Autoantibodies against podocytic UCHL1 are associated with idiopathic nephrotic syndrome relapses and induce proteinuria in mice

J Autoimmun. 2018 May:89:149-161. doi: 10.1016/j.jaut.2017.12.014. Epub 2018 Jan 4.

Abstract

Idiopathic steroid sensitive nephrotic syndrome (INS), the most frequent childhood nephropathy, is thought to be mediated by a circulating soluble factor that reversibly affects the renal protein sieving. The efficiency of rituximab therapy recently highlighted the involvement of B cells. Here we studied the involvement of a specific immunoglobulin G (IgG) in the disease. After plasma fractionation by size exclusion chromatography, a detachment of cultured podocyte was observed with one IgG-containing fraction from 47% patients in relapse, 9% of patients in remission and 0% of controls. Podocyte protein lysates were immunoprecipitated by IgG from those plasma fractions identifying a list of 41 podocyte proteins after proteomic analysis. Five podocyte targets were selected on statistical and biological criteria. Specific antibodies were tested and only anti-Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) IgG led to podocyte detachment. UCHL1 was mainly found inside the podocyte but also weakly expressed on podocyte cell surface. Incubation of either anti-UCHL1 IgG or plasma fractions with recombinant UCHL1 prevented podocyte detachment. Plasma levels of anti-UCHL1 IgG were significantly increased in relapsing INS patients compared to patients in remission and controls. Proteinuria correlated with anti-UCHL1 IgG level at various stages of the disease. Purified patient anti-UCHL1 antibodies induced proteinuria and podocyte foot effacement in mice. Altogether, these results identified UCHL1 as a target podocyte protein of autoantibodies in a set of relapsing patients and support a causative role of anti-UCHL1 autoantibodies in the development of INS.

Keywords: Foot process effacement; Immunoglobulin; Pediatric nephrology; Proteinuria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Autoantibodies / blood
  • Cell Adhesion
  • Cells, Cultured
  • Child
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin G / isolation & purification
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Nephrotic Syndrome / immunology*
  • Podocytes / physiology*
  • Proteinuria / immunology*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / immunology*

Substances

  • Autoantibodies
  • Immunoglobulin G
  • UCHL1 protein, human
  • Ubiquitin Thiolesterase