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 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.

Translational value of animal models of kidney failure

“…The most commonly studied experimental models of lupus nephritis are murine, such as MRL lpr/lpr mice which carry a mutation of the Fas receptor, lupus-prone (NZBxNZW)F1 mice and the chronic graft-vs-host model (Davidson and Aranow, 2010;Grande, 2011;Seredkina et al, 2013). These animals develop proteinuria and kidney failure, but the models have been used mainly to unravel the immune regulation disturbances that lead to autoimmunity.…”

Epigenetics and Systemic Lupus Erythematosus: Unmet Needs

“…Antibody-binding triggers inflammation and eventually induces tissue damage. Another model suggests glomerular deposition of autoantibodies in complex with chromatin, thereby inducing classic immune complexmediated tissue damage [58].…”

“…In fact, TLR7-9 and Clec4e have been found upregulated in BW mice at the same time when chromatin-IgG complex deposition in the glomerular basement membrane (GBM) and loss of DNasI activity are demonstrated [62]. TLR7-9 is involved in the processing of DNA-protein complexes while incomplete clearance and degradation of apoptotic material may transform it into necrotic cell debris which contains SAP130, the ligand for the inflammation-related receptor Clec4e [58]. The signalling triggered by SAP130-Clec4e may promote pro-inflammatory cytokine production and upregulation of metalloproteases that altogether can facilitate the chromatin fragment-IgG complex deposition in both the mesangial matrix and the GBM.…”

Experimental modeling of nucleoprotein disposal disorders in systemic lupus erythematosus

“…Причины активации аутореактивных В-лимфоцитов, отвечающих за выработку таких антител, окончательно не установлены. Согласно наиболее распространенной на данный момент гипотезе, нарушение процессов апоптоза и/или элиминации продуктов распада клеток приводит к значительному повышению содержания дезоксирибонуклеопротеинов и других внутриклеточных молекул во внеклеточном пространстве, что инициирует выработку патогенных аутоантител [3]. Известные факторы риска данного заболевания (генетические, средовые и гормональные) не всегда "вписываются" в существующие концепции патогенеза СКВ [4,5].…”