title: The evolution of crescentic nephritis and alveolar haemorrhage following induction of autoimmunity to glomerular basement membrane in an experimental model of Goodpasture's disease.
abstract: Goodpasture's, or anti-glomerular basement membrane (GBM), disease presents with rapidly progressive glomerulonephritis and lung haemorrhage, and is caused by autoimmunity to the NC1 domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1). This study examines the development of crescentic nephritis and alveolar haemorrhage in a model of Goodpasture's disease, experimental autoimmune glomerulonephritis (EAG), induced in WKY rats by immunization with rat GBM in adjuvant. An increase in circulating anti-GBM antibodies and albuminuria was observed by week 2, which increased further by weeks 3 and 4, while a decrease in creatinine clearance was observed by week 2, which decreased further by weeks 3 and 4. The kidneys of animals with EAG showed linear deposits of IgG on the GBM and a transient glomerular infiltration by CD4+ T cells at week 2. By week 3 there were large deposits of fibrin in Bowman's space, and glomerular infiltration by CD8+ T cells and macrophages, accompanied by focal necrotizing glomerulonephritis with crescent formation. Ultrastructural studies showed glomerular endothelial cell swelling and epithelial cell foot process effacement at week 2. As the lesion progressed, capillary loops became occluded and the mesangium became expanded by mononuclear cells. By week 3 there was detachment of the endothelium from the GBM, and accumulation of fibrin beneath the disrupted endothelial cells and in Bowman's space. Occasional breaks were observed in the continuity of the basement membrane, and cytoplasmic projections from infiltrating mononuclear cells could be seen crossing the capillary wall between the lumen and the crescent. The lungs of animals with EAG showed patchy binding of IgG to the alveolar basement membrane (ABM) at week 2, and infiltration of the interstitium by CD8+ T cells and macrophages by weeks 3 and 4, accompanied by both interstitial and alveolar haemorrhage. Ultrastructural studies showed focal mononuclear cell infiltrates in alveolar walls at week 2. Occasional breaks were observed in the basement membrane and adjacent endothelium by weeks 3 and 4, together with accumulation of surfactant and erythrocytes within the alveolar spaces. This study defines for the first time the relationship between the immunological and pathological events during the evolution of EAG, and provides the basis for further work on the pathogenesis of Goodpasture's disease.
authors.affiliation: Renal Section, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK. john.reynolds@imperial.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.forename: Jill
authors.initials: J
authors.lastname: Moss
authors.forename: Mark A
authors.initials: MA
authors.lastname: Duda
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Karkar
authors.forename: Vamshi
authors.initials: V
authors.lastname: Macherla
authors.forename: Ian
authors.initials: I
authors.lastname: Shore
authors.forename: David J
authors.initials: DJ
authors.lastname: Evans
authors.forename: David F
authors.initials: DF
authors.lastname: Woodrow
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology / Q000473:pathology*; D000906:Antibodies / Q000276:immunology; D001323:Autoantibodies; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology*; D015551:Autoimmunity / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology / Q000473:pathology; D003404:Creatinine / Q000032:analysis; D004195:Disease Models, Animal; D005337:Fibrin / Q000032:analysis; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology*; D006470:Hemorrhage / Q000276:immunology / Q000473:pathology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology / Q000473:pathology*; D008297:Male; D008854:Microscopy, Electron; D009393:Nephritis / Q000276:immunology / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology; D051381:Rats; D011921:Rats, Inbred WKY
chemical_list: D000906:Antibodies; D001323:Autoantibodies; C051951:antiglomerular basement membrane antibody; D005337:Fibrin; D003404:Creatinine