Chromatin as a target antigen in human and murine lupus nephritis

Abstract

The present review focuses on pathogenic molecular and transcriptional events in patients with lupus nephritis. These factors are renal DNaseI, exposed chromatin fragments and the corresponding chromatin-reactive autoantibodies. Lupus nephritis is the most serious complication in human systemic lupus erythematosus, and is characterised by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes. The latter deposition defines end-stage disease. This event is stringently linked to a renal-restricted shutdown of expression of the DNaseI gene, as determined by loss of DNaseI mRNA level and DNaseI enzyme activity. The major aim of the present review is to generate new therapeutic strategies based on new insight into the disease pathogenesis.

Evaluation of all non‐synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I‐like 3 as a functional SNP potentially implicated in autoimmunity

“…It has been reported that, in comparison with healthy subjects, levels of serum DNase I activity are reduced in patients with SLE [36][37][38][39]. Recently, Rekvig and colleagues have demonstrated that in lupus nephritis, which is the most serious complication of SLE, downregulation of renal DNase I results in reduced chromatin fragmentation and deposition of extracellular chromatin-IgG complexes in the glomerular basement membranes in subjects that produce IgG antibodies against chromatin [8,40]. On the other hand, another member of the DNase I family, DNase 1L3, is present in serum in addition to DNase I, and it was assumed that these DNases may be concerned with each other during DNA degradation, providing effective clearance after exposure or release from dying cells [2,16,41].…”

“…DNase 1L3 is a member of the DNase I family, which also includes DNase I-like 1/DNase X/DNase Xib and DNase I-like 2, whose nucleotide and amino acid sequences resemble those of the originally characterized DNase I [4,5]. In this context, triggered by nuclear antigens, the clearance of cell debris resulting from cell death through apoptosis and/or necrosis might be primarily involved in the prevention of autoimmune conditions such as systemic lupus erythematosus (SLE); DNase I has been especially highlighted for its possible involvement in the pathogenesis of autoimmune diseases [6][7][8]. Yasutomo et al [9] and Dittmar et al [10] have identified novel nonsense (p.Lys5Ter) and missense (p.Val111Met) mutations that abolished and reduced DNase I activity, respectively, in patients with autoimmune diseases [11].…”

C-reactive protein, immunoglobulin G and complement co-localize in renal immune deposits of proliferative lupus nephritis

“…CRP binds extracellular glomerular matrix proteins such as laminin and fibronectin and could thereby constitute a target for anti-CRP antibodies [51,52]. It has further been shown in vitro that CRP and anti-CRP antibodies assemble on the surfaces of cell remnants and induce a pro-inflammatory response when exposed to macrophages [53].…”

Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus

“…9 Other biomarkers may reflect specific organ involvements, most notably lupus nephritis which is often mirrored by raised levels of autoantibodies against double-stranded (ds) DNA, nucleosomes and/or complement protein (C) 1q. 2,5,10 The Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI) 11 covers 12 organ systems and measures accumulated organ damage that has occurred since the onset of SLE. SDI is scored regardless of whether the damage can be attributed to SLE or to other causes.…”

“…1 Autoantibody-binding to tissueexposed autoantigens and/or insufficient receptor-mediated clearance of circulating immune complexes via the reticuloendothelial system are explanations to extrahepatic immune complex formation/deposition. [2][3][4] Although autoantibodies, complement proteins, blood cell counts and erythrocyte sedimentation rate (ESR) can be helpful markers of diagnosis, prognosis, and/or degree of ongoing inflammation, distinction of disease activity from irreversible organ damage remains a challenge. 5 C-reactive protein (CRP) is usually a reliable marker of systemic inflammation, but this is not the case in SLE 6,7 or viral infections 8 probably due to interferon alpha (IFN dependent inhibition of hepatic CRP production.…”