Immunoglobulin light-chain toxicity in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Sébastien Bender, Maria Victoria Ayala, Amélie Bonaud, Vincent Javaugue, Claire Carrion, Christelle Oblet, Alexia Rinsant, Sihem Kaaki, Zeliha Oruc, François Boyer, Agnès Paquet, Nicolas Pons, Bastien Hervé, Mohamad Omar Ashi, Arnaud Jaccard, Laurent Delpy, Guy Touchard, Michel Cogné, Frank Bridoux, Christophe Sirac

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Résumé

Light chain (LC) deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin LC, leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse immunoglobulin κ locus, ensuring its production by all plasma cells (PCs). High free LC levels were achieved after backcrossing with mice presenting increased PC differentiation and no immunoglobulin heavy chain production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria, and finally kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on PCs demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor–based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function but also partially reversed kidney lesions. Finally, transcriptome analysis of presclerotic glomeruli revealed that proliferation and extracellular matrix remodeling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy. Key Points: • Human pathogenic immunoglobulin LC fully reproduces LCDD in a transgenic mouse, including glomerulosclerosis and end-stage renal failure. • In addition to its kidney toxicity, LCDD LC induces endoplasmic reticulum stress and sensitizes PCs to proteasome inhibitors.

langue originaleAnglais
Pages (de - à)1645-1656
Nombre de pages12
journalBlood
Volume136
Numéro de publication14
Les DOIs
étatPublié - 1 oct. 2020
Modification externeOui

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