Nephritogenic potential of anti-DNA antibodies against necrotic nucleosomes

Abstract

Systemic lupus erythematosus is an inflammatory autoimmune syndrome of unknown cause. Kidney disease is a central and serious complication in this syndrome. Deposition of chromatin-containing immune complexes within glomerular membranes is considered a key event in the pathogenesis of lupus nephritis. One set of autoantibodies that participate in these complexes is directed against components of chromatin, particularly against double-stranded DNA (dsDNA). Matzinger's danger model implicates chromatin fragments as both inducers and glomerular targets for nephritogenic anti-dsDNA and anti-nucleosome antibodies. In context of this model, apoptosis, secondary necrosis, and exposure of chromatin fragments may causally trigger autoimmunity and subsequent lupus nephritis. The exposure of glomerular basement membrane-associated extracellular chromatin depends on an observed acquired downregulation of renal DNase1 transcription and loss of nuclease activity preceding development of severe nephritis; this downregulation would result in reduced fragmentation and clearance of chromatin fragments. These fragments bind glomerular basement membrane structures with high affinity. In addition, exposed chromatin fragments contain structures that stimulate the innate immune system through Toll-like receptors and the adaptive immune system to produce affinity-maturated pathogenic anti-chromatin and anti-dsDNA antibodies that are central to the development of lupus nephritis.