A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy

Abstract

Key Points• We created the first transgenic mouse model recapitulating the early pathologic features of Randall-type heavy chain deposition disease.• Production of a truncated immunoglobulin heavy chain heightens plasma cell sensitivity to bortezomib via a terminal unfolded protein response.Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a truncated monoclonal immunoglobulin heavy chain (HC) bearing a deletion of the first constant domain (CH1). We created a transgenic mouse model of HCDD using targeted insertion in the immunoglobulin k locus of a human HC extracted from a HCDD patient. Our strategy allows the efficient expression of the human HC in mouse B and plasma cells, and conditional deletion of the CH1 domain reproduces the major event underlying HCDD. We show that the deletion of the CH1 domain dramatically reduced serum HC levels. Strikingly, even with very low serum level of truncated monoclonal HC, histologic studies revealed typical Randall-type renal lesions that were absent in mice expressing the complete human HC. Bortezomibbased treatment resulted in a strong decrease of renal deposits. We further demonstrated that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated HC that sensitizes plasma cells to bortezomib through an elevated unfolded protein response (UPR). This new transgenic model of HCDD efficiently recapitulates the pathophysiologic features of the disease and demonstrates that the renal damage in HCDD relies on the production of an isolated truncated HC, which, in the absence of a LC partner, displays a high propensity to aggregate even at very low concentration. It also brings new insights into the efficacy of proteasome inhibitor-based therapy in this pathology. (Blood. 2015;126(6):757-765) IntroductionTissue deposition of a monoclonal immunoglobulin fragment frequently complicates plasma cell disorders.1,2 Among the wide spectrum of renal diseases associated with monoclonal gammopathies, Randall-type monoclonal immunoglobulin deposition disease (MIDD) is a multisystemic disorder with prominent renal manifestations including glomerular proteinuria and renal failure. 1,[3][4][5] Kidney lesions in MIDD are characterized by nonamyloid amorphous linear deposits of a monoclonal immunoglobulin fragment along tubular, and in most cases, vascular and glomerular basement membranes (BMs). Nodular glomerulosclerosis and diffuse thickening of tubular BMs are commonly observed. 3,6 The most frequent type of MIDD is related to deposition of monoclonal light chain (LC) (LCDD), mostly of the k isotype, but deposits composed of monoclonal heavy chain (HC) only (HCDD) or of light and heavy chain (LHCDD) have been also described. 3,7 Most reported cases of HCDD were characterized by gHC deposits. 4,5,[8][9][10][11] The mechanisms involved in the deposition of monoclonal Ig fragments in MIDD remain poorly understood. Structural peculiarities of the V domains o...

IgA Structure Variations Associate with Immune Stimulations and IgA Mesangial Deposition

“…IgA1 mAb6 and its IgG1 variant were injected in parallel, and kidneys were examined 2 hours later. Deposits formed with IgA1 mAb6 but not with its IgG1 variant (only yielding faint background staining), whereas recently reported transgenic models with monoclonal IgG1 deposition provided a positive staining control 17 (Figure 12).…”

“…The CH12 mice feature expression and glomerular kidney deposition of a truncated human-g1 Ig chain cloned in a patient with Randall-type glomerular Ig deposition disease. 17 Three animal facilities were used. The conventional animal facility of the Limoges University, in which multiple pathogens were endemic (including Norovirus, murine hepatitis virus, Staphylococcus aureus, Pasteurella multocida, Syphacia obvelata, and multiple ectoparasites, etc.…”

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

“…We performed real-time PCR on selected genes (Herpud1, Hspa5, Ddit3, Xbp1s) and confirmed a similar tendency for upregulation of genes involved in UPR even if, consistent with RNA-Seq analysis, no increase in Xbp1s was observed ( Figure 5D). Having demonstrated that LCDD LC-producing PCs have an exacerbated UPR, we next verified if such ER stress could sensitize PCs to proteasome inhibitors (PI), as we previously showed in a HCDD mouse model (17). We treated mice with suboptimal doses of bortezomib (Bz) for two consecutive days to evaluate the level of PC depletion.…”

“…An efficient transgenic strategy to produce high amounts of human pathogenic LCs in mouse. To obtain a high production of the pathogenic human kappa LC, we chose to use a Ig kappa knock-in strategy that proved successful in previous models of Fanconi syndrome and HCDD (17,19). We introduced the VJ exon sequence obtained from a patient (F) with biopsy-proven LCDD in place of the J segments, precluding all further mouse kappa rearrangements in homozygous mice ( Figure 1A).…”

“…LCDD LC induces ER stress and sensitizes plasma cell to proteasome inhibitors. Several studies tend to demonstrate that the production of a pathogenic monoclonal Ig or Ig fragment could influence plasma cell fitness and sensitivity to treatments through a general cellular stress involving ER stress, decreased autophagy and oxidative stress (17,28). To determine if such cellular stress occurred in plasma cells producing LCDD LC and to better delineate the molecular pathways involved, we performed a RNA-sequencing (RNA-seq) on magnetically sorted spleen plasma cells (>80%) of F-DH mice compared to WT mice producing polyclonal complete Ig, and to DH mice producing polyclonal FLCs (n = 3 mice of each strain).…”