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

Jamin, Agnès; Berthelot, Laureline; Couderc, Anne; Chemouny, Jonathan M; Boedec, Erwan; Dehoux, Laurène; Abbad, Lilia; Dossier, Claire; Daugas, Eric; Monteiro, Renato C; Deschênes, Georges.
J Autoimmun; 89: 149-161, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29307588
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.
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