A Novel Insight into the Role of PLA2R and THSD7A in Membranous Nephropathy

Abstract

Membranous nephropathy (MN) is an organ-restricted autoimmune disease mainly caused by circulating autoantibodies against podocyte antigens, including the M-type phospholipase A2 receptor (PLA2R) and thrombospondin domain-containing 7A (THSD7A). Antibodies against PLA2R are present in 70%–80% and against THSD7A in 2% of adult patients, which provides a paradigm shift in molecular diagnosis and management monitoring. Both antigens share some similar characteristics: they are expressed by podocytes and have wide tissue distributions; they are bound by autoantibodies only under nonreducing conditions, and the subtype of most autoantibodies is IgG4. However, the factors triggering autoantibody production as well as the association among air pollution, malignancy, and the pathogenesis of MN remain unclear. In this review, we discuss the similarity between the pathological mechanisms triggered by disparate antigens and their associated diseases. Furthermore, we demonstrated the possibility that PM2.5, malignancy, and gene expression specifically induce exposure of these antigens through conformational changes, molecular mimicry, or increased expression eliciting autoimmune responses. Thus, this review provides novel insights into the pathological mechanism of MN.

Recent Advances in Clinical Diagnosis and Pharmacotherapy Options of Membranous Nephropathy

“…It is presently uncertain whether there are patients with dual PLA 2 R and THSD7A antibody positivity ( Zhang et al, 2021a ). When PLA 2 R antibodies were detected in serum and there is no evidence for secondary MN, one may consider that patients do not undergo a kidney biopsy sample, provided that patients presented normal or only mild renal function decline.…”

“…In 2014, this was followed by the discovery of a second antigen, namely, thrombospondin type-1 domain-containing 7A (THSD7A) in human IMN ( Tomas et al, 2014 ). PLA 2 R-related and THSD7A-related MN accounted for about 70% and 1–5% of IMN patients, respectively ( Zhang et al, 2021a ). A genome-wide association study indicated that single nucleotide polymorphisms in the PLA 2 R gene were closely related to IMN, which again revealed the involvement of this antigen by using an untargeted genetic approach ( Xu et al, 2020 ; Yoshikawa and Asaba, 2020 ).…”

Membranous nephropathy: Systems biology-based novel mechanism and traditional Chinese medicine therapy

“…Immune deposit formation is fuelled by de novo synthesis of megalin. Epitope mapping analysis revealed that although subepithelial immune deposits were mediated by 4 megalin ligand-binding domains, full-blown disease with proteinuria was related to a specific epitope in first ligand-binding domain located in a 60 kDa N-terminal fragment ( Larsen et al, 2018 ), and with intramolecular epitope spreading ( Zhang et al, 2021 ).…”

“…Studies have suggested that most MN patients produced an autoimmune response for either PLA 2 R or THSD7A, but not for two antigens ( Larsen et al, 2016 ; Logt et al, 2021 ), indicating that both antigens are primary target of specific autoimmunity and verifies that PLA 2 R-related MN and THSD7A-related MN are separate disease entities. Several publications have demonstrated that anti-PLA 2 R antibody titre correlate with disease effect and patient outcomes ( Brglez et al, 2020 ; Logt et al, 2021 ; Nieto-Gañán et al, 2021 ; Zhang et al, 2021 ). Low anti-PLA 2 R autoantibody concentrations were used for the diagnosis prediction of spontaneous remission ( Jurubiță et al, 2021 ; Reinhard et al, 2021 ; Zhang et al, 2021 ).…”

“…Several publications have demonstrated that anti-PLA 2 R antibody titre correlate with disease effect and patient outcomes ( Brglez et al, 2020 ; Logt et al, 2021 ; Nieto-Gañán et al, 2021 ; Zhang et al, 2021 ). Low anti-PLA 2 R autoantibody concentrations were used for the diagnosis prediction of spontaneous remission ( Jurubiță et al, 2021 ; Reinhard et al, 2021 ; Zhang et al, 2021 ). In addition, reduced concentrations of anti-PLA 2 R antibody could also predict proteinuria remission ( Radice et al, 2016 ) and response to the traditional and new CD20-targeted immunosuppressive treatments ( Ruggenenti et al, 2015 ).…”