Abstract
The identification of the major target antigen phospholipase A2 receptor (PLA2R) in the majority of primary (idiopathic) cases of membranous nephropathy (MN) has been followed by the rapid identification of numerous minor antigens that appear to define phenotypically distinct forms of disease. This article serves to review all the known antigens that have been shown to localize to subepithelial deposits in MN, as well as the distinctive characteristics associated with each subtype of MN. We will also shed light on the novel proteomic approaches that have allowed identification of the most recent antigens. The paradigm of an antigen normally expressed on the podocyte cell surface leading to in-situ immune complex formation, complement activation, and subsequent podocyte injury will be discussed and challenged in light of the current repertoire of multiple MN antigens. Since disease phenotypes associated with each individual target antigens can often blur the distinction between primary and secondary disease, we encourage the use of antigen-based classification of membranous nephropathy.
Highlights
Membranous nephropathy (MN) is an autoimmune kidney disease that is the second leading cause of nephrotic syndrome
Immune complexes can form in situ due to circulating antibodies targeting an intrinsic or planted antigen within the glomeruli or from deposition of immune complexes that form in the circulation and become trapped in the subepithelial space [1, 2]
Similar to what had been shown for anti-phospholipase A2 receptor (PLA2R) and anti-THSD7A, immunoglobulin G (IgG) reactive with recombinant protocadherin 7 (PCDH7) could be eluted from the frozen tissue under non-reducing conditions demonstrating the presence of antibodies within the tissue in addition to enrichment of the antigen within glomerular immune deposits [31]
Summary
Membranous nephropathy (MN) is an autoimmune kidney disease that is the second leading cause of nephrotic syndrome. Similar to what had been shown for anti-PLA2R and anti-THSD7A, IgG reactive with recombinant PCDH7 could be eluted from the frozen tissue under non-reducing conditions demonstrating the presence of antibodies within the tissue in addition to enrichment of the antigen within glomerular immune deposits [31] Unique to this form of MN, PCDH7associated MN has only low levels of complement staining on biopsy, a feature which might prompt the renal pathologist to further evaluate such a biopsy for PCDH7 positivity [31]. Confocal microscopy studies have confirmed the presence of EXT1/EXT2 immune complexes along the subepithelial surface of the GBM and have demonstrated co-localization with IgG While accumulation of this protein occurs in the subepithelial space, no autoantibodies were identified within serum under reducing or non-reducing conditions, questioning whether this represented a true autoantigen or may merely represent a biomarker of disease [21]. Specific depletion of the responsible clones may result in individualized medicine with improved efficacy and reduced off-target toxicities
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