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Mouse models to study plasma cells and monoclonal immunoglobulin-related diseases

Abstract : Abnormal plasma cells (PC) proliferation is frequent (approximately 5% of people over 50) but in most cases remains asymptomatic, detected by the presence of a monoclonal Immunoglobulin (Ig) in excess. These Ig can be unstable and cause complications related to their precipitation, aggregation or crystallization in different organs. Due to the inherent variability of Igs, with different sequences from one patient to the other, and the wide spectrum of the different pathologies, reliable experimental models for Ig-induced deposition diseases are challenging to obtain. In our laboratory, we were able to develop a Light Chain Deposition Disease (LCDD) mouse model that reproduces the renal lesions found in patients and that allowed us to show that pathogenic Light Chain (LC) expressed sensitizes the PC to proteasome inhibitors by the activation of the endoplasmic reticulum stress response pathway. Additionally, we proved that eliminating the pathogenic LC mice recovered their renal function. Over the years, different strategies have been carried out to obtain a model for AL Amyloidosis , the most frequent and severe form of Ig-related deposition disease. We have created a rat and a mouse transgenic model expressing an amyloidogenic LC that did not spontaneously develop amyloidosis. Thanks to in vitro studies, we have showed that the Variable LC domain (VL) is the key for fibril formation and mice injected with them generate amyloid deposits in heart and spleen. We have also focused in the targeting and modification of PCs. For this, we searched for a gene only expressed in this cell lineage, the J Chain. Using a conditional deletion mouse model expressing a tamoxifen-dependent Cre recombinase under the regulatory elements of the J Chain, we were able to modify gene expression specifically in PCs. Thanks to this model and others already available in the laboratory, we started the exploration of the therapeutic potential of targeting the Ig.
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Submitted on : Monday, November 15, 2021 - 5:37:10 PM
Last modification on : Wednesday, October 5, 2022 - 4:01:38 AM
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  • HAL Id : tel-03429587, version 1



Maria Victoria Ayala. Mouse models to study plasma cells and monoclonal immunoglobulin-related diseases. Human health and pathology. Université de Limoges, 2020. English. ⟨NNT : 2020LIMO0028⟩. ⟨tel-03429587⟩



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