The Genetic and Environmental Factors of Primary Membranous Nephropathy: An Overview from China

Abstract

Background: Primary membranous nephropathy (pMN) is the most common cause of nephrotic syndrome in adults. The discovery of the 2 autoantigens, M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A), has defined pMN as an autoimmune disease. A remarkable increase in the frequency of pMN in primary glomerular disease was witnessed in China. The genetic and environmental contributors to disease susceptibility have been investigated in these patients. Summary: We reviewed recent publications in genetic and environmental studies of pMN, focusing mainly on those undertaken in China. Following a genome-wide association study, the gene-gene interaction between the 2 most significant risk factors, PLA2R1 and DQA1, was validated in Chinese patients with MN. Fine mapping on human leukocyte antigen (HLA) locus found that DRB1*1501 and DRB1*0301 were risk alleles. Three amino acid residues on positions 13 and 71 of HLA-DRβ1 chain may confer the susceptibility to pMN by presenting T-cell epitopes on PLA2R. Another study found that DRB3*0202 was the most likely culprit allele for the signal at DRB1*0301. One environmental risk factor for pMN has been identified as the long-term exposure to high levels of PM_2.5 in Chinese patients with MN. Each 10 μg/m³ increase in PM_2.5 concentration was associated with 14% higher odds for pMN in the regions with PM_2.5 above 70 μg/m³. Key Message: A gene-environment interaction is suspected as an underlying mechanism for the increasing trend of pMN in China.

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

“…Inflammation enhances the immunogenicity of autoantigens and affects the antigen processing capacity of APCs, which contributes to the autoimmune response. Undoubtedly, genetic susceptibility influences the development of MN, and other pathogenic factors exert an additive effect in determining whether the genetic potential is manifested [94]. Immunization can be augmented by the unmasking of hidden cryptic epitopes undergoing conformational changes upon exposure to environmental stimuli [95].…”

Idiopathic Membranous Nephropathy: Glomerular Pathological Pattern Caused by Extrarenal Immunity Activity

“…The pathogenesis of IMN has been associated with environmental stimuli ( 40 ). The morbidity of MN in China has been gradually increasing, which could be possibly related to the long-term exposure to air pollution.…”

Unmet challenges in membranous nephropathy

“…Another study of Han Chinese patients with PLA2R-associated MN reported a strong association with DRB3*0202 [23*], which probably accounts for the DRB1*0301 signal as they are on the same haplotype. Based on in silico modeling studies, the Beijing group reported on three amino acids in the antigen-binding pocket of the HLA-DR beta1 chain that might help to present PLA2R T cell epitopes to activate the immune response, and the authors have suggested that this confers a genetic susceptibility to environmental factors such as industrial pollution [24]. While these are encouraging observations, the functional studies to document immune cell activation and identification of T cell epitopes have yet to be done.…”

“…A recent increase in the incidence of MN in parts of China has been attributed to environmental air pollution, especially in regions with the highest level of pollution with PM 2.5 particles [25*]. The mechanisms for this are still undefined but gene/environmental interactions and release of pro-inflammatory cytokines have been proposed [24]. Although human PLA2R is most strongly expressed in kidney (and in glomerular podocytes in particular), it is also expressed in lung, placenta, liver and skeletal muscle [26].…”