New ‘Antigens’ in Membranous Nephropathy

Abstract

Membranous nephropathy (MN) occurs due to deposition of immune complexes along the subepithelial region of glomerular basement membrane. Two previously identified target antigens for the immune complexes, PLA2R (identified in 2009) and THSD7A (in 2014), account for approximately 60% of all MN, both primary and secondary. In the remaining MN, target antigens were unknown. Use of laser microdissection and mass spectrometry enabled identification of new “antigens.” This approach led to the identification of four novel types of MN: exotosin 1 (EXT1)– and exotosin 2 (EXT2)–associated MN, NELL1-associated MN, Sema3B-associated MN, and PCDH7-associated MN. Each of these represents a distinct disease entity, with different clinical and pathologic findings. In this review, the structure of the proteins and the clinical and pathologic findings of the new types of MN are discussed. The role of mass spectrometry for accurate diagnosis of MN cannot be overemphasized. Finally, any classification of MN should be made on the basis of the antigens that are detected. Further studies are required to understand the pathophysiology, response to treatment, and outcomes of these new MNs.

Clinical Phenotypes and Predictors of Remission in Primary Membranous Nephropathy

“…Despite the increasing prevalence of diabetic nephropathy or focal and segmental glomerulosclerosis in certain subpopulations, primary membranous nephropathy remains an important cause of nephrotic syndrome [2]. Since the landmark papers describing, in 2009, the M-type phospholipase A2 receptor and, in 2014, the Thrombospondin type-1 Domain Containing-7A as the first human target autoantigens, the field of MN has significantly changed, and currently several new "putative" antigens have been proposed to underlie different phenotypes of MN (e.g., malignancy-associated, MN in the context of systemic autoimmune disorders) [9].…”

“…Since the landmark study in 2009 describing the first human target autoantigen, M-type phospholipase A2 receptor 1 (PLA2R) [3], the landscape of pMN has significantly changed with the description of several new putative "antigens" (THSD7A, exostosin 1/exostosin 2, NELL1, semaphorin 3B, protocadherin 7) [4][5][6][7][8]. Accordingly, it becomes evident that each distinct antigen might drive a different clinical phenotype in the context of a different pathophysiological phenomenon [9]. Nonetheless, anti-PLA2R antibodies account for up to 50-80% of pMN cases [2].…”

Membranous Nephropathy With Monoclonal IgM Lambda Deposits in a Patient With IgM Monoclonal Gammopathy: A Case Report

“…IgG subclass staining showed dominant IgG2 deposition in the second renal biopsy tissue. Although several new antigens in MN have recently been proposed ( 3 ), no corresponding antibodies predominantly of the IgG2 subclass have been identified to date. Thus, polyclonal IgG antibodies that react with monoclonal IgM, which are deposited on the glomerular capillary walls, may be produced via autoimmune mechanisms in this patient.…”

“…Podocyte phospholipase A 2 receptor (PLA 2 R) was the first reported target antigen for the immune complexes observed in patients with idiopathic MN ( 1 ). Subsequently, another target antigen, thrombospondin-type-1-domain-containing-7A (THSD7A) ( 2 ), was identified, and more recently, several other antigens have been proposed ( 3 ). Importantly, these antigens have been suggested to be associated with the etiology of patients with MN ( 3 , 4 ), and the expression of THSD7A may also be associated with malignancy ( 5 , 6 ).…”

Advances in Lupus Nephritis Pathogenesis: From Bench to Bedside

“…Distinctly, autoantibodies targeting NCAM1 (neural cell adhesion molecule 1), a member of the immunoglobulin superfamily of proteins that is expressed on podocytes, were identified in 6.6% of cases of membranous LN [39]. Recently, glomerular subepithelial deposits containing exostosin 1 and exostosin 2 (EXT1/2) were identified in patients with PLA2R-negative and THSD7A-negative membranous nephropathy [40,41]. Over 80% of patients showing positive staining for EXT1/2 had clinical or histological features suggestive of autoimmunity, mostly SLE, such as antinuclear antibodies, anti-dsDNA antibodies, tubuloreticular inclusions.…”