Idiopathic nephrotic syndrome: the EBV hypothesis

Abstract

Steroid sensitive nephrotic syndrome is marked by a massive proteinuria and loss of podocytes foot processes. The mechanism of the disease remains debated but recent publications suggest a primary role of Epstein-Barr Virus (EBV). EBV replication in the peripheral blood is found in 50% of patients during the first flare of the disease. The genetic locus of steroid sensitive nephrotic syndrome was also identified as influencing antibodies directed against EBNA1. EBV is able to establish, latent benign infection in memory B cells that display phenotypes similar to antigen-selected memory B cells. Consistently, memory B cells reconstitution after rituximab infusion is a predictor of the relapse of proteinuria. We suggest that a specific anti-EBNA1 antibody internalized in the podocytes via the neonatal Fc receptor might cross-react with a major protein present in the same cell trafficking compartment. The diversion of this major podocyte protein in the urinary space and the subsequent depletion is supposed to result in podocyte damages with loss of foot processes and massive proteinuria. Immunosuppression of B cells and subsequent clearance of anti-EBNA1 antibodies would lead to a restoration of the normal level of the protein allowing recovery of proteinuria and of normal podocyte morphology.

Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome

“…Dossier et al hypothesized that anti-EBNA1 antibodies may cause an instability of the podocyte cytoskeleton by cross-reacting with podocyte proteins; clearance of these antibodies results in recovery of proteinuria. 33 None of our patients showed any known viral infection at the time of relapse. Long-term memory B-cell depletion may also be detrimental.…”

“…The pathogenicity of memory B cells is also defined in terms of providing antiapoptotic signals for viral replication. 33 Epstein-Barr virus (EBV) resides lifelong in resting-memory B cells; in immunocompromised individuals, these B cells release the virus during the lytic phase of infection. Dossier et al hypothesized that anti-EBNA1 antibodies may cause an instability of the podocyte cytoskeleton by cross-reacting with podocyte proteins; clearance of these antibodies results in recovery of proteinuria.…”

Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome

“…39 Of note, HLA-DQB1 and HLA-DRB1 loci are strongly associated with EBV infection, which has been previously hypothesized to be involved in NS pathogenesis. 40,41 Engagement of HLA class 2 on the podocyte surface might also regulate podocyte function and survival as it does for APCs. 42,43 Given that the two main SSNS targets are putatively the podocyte and the lymphocyte, 7,9 we used eQTL analysis to gain insight into transcriptional effects of these SNPs on gene expression across tissues.…”

Long-term Successful Treatment of Rituximab for Steroid-resistant Minimal Change Nephrotic Syndrome and Idiopathic Thrombocytopenic Purpura

“…We therefore believe it necessary to measure not only the percentage but also the function. The involvement of Epstein-Barr virus as a common cause of nephrotic syndrome (13) and thrombocytopenia (14) has also been reported. However, IgG antibody, IgM antibody, and Epstein-Barr nuclear antigen as well as virus DNA were all negative when she developed MCNS.…”