title: A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy.
abstract: 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 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.
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France; Centre National de Référence Amylose AL et Autres Maladies par Dépôt d'Immunoglobulines Monoclonales, Centre Hospitalier Universitaire de Limoges, Limoges, France; and.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonaud
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France; Centre National de Référence Amylose AL et Autres Maladies par Dépôt d'Immunoglobulines Monoclonales, Centre Hospitalier Universitaire de Limoges, Limoges, France; and.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bender
authors.affiliation: Service de Néphrologie et Transplantation.
authors.forename: Guy
authors.initials: G
authors.lastname: Touchard
authors.affiliation: Centre National de Référence Amylose AL et Autres Maladies par Dépôt d'Immunoglobulines Monoclonales, Centre Hospitalier Universitaire de Limoges, Limoges, France; and Service d'Immunologie, and.
authors.forename: Corinne
authors.initials: C
authors.lastname: Lacombe
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France;
authors.forename: Nivine
authors.initials: N
authors.lastname: Srour
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Delpy
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France;
authors.forename: Christelle
authors.initials: C
authors.lastname: Oblet
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France;
authors.forename: Anne
authors.initials: A
authors.lastname: Druilhe
authors.affiliation: Centre National de Référence Amylose AL et Autres Maladies par Dépôt d'Immunoglobulines Monoclonales, Centre Hospitalier Universitaire de Limoges, Limoges, France; and Service d'Anatomo-Pathologie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Quellard
authors.affiliation: Centre National de Référence Amylose AL et Autres Maladies par Dépôt d'Immunoglobulines Monoclonales, Centre Hospitalier Universitaire de Limoges, Limoges, France; and Service de Néphrologie et Transplantation.
authors.forename: Vincent
authors.initials: V
authors.lastname: Javaugue
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France; Centre National de Référence Amylose AL et Autres Maladies par Dépôt d'Immunoglobulines Monoclonales, Centre Hospitalier Universitaire de Limoges, Limoges, France; and Service de Néphrologie et Transplantation.
authors.forename: Frank
authors.initials: F
authors.lastname: Bridoux
authors.affiliation: Centre National de la Recherche Scientifique, UMR 7276, Université de Limoges, Limoges, France; Centre National de Référence Amylose AL et Autres Maladies par Dépôt d'Immunoglobulines Monoclonales, Centre Hospitalier Universitaire de Limoges, Limoges, France; and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Sirac
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004195:Disease Models, Animal; D015870:Gene Expression; D056426:Genetic Loci; D006362:Heavy Chain Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000494:pharmacology*; D017384:Sequence Deletion; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007143:Immunoglobulin Heavy Chains; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex