary MGN.
Although protocols similar to those that identified PLA2R and THSD7A may be successful in the identification of novel antigenic targets in MN, newer techniques such as laser-capture mass spectrometry or protein arrays may be helpful as well.
Thrombospondin type-I domain-containing 7A (THSD7A) was recently identified as the target antigen in about 10% of patients with M-type phospholipase A2 receptor (PLA2R)-negative membranous nephropathy in European and North American populations.