Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression (original) (raw)
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Acta reumatologica portuguesa, 2015
Objetives: Systemic lupus erythematosus is a multifactorial autoimmune disease and the glomerulonephritis is one of the most severe complications, which leads to severe persistent proteinuria, chronic renal failure, and end-stage renal disease. This multicenter study investigated the genetic associations of a non-synonymous single-nucleotide polymorphism in DNase I with the risk of lupus and its influence on development of nephropathy in an Argentinean population. Using the Polymerase chain reaction restriction fragment length polymorphism method, the Q222R (+2373A→G; Gln244Arg) DNase I polymorphism was studied in 156 systemic lupus erythematosus patients and 170 healthy controls. Although no significant association between Q222R polymorphism and the risk of systemic lupus erythematosus was found, the presence of the A allele was associated with an increased risk for the development of nephropathy (p=0.019, Odd Ratio=2.196, 95 % confidence interval [1.135-4.247]) and a worse disease...
Features of systemic lupus erythematosus in Dnase1-deficient mice
Nature genetics, 2000
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that affects over one million people in the United States. SLE is characterized by the presence of anti-nuclear antibodies (ANA) directed against naked DNA and entire nucleosomes. It is thought that the resulting immune complexes accumulate in vessel walls, glomeruli and joints and cause a hypersensitivity reaction type III, which manifests as glomerulonephritis, arthritis and general vasculitis. The aetiology of SLE is unknown, but several studies suggest that increased liberation or disturbed clearance of nuclear DNA-protein complexes after cell death may initiate and propagate the disease. Consequently, Dnase1, which is the major nuclease present in serum, urine and secreta, may be responsible for the removal of DNA from nuclear antigens at sites of high cell turnover and thus for the prevention of SLE (refs 7-11). To test this hypothesis, we have generated Dnase1-deficient mice by gene targeting. We report...
Clinical Chemistry and Laboratory Medicine, 2000
Background : Decreased activity of serum desoxyribonuclease I (DNase I) in systemic lupus erythematosus (SLE) has been reported, but its role as a biomarker in SLE is still unelucidated. Methods : Seventy-seven SLE patients (aged 39.6 ± 13.1 years) were studied for serum DNase I activity, levels of antinuclear (ANA), anti-dsDNA [high-avidity ELISA, conventional ELISA and indirect immunofluorescence (IIF)], anti-nucleosome, anti-histone antibodies, complement components C3 and C4. SLE disease activity was evaluated by disease activity index (SLEDAI-2K). Thirty-five patients were serologically and clinically followed for 3 -12 months (mean 5.6 ± 2.8). Thirty-seven healthy blood donors were the control group. Results : DNase I activity in SLE patients was lower than in healthy controls (p < 0.01). DNase I activity was in positive correlation with SLEDAI-2K (p < 0.01), levels of ANA, anti-dsDNA, anti-nucleosome and anti-histone antibodies (p < 0.01) and in negative correlation with C3 concentration (p < 0.05). The highest correlation was found between DNase I activity and anti-dsDNA concentrations determined by high-avidity ELISA (r = 0.624), followed by IIF (r = 0.541) and conventional ELISA (r = 0.405). In the follow-up study, DNase I activity also correlated with SLEDAI-2K (p < 0.01). SLE patients with low DNase I activity more frequently had SLE-specific cutaneous lesions (p < 0.05). Conclusions : Monitoring of DNase I activity simultaneously with SLEDAI-2K might be a useful tool in the followup of SLE. An increase of DNase I activity characterized relapse in most SLE patients, although it did not reach the levels of healthy individuals. A decrease of DNase I activity in SLE flare-ups might be a functional biomarker of a subset of patients with specific dysfunction of apoptotic chromatin degradation.
