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

Figure 4

A multihit mechanism for the development of membranous nephropathy (MN). Genetic susceptibility or immune predisposition is thought to be involved in the ‘first hit’ that probably drives the initial development of MN. Furthermore, PM2.5 or malignancy probably emerges as “second hit” that exerts an additive effect on the activation of the immune response. In the context of multihit that causes loss of immune tolerance, T helper 1 (T_H1) and 17 (T_H17) cells are essential for autoantibody production. Once such an autoimmune response is established, proinflammatory cytokines would act to exacerbate the ongoing response. Besides, inflammation or pathogenic factors alter renal microenvironment, injure podocytes, and enhance the immunogenicity of autoantigens, which contribute to the development of MN. During the development of MN, circulating antibodies binding to the podocyte may be a perfect storm, rather than a straight forward conformeropathy. ① Risk allele associated with MN. ② Immune predisposition. ③ PM2.5 induces extrarenal phospholipase A2receptor (PLA2R) exposure to immune cells. ④ Malignancy induces thrombospondin domain-containing 7A (THSD7A) overexpression. Abbreviations: APC: antigen-presenting cell; HLA: human leukocyte antigen; TCR: T cell receptor; NETs: neutrophil extracellular traps; METs: macrophage extracellular traps.