title: A transgenic mouse model of autoimmune glomerulonephritis and necrotizing arteritis associated with cryoglobulinemia.
abstract: Mice implanted with hybridoma secreting 6-19 IgG3 anti-IgG2a rheumatoid factor (RF) with cryoglobulin activity develop acute glomerulonephritis and cutaneous leukocytoclastic vasculitis. As the RF activity is implicated in the skin, but not glomerular lesions, it is still unclear whether the renal pathogenicity is determined by 6-19 H chains alone or their combination with L chains. To address this question, we have generated transgenic mice expressing only the H chain gene or both H and L chain genes of the 6-19 IgG3 anti-IgG2a RF and determined the development of glomerular and vascular lesions. H-single and H/L-double transgenic mice displayed comparable high amounts of IgG3 cryoglobulins, but only H/L-double transgenic mice having 10-fold higher levels of IgG3 anti-IgG2a RF progressively developed chronic, lethal glomerulonephritis. The severe glomerular lesions observed at 8-10 mo of age were very heterogeneous (membranoproliferative changes, crescents, and sclerosis); in addition, one-third of them had necrotizing arteritis in the kidneys and skeletal muscles. These renal and vascular changes were very different from those observed in the acute cryoglobulinemia, characterized by mainly "wire-loop" glomerular lesions and a cutaneous leukocytoclastic form of vasculitis. Thus, our data demonstrate the importance of a unique combination of the H and L chains for the expression of the pathogenic activity of IgG3 cryoglobulins and that a single autoantibody is able to induce different types of glomerular and vascular complications, depending on its production levels and kinetics.
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Yves
authors.initials: Y
authors.lastname: Pastore
authors.forename: Liliane
authors.initials: L
authors.lastname: Fossati-Jimack
authors.forename: Aki
authors.initials: A
authors.lastname: Kuroki
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Thierry
authors.initials: T
authors.lastname: Fulpius
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Robert
authors.initials: R
authors.lastname: Lemoine
authors.forename: Luc
authors.initials: L
authors.lastname: Reininger
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D001167:Arteritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003449:Cryoglobulinemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D009336:Necrosis; D012217:Rheumatoid Factor / Q000235:genetics / Q000276:immunology; D018366:Vasculitis, Leukocytoclastic, Cutaneous / Q000235:genetics / Q000276:immunology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D001323:Autoantibodies; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; C048844:anti-IgG; D012217:Rheumatoid Factor