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...

Srour et al. identify a quality control, truncated Ig exclusion checkpoint dampening terminal plasma cell differentiation by eliminating cells expressing nonfunctionally rearranged Igκ alleles

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