1. Figure 3 Models of monoclonal immunoglobulin-induced glomerulopathies
Figure 3 | Models of monoclonal immunoglobulin-induced glomerulopathies. A | Mouse model of immunoglobulin light chain amyloidosis (AL amyloidosis). Aa | Penile vein injections of purified light chains from a patient with AL amyloidosis leads to Congo red-positive light chain deposits in the kidneys after 2 weeks of repeated injections. Ab | Scanning electron micrograph of a glomerulus showing tangled, non-branching fibrils that are typical of amyloidosis. Ac | Mesangial cells undergo a phenotypic change from a smooth muscle-like to a macrophage-like phenotype, as shown by intracytoplasmic staining for CD68, after injection of AL amyloidosis light chains (top) but not of light chain deposition disease (LCDD)-associated light chains (bottom). Ad | Transmission electron microscopy showing abundant, heterogeneous lysosomes that are closely associated with the plasma membrane in mesangial cells. Ae | Scanning electron microscopy of mesangial cells 1 week after initial injection of AL amyloidosis light chains, showing extrusion of single amyloid fibrils from a cell. Af | Schematic representation of the amyloidogenesis process in mesangial cells. AL amyloidosis-associated light chains are endocytosed and trafficked to the endolysosomal compartment, where they are processed and fibrils are formed. Amyloid fibrils are then extruded to the exterior of the cell. B | Transgenic mouse models of monoclonal immunoglobulin deposition disease (MIDD) using the κ-light chain knock-in strategy. Ba,Bb | Transgenic model of heavy chain deposition disease (HCDD). Bc,Bd | Transgenic model of light chain deposition disease (LCDD). These transgenic models faithfully reproduce human renal lesions, with typical glomerular and tubular deposits (parts Ba and Bc; immunofluorescence with anti-human immunoglobulin antibodies). A slight expansion of mesangial matrix is observed in the kidneys of the HCDD model but no glomerulosclerosis (part Bb), probably owing to the very low level of free heavy chains in the serum. By contrast, LCDD mice develop a typical nodular glomerulosclerosis (part Bd). Parts Bb and Bd show periodic acid–Schiff staining. Be | On bortezomib (Bz)-based treatment, a rapid reduction in immunoglobulin deposits (5 weeks) was observed in the kidneys in the HCDD model. Means ± SEM are shown; n = 6–7 mice in two independent experiments. Bf | Mouse plasma cells producing the HCDD heavy chain are highly sensitive to proteasome inhibitors, as seen by the substantial decrease in plasma cell number following two daily injections of low-dose Bz. Each symbol represents a mouse, and numbers indicate the overall means of the fold-decrease in each strain. Bg | Proteasome inhibitor sensitivity seems to be due to the intrinsic toxicity of the truncated heavy chain, causing a terminal endoplasmic reticulum (ER) stress response, as shown by the markedly elevated expression of the ER stress markers C/EBP-homologous protein (CHOP; also known as DDIT3), hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2; also known as HERP) and immunoglobulin heavy chain-binding protein (BiP)) in the plasma cells producing the HCDD heavy chain. The data are means ± SEM of three independent experiments with two mice of each strain. All statistical tests are unpaired Student's t tests (*P < 0.05 and **P < 0.01). Ctrl, control; LC, light chain; LPS, lipopolysaccharide; ns, not significant; WT, wild type. Parts Aa–e reproduced with permission from Ref. 62, International Society of Nephrology. Part Ba is reproduced and parts Be–g are adapted with permission from Ref. 73, American Society of Hematology. Parts Bc and Bd: C.S., S.B., M.V.A., V.J., M.C., G.T. and F.B., unpublished observations.
Parts Aa–e reproduced with permission from Teng, J., Turbat-Herrera, E. A. & Herrera, G. A.
An animal model of glomerular light-chain-associated amyloidogenesis depicts the crucial role of lysosomes.
Kidney Int. 86, 738–746 (2014), International Society of Nephrology. Part Ba is reproduced and parts Be–g
are adapted with permission from Bonaud, A. et al. A mouse model recapitulating human monoclonal heavy
chain deposition disease evidences the relevance of proteasome inhibitor therapy. Blood 126, 757–765 (2015),
American Society of Hematology. Parts Bc and Bd: C.S., S.B., M.V.A., V.J., M.C., G.T. and F.B., unpublished observations.
Sirac, C. et al. (2018) Animal models of monoclonal immunoglobulin-related renal diseases
Nat. Rev. Nephrol. doi: /nrneph