Lupus nephritis: enigmas, conflicting models and an emerging concept

Contains fulltext : 125627.pdf (publisher's version ) (Open Access)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

Review: antinucleosome antibodies: a critical reflection on their specificities and diagnostic impact

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Nephritogenic antibodies bind in glomeruli through interaction with exposed chromatin fragments and not with renal cross-reactive antigens.

Contains fulltext : 98144.pdf (publisher's version ) (Closed access

Regulatory and pathogenetic mechanisms of autoantibodies in SLE

Contains fulltext : 96275.pdf (publisher's version ) (Closed access)In the 53 years since the discovery of anti-DNA autoantibodies in lupus [1, 2, 3] , recalcitrant questions have been pondered and possible answers have been debated. The discovery of anti-DNA autoantibodies presented many puzzles: How is immunological tolerance to native B-form DNA broken? What elicits characteristic systemic lupus erythematosus (SLE) autoantibodies? Which of the diverse anti-nuclear reactivities are pathogenic? What is the role of autoantibodies in the clinical presentation of disease? How do genetic predisposition and environmental triggers contribute to SLE? These questions were brought into focus by Professor David Stollar in an introductory presentation to an intense, three-day meeting set among the rugged and inspiring scenery of the Norwegian arctic coastline (the Scientific Program is included as supplemental File 1). Other participants presented and discussed topics directed to understanding the origin and clinico-pathological impact of autoantibodies to chromatin and phospholipid antigens. In the following, several aspects of the workshop are discussed