Immunology of membranous nephropathy: from animal models to humans

Abstract

SummaryMembranous nephropathy (MN), the leading cause of nephrotic syndrome in adults, is characterized by the deposition of subepithelial immune deposits that consist mainly of immunoglobulin (Ig)G and complement. Most of the cases are primary or idiopathic (iMN), while only approximately 25% of the cases are secondary to some known disease such as systemic lupus erythematosus, hepatitis B, drugs and malignancies. Most of our knowledge on the pathogenesis of iMN has relied upon old experimental models (i.e. Heymann nephritis) that have shown that immune deposits are formed in situ by the reaction of autoantibodies against the respective podocyte antigen. Recent findings indicate that podocyte proteins also act as an autoantigen in human iMN. The M-type phospholipase A2 receptor (PLA2R) has been identified as the main target antigen, as it can be found in approximately 70% of iMN patients but only rarely in other glomerulonephritides. Podocytes damage in the experimental model of Heymann nephritis is complementmediated. In humans, the presence of complement within the subepithelial deposits is well established, but IgG4, which does not activate complement by classical or alternative pathways, represents the predominant subclass of IgG anti-PLA2R. Some evidence suggests that IgG4 anti-PLA2R autoantibodies can bind mannan-binding lectin (MBL) and activate the lectin complement pathway. A genetic background for iMN has been demonstrated by genomewide association studies that have shown highly significant associations of the PLA2R1 and the human leucocyte antigen (HLA)-DQA1 loci with iMN. In addition to their diagnostic value, anti-PLA2R antibodies may be useful to monitor disease activity and predict response to treatment.

Clinical significance of C4d deposition in renal tissues from patients with primary Sjögren’s syndrome—A preliminary study

“…Besides C3, the component of the alternative pathway, glomerular deposition of C4d and MBL were detected in PMN, indicating involvement of the lectin pathway(Hayashi et al, 2018;Hui et al, 2014). The lectin pathway of complement may be possibly triggered by the in situ formed immune complexes comprising the IgG4 type of anti-PLA2R antibodies(Sinico et al, 2016). In patients with SLE-MN, circulating immune complexes deposition and the subsequent activation of the complement system resulted in the full house deposition of immune complexes and C1q, and all the three pathways of complement activation were involved, namely the classical, lectin(Kim et al, 2013) and alternative pathway(Song et al, 2017).…”

“…Primary membranous nephropathy (PMN) is a kidney-specific disease with increased proteinuria and pathological characteristics of sub-epithelial immune complex deposition (predominantly IgG4 and C3 deposition)(Sinico et al, 2016). PMN is characterized by the presence of serum autoantibodies against the podocyte component M-type phospholipase A2 receptor (PLA2R) in approximately 70% of patients(Beck et al, 2009) and anti-thrombospondin type 1 domain containing 7A (THSD7A) antibodies in approximately 10% of those with negative anti-PLA2R antibodies (nearly 3% of patients with intrinsic antibodies related MN)(Hayashi et al, 2018;Tomas et al, 2014).…”

Case Follow-Up: Development of Primary Membranous Glomerulonephritis in a Patient with IgG4 Related Disease

“…This suggests that despite a common immunoglobulin subclass, the pathophysiology of primary MGN is dissimilar from IgG4-RD. Early evidence suggests pathophysiology is indeed different, as PLA2R antibodies may activate the lectin complement pathway, as opposed to the lymphoplasmacytic infiltration and fibrosis seen with IgG4-RD [2,16]. In addition, elevated levels of IgG4 and PLA2R antibodies in serum can be found in IgG4-RD and primary MGN respectively, but only serum elevations in PLA2R antibodies have been closely associated with disease activity [16].…”

“…Early evidence suggests pathophysiology is indeed different, as PLA2R antibodies may activate the lectin complement pathway, as opposed to the lymphoplasmacytic infiltration and fibrosis seen with IgG4-RD [2,16]. In addition, elevated levels of IgG4 and PLA2R antibodies in serum can be found in IgG4-RD and primary MGN respectively, but only serum elevations in PLA2R antibodies have been closely associated with disease activity [16]. The association between PLA2R antibodies and disease activity may be due to the direct damaging effect of PLA2R antibodies on their end target, the podocyte.…”

“…In contrast, the lack of correlation between IgG4 levels and IgG4-RD disease activity argues that IgG4 itself doesn't trigger end organ damage, but that another hit, such as an inappropriate immune response to IgG4, results in the end organ damage. The recent discovery of an association between PLA2R antibodies and human leukocyte antigen DQA1 alleles may shed more light on the pathogenesis of primary MGN, and help distinguish it from other diseases involving IgG4, including IgG4-RD [16]. While our patient could potentially represent another manifestation of IgG4-RD that will become more common in the literature as the sample size of IgG4-RD patients continues to grow, it appears more likely that our patient may represent a rare co-occurrence of two isolated diseases, primary MGN and IgG4-RD.…”