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 autoant...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2013-06-01
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| Series: | Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.2119/molmed.2013.00010 |
| _version_ | 1797752705433731072 |
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| author | Natalya Seredkina Johan van der Vlag Jo Berden Elin Mortensen Ole Petter Rekvig |
| author_facet | Natalya Seredkina Johan van der Vlag Jo Berden Elin Mortensen Ole Petter Rekvig |
| author_sort | Natalya Seredkina |
| collection | DOAJ |
| description | 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 DNasel 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 DNasel 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 DNasel gene and the biological consequences of reduced chromatin fragmentation in nephritic kidneys are discussed. |
| first_indexed | 2024-03-12T17:08:24Z |
| format | Article |
| id | doaj.art-95f37a4639644a489c858aab733e9b9b |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-03-12T17:08:24Z |
| publishDate | 2013-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-95f37a4639644a489c858aab733e9b9b2023-08-06T11:17:37ZengBMCMolecular Medicine1076-15511528-36582013-06-0119116116910.2119/molmed.2013.00010Lupus Nephritis: Enigmas, Conflicting Models and an Emerging ConceptNatalya Seredkina0Johan van der Vlag1Jo Berden2Elin Mortensen3Ole Petter Rekvig4Molecular Pathology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of TromsøNephrology Research Laboratory, Department of Nephrology, Radboud University Nijmegen Medical CentreNephrology Research Laboratory, Department of Nephrology, Radboud University Nijmegen Medical CentreMolecular Pathology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of TromsøMolecular Pathology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of TromsøAbstract 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 DNasel 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 DNasel 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 DNasel gene and the biological consequences of reduced chromatin fragmentation in nephritic kidneys are discussed.https://doi.org/10.2119/molmed.2013.00010Lupus NephritisNephritic KidneysDNaselChromatin Fragmentationanti-dsDNA Antibodies |
| spellingShingle | Natalya Seredkina Johan van der Vlag Jo Berden Elin Mortensen Ole Petter Rekvig Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept Molecular Medicine Lupus Nephritis Nephritic Kidneys DNasel Chromatin Fragmentation anti-dsDNA Antibodies |
| title | Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept |
| title_full | Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept |
| title_fullStr | Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept |
| title_full_unstemmed | Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept |
| title_short | Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept |
| title_sort | lupus nephritis enigmas conflicting models and an emerging concept |
| topic | Lupus Nephritis Nephritic Kidneys DNasel Chromatin Fragmentation anti-dsDNA Antibodies |
| url | https://doi.org/10.2119/molmed.2013.00010 |
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