title: Lupus nephritis: enigmas, conflicting models and an emerging concept.
abstract: Autoantibodies to components of chromatin, which include double-stranded DNA (dsDNA), histones and nucleosomes, are central in the pathogenesis of lupus nephritis. How anti-chromatin autoantibodies exert their nephritogenic activity, however, is controversial. One model assumes that autoantibodies initiate inflammation when they cross-react with intrinsic glomerular structures such as components of membranes, matrices or exposed nonchromatin ligands released from cells. Another model suggests glomerular deposition of autoantibodies in complex with chromatin, thereby inducing classic immune complex-mediated tissue damage. Recent data suggest acquired error of renal chromatin degradation due to the loss of renal DNaseI enzyme activity is an important contributing factor to the development of lupus nephritis in lupus-prone (NZBxNZW)F1 mice and in patients with lupus nephritis. Down-regulation of DNaseI expression results in reduced chromatin fragmentation and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals who produce IgG anti-chromatin autoantibodies. The main focus of the present review is to discuss whether exposed chromatin fragments in glomeruli are targeted by potentially nephritogenic anti-dsDNA autoantibodies or if the nephritogenic activity of these autoantibodies is explained by cross-reaction with intrinsic glomerular constituents or if both models coexist in diseased kidneys. In addition, the role of silencing of the renal DNaseI gene and the biological consequences of reduced chromatin fragmentation in nephritic kidneys are discussed.
authors.affiliation: Molecular Pathology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Natalya
authors.initials: N
authors.lastname: Seredkina
authors.forename: Johan
authors.initials: J
authors.lastname: Van Der Vlag
authors.forename: Jo
authors.initials: J
authors.lastname: Berden
authors.forename: Elin
authors.initials: E
authors.lastname: Mortensen
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Rekvig
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D002843:Chromatin / Q000276:immunology; D003850:Deoxyribonuclease I / Q000235:genetics; D006801:Humans; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D002843:Chromatin; D003850:Deoxyribonuclease I