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Review
. 2019 May 24:8:F1000 Faculty Rev-734.
doi: 10.12688/f1000research.17589.1. eCollection 2019.

Immunology of membranous nephropathy

Shin'ichi Akiyama  1 , Enyu Imai  2 , Shoichi Maruyama  1
Affiliations
Review

Immunology of membranous nephropathy

Shin'ichi Akiyama et al. F1000Res. .

Abstract

Accounting for about 20 to 50% of cases of primary nephrotic syndrome, membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. A rat model created nearly 60 years ago to research the primary MN disorder, Heymann nephritis, has provided us with a plethora of important information. Recently, our knowledge about MN has dramatically progressed. Heymann nephritis and human MN are now known to share a high degree of similarity in pathogenesis. This review summarizes our current understanding of MN pathogenesis while focusing particularly on the immunological aspects.

Keywords: Epitope spreading; Heymann nephritis; Membranous nephropathy; NEP; PLA2R; THSD7A; podocyte.

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Conflict of interest statement

No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. PLA2R and THSD7A protein structures and their staining images in the glomeruli of a patient with membranous nephropathy (MN).
PLA2R ( A) and THSD7A ( B) are corresponding antigens of primary MN. These two proteins have similar structures. Autoantibodies against PLA2R and THSD7A in patients with MN can bind to epitopes only under non-reducing conditions. They show enhanced granular expression on podocyte surfaces in patients with MN after indirect immunofluorescence staining with Abs against PLA2R or THSD7A. CTL, C-type lectin; MW, molecular weight; NCBI, National Center for Biotechnology Information; PLA2R, phospholipase A2 receptor; THSD7A, thrombospondin type 1 domain-containing 7A; TSP, thrombospondin.
Figure 2.
Figure 2.. Schematic of autoantibody-driven temporal pathogenesis in PLA2R-associated membranous nephropathy.
The graph shows the temporal change in circulating anti-PLA2R antibodies (Abs) and urinary protein levels (modified from Francis et al. ). The middle table shows the disease phases classified on the basis of Ab production, serum tests for Abs in circulation, glomerular staining for PLA2R, and proteinuria. The bottom schema illustrates the course of the disease from Ab production to proteinuria remission. PLA2R, phospholipase A2 receptor.
Figure 3.
Figure 3.. Schematic of epitope spreading.
( A) Intramolecular epitope spreading. The upper panel shows the primary immune response to the outermost epitope of the target antigen. The middle panel shows the secondary immune response to the inner epitopes caused by tissue destruction and presentation of the inner epitopes. The lower panel shows the result of epitope spreading. ( B) Experimental model of Heymann nephritis–induced epitope spreading in rats. The outermost megalin epitope (LBD#1) was injected into rats, which initiated antibody (Ab) production against inner epitopes (LBD#2–LBD#4), eventually leading to severe proteinuria. ( C) Clinical evidence of epitope spreading in human membranous nephropathy (MN). In MN patients with PLA2R Abs, the target epitope changes from the outermost epitope (CysR) to the inner epitopes (CTDL1 to CTDL7) as the disease progresses. Patients exhibiting Abs against the inner epitopes tend to be old and resistant to therapy. PLA2R, phospholipase A2 receptor.
See this image and copyright information in PMC

References

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