TY - JOUR
T1 - Immunoglobulin light-chain toxicity in a mouse model of monoclonal immunoglobulin light-chain deposition disease
AU - Bender, Sébastien
AU - Ayala, Maria Victoria
AU - Bonaud, Amélie
AU - Javaugue, Vincent
AU - Carrion, Claire
AU - Oblet, Christelle
AU - Rinsant, Alexia
AU - Kaaki, Sihem
AU - Oruc, Zeliha
AU - Boyer, François
AU - Paquet, Agnès
AU - Pons, Nicolas
AU - Hervé, Bastien
AU - Ashi, Mohamad Omar
AU - Jaccard, Arnaud
AU - Delpy, Laurent
AU - Touchard, Guy
AU - Cogné, Michel
AU - Bridoux, Frank
AU - Sirac, Christophe
N1 - Publisher Copyright:
© 2020 American Society of Hematology
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85092680552&partnerID=8YFLogxK
U2 - 10.1182/blood.2020005980
DO - 10.1182/blood.2020005980
M3 - Article
C2 - 32559766
AN - SCOPUS:85092680552
SN - 0006-4971
VL - 136
SP - 1645
EP - 1656
JO - Blood
JF - Blood
IS - 14
ER -