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Blood, 15 July 2006, Vol. 108, No. 2, pp. 536-543.
Prepublished online as a Blood First Edition Paper on March 16, 2006; DOI 10.1182/blood-2005-11-4419.
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IMMUNOBIOLOGY
Role of the monoclonal  chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome
Christophe Sirac,
Frank Bridoux,
Claire Carrion,
Olivier Devuyst,
Béatrice Fernandez,
Jean-Michel Goujon,
Chahrazed El Hamel,
Jean-Claude Aldigier,
Guy Touchard, and
Michel Cogné
From the Laboratoire d'Immunologie, Centre National de la Recherche Scientifique (CNRS) Unite Mixté de Recherche (UMR) 6101, Equipe labellisée La Ligue, Centre Hospitalier Universitaire (CHU) Dupuytren, Université de Limoges, France; Service de Néphrologie, CHU Jean Bernard, Poitiers, France; Division of Nephrology, Université Catholique de Louvain Medical School, Brussels, Belgium; and Unité de Pathologie Ultrastructurale et Expérimentale, Service d'Anatomie Pathologique, CHU Jean Bernard, Poitiers, France.
Acquired Fanconi syndrome (FS) is a complication of monoclonal gammopathies featuring a generalized dysfunction of the proximal tubule of the kidney, due to the storage within proximal tubular cells of a monoclonal immunoglobulin light chain. We engineered transgenic mice in which the endogenous mouse J cluster was replaced by a human VJ rearranged gene cloned from a patient with smoldering myeloma-associated FS. The V region belonged to the VI subgroup and was related to the O2-O12 germ-line gene, a V segment previously found associated with FS and light-chain crystallization in several patients with myeloma. Association of the human VI domain with a mouse constant domain in transgenic animals yielded a nephrotoxicity pattern similar to that observed in patients, strongly suggesting that the whole pathogenic effect of FS light chains can be ascribed to a peculiar structure of the V domain. Morphologic alterations of the kidney tubular cells, which contained rhomboid-shape crystals, were observed in mice, together with alterations of the proximal tubule reabsorption function. Moreover, the number of renal crystalline inclusions was dramatically reduced after conditional deletion of the human VI transgene, showing that proximal tubular lesions are reversible upon suppression of the nephrotoxic light chain secretion.
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