Circulating DNA and lupus nephritis
Kidney International, 1988
Historical perspective The association between antibodies directed against nuclear antigens and systemic lupus erythematosus (SLE) has been well established since the discovery 40 years ago of the "LE cell" [1]. Antibodies directed against deoxyribonucleic acid (DNA, anti-DNA Ab) were later characterized in sera from lupus patients [2-5] as well as from (NZBxNZW) mice [6, 7] which spontaneously develop an immune complex type of glomerulonephritis [8, 9]. Granular deposits of immunoglobulin and complement were found in glomeruli of kidneys from lupus patients with nephritis [10, 11] and from NZBxNZW mice [12]. Anti-DNA Ab were rapidly recognized as participants in pathogenic mechanisms leading to the kidney disease seen in lupus patients. However, several studies have shown they were not, by themselves, pathogenic in vivo [13, 14] or cytotoxic to tissue culture cells in vitro [15, 16]. In addition, clinical as well as experimental studies strongly suggested that anti-DNA Ab played their pathogenic role through the formation of DNAanti-DNA immune complexes, and that these complexes represented the main pathogenic immune complex system at work in the development of lupus nephritis [17, 18]. Between 1950 and 1960, studies done on the serum sickness model in rabbits [19, 20] provided evidence that glomerular injury might result from the deposition in glomeruli of immune complexes formed in the circulation [211, supplanting the most widely accepted view of the time that, as in the Arthus reaction, the nephritogenic antigens fix in tissue before reacting with antibodies to produce disease [22]. In the absence of any other well studied experimental model, most cases of human immune complex glomerulonephritis were thought to be induced by the deposition of circulating immune complexes. In lupus patients, as well as in (NZBxNZW) mice, it was postulated that circulating DNA-anti-DNA immune complexes in antigen excess were responsible for the development of glomerular lesions. Then came the time of contradictory results. As soon as suitable assays became available [23, 24] circulating immune complexes were frequently found in sera from lupus patients [24, 25], but attempts to identify DNA-anti-DNA were variable and confusing. It was suggested that, if present, they represented at most a few percent of the total pool of immune complexes which circulated in these patients [26]. At the same time much work was devoted to both the antibody and the antigenic components of DNA-anti-DNA complexes. A great deal was learned about the physicochemical and immunologic properties of anti-DNA Ab, in part with the help of monoclonal antibodies [27, 28]. On the other hand, data on extracellular DNA appeared contradictory. First, mainly for technical rea
Arthritis Research & Therapy, 2009
Introduction Glomerulonephritis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Deposition of autoantibodies in the glomeruli plays a key role in the development of lupus nephritis (LN). Different groups have proposed that either anti-nucleosome antibodies or antibodies that bind the intrinsic renal antigen, α-actinin, are central to the pathogenesis of LN. These theories have been based mainly on cross-sectional studies in patients and on experiments in animal models. No previous longitudinal studies have compared the relationships between levels of these antibodies and markers of renal function. We assessed how well anti-α-actinin, anti-nucleosome and anti-double-stranded DNA (anti-dsDNA) antibodies reflected renal outcome measures in patients with new-onset LN followed for up to 2 years.
Journal of Experimental Medicine, 2004
In lupus-prone NZM2328 mice, a locus Cgnz1 on chromosome 1 was linked to chronic glomerulonephritis, severe proteinuria, and early mortality in females. A locus Adnz1 on chromosome 4 was linked to antinuclear antibody (ANA) and anti-double stranded DNA (dsDNA) antibody (Ab) production. In this investigation, two congenic strains, NZM2328.C57L/Jc1 (NZM.C57Lc1) and NZM2328.C57L/Jc4 (NZM.C57Lc4), were generated by replacing the respective genetic intervals containing either Cgnz1 or Adnz1 with those from C57L/J, a nonlupus-prone strain. The NZM.C57Lc1 females had markedly reduced incidence of chronic glomerulonephritis and severe proteinuria. NZM.C57Lc4 females had chronic glomerulonephritis and severe proteinuria without circulating ANA, anti-dsDNA, and antinucleosome Ab. These data confirm the linkage analysis. Unexpectedly, NZM.C57Lc1 females had little anti-dsDNA and related Ab, suggesting the presence of a second locus Adnz2 on chromosome 1. The diseased NZM.C57Lc4 kidneys had immune complexes by immunofluorescence and electron microscopy. The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non-anti-dsDNA nephritogenic Ab. Thus, breaking tolerance to dsDNA and chromatin is not required for the pathogenesis of lupus nephritis. These results reaffirm that anti-dsDNA and related Ab production and chronic glomerulonephritis are under independent genetic control. These findings have significant implications in the pathogenesis of systemic lupus erythematosus.
Serum Renalase Levels Correlate with Disease Activity in Lupus Nephritis
PloS one, 2015
Lupus nephritis (LN) is among the most serious complications of systemic lupus erythematosus (SLE), which causes significant morbidity and mortality. Renalase is a novel, kidney-secreted cytokine-like protein that promotes cell survival. Here, we aimed to investigate the relationship of serum renalase levels with LN and its role in the disease progression of LN. For this cross-sectional study, 67 LN patients and 35 healthy controls were enrolled. Seventeen active LN patients who received standard therapies were followed up for six months. Disease activity was determined by the SLE Disease Activity-2000 (SLEDAI-2K) scoring system and serum renalase amounts were determined by ELISA. Predictive value of renalase for disease activity was assessed. Furthermore, the expression of renalase in the kidneys of patients and macrophage infiltration was assessed by immunohistochemistry. Serum renalase amounts were significantly higher in LN patients than in healthy controls. Moreover, patients w...
Seminars in nephrology, 2015
Kidney disease, or lupus nephritis, is the organ involvement that is most closely associated with specific autoantibodies in patients with SLE. The concept of anti-DNA antibodies being instrumental in the pathogenesis of lupus nephritis emerged ~50 years ago, and has been a topic of debate ever since. This article focuses on the description of the renal sub-cellular targets of nephritogenic autoantibodies and offers a counter-point opinion to the article by Pedersen et al. In addition, we provide an overview of some of the mechanisms by which anti-DNA antibodies bind to their renal targets and the pathogenic relevance to clinical nephritis.