Strategies to model AL amyloidosis in mice.

International audienceMonoclonal immunoglobulin (Ig) deposition in AL amyloidosis is a severe complication of lymphoproliferative disorders. Research on this disease suffers from the lack of animal models, as they could allow for the testing of new innovative therapeutic strategies. We are trying to develop a transgenic animal model for this disease by overexpressing Ig light chain (LC) sequences cloned from AL amyloidosis patients. After several unsuccessful attempts using additional transgenesis due to low LC expression, we currently are following a strategy of targeted insertion of human LC sequences in the mouse endogenous kappa LC locus. We describe here the first data from this ‘knock-in’ model and propose future prospects to increase the rates of free LC and mimic the human disease. Absence of amyloid deposits in such models would raise the possibility of a resistance to AL amyloidosis in mice and question the feasibility of a reliable animal model for this disease

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

International audienceRandall-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 κ 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. Bortezomib-based 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

Classification et prise en charge thérapeutique des gammapathies monoclonales de signification rénale

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Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity

Mice in which the Jκ cluster was replaced with a VκJκ rearranged gene were studied. More than 90% of B cells from homozygous mutant mice expressed the transgenic κ chain but showed a slightly reduced level of κ transcripts compared with WT B lymphocytes. Light chain inclusion was apparent in 10% of B cells from these mice and raised 25% in hemizygous mice with a still lower expression of the knockin κ chain. Beyond the rules of clonal selection, peripheral B cells developed in such animals, with included cells being activated and differentiating into class-switched or antibody-secreting cells. The high amount of included mature B cells was associated with an increase of hybrid κ/λ immunoglobulins but not with the increased prevalence of autoantibodies. Altogether, these data suggest that light chain exclusion prevalent in normal B cells mostly results from ordered rearrangements and stochastic mechanisms but is neither tightly ensured by a stringent cell selection process nor absolutely required for normal B cell function