Significance of enzyme linked immunosorbent assay (ELISA) for antibodies to double stranded and single stranded DNA in patients with lupus nephritis: correlation with severity of renal histology.

Okamura, Mitsu; Kanayama, Yoshio; Amastu, K; Negoro, Nobuo; Kohda, S; Takeda, Tadanao; Inoue, Takatoshi

doi:10.1136/ard.52.1.14

Cited by 139 publications

(85 citation statements)

References 22 publications

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“…However, it should be mentioned that the correlation was not perfect, since 5 of the 10 patients with the highest antichromatin reactivity did not display proteinuria. Protein in the urine is not a sensitive indication of all forms of renal disease because glomerular damage as judged by microscopic examination of biopsies was not well correlated to proteinuria (47). Renal biopsies were not performed in the present study.…”

Section: Resultsmentioning

confidence: 76%

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The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus.

Burlingame¹,

Ml²,

Starkebaum³

et al. 1994

J. Clin. Invest.

289

177

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To gain insight into the mechanisms of autoantibody induction, sera from 40 patients with systemic lupus erythematosus (SLE) were tested by ELISAs for antibody binding to denatured individual histones, native histone-histone complexes, histone-DNA subnucleosome complexes, three forms of chromatin, and DNA. Whole chromatin was the most reactive substrate, with 88% of the patients positive. By chi-square analysis, only the presence of anti-(H2A-H2B), anti-[(H2A-H2B) -DNA], and antichromatin were correlated with kidney disease measured by proteinuria > 0.5 g/d. SLE patients could be divided into two groups based on their antibody-binding pattern to the above substrates. Antibodies from about half of the patients reacted with chromatin and the (H2A-H2B) -DNA subnucleosome complex but displayed very low or no reactivity with native DNA or the (H3-H4)2-DNA subnucleosome complex. An additional third of the patients had antibody reactivity to chromatin, as well as to both subnucleosome structures and DNA. Strikingly, all sera that bound to any of the components of chromatin also bound to whole chromatin, and adsorption with chromatin removed 85-100% of reactivity to (H2A-H2B)-DNA, (H3-H4)2-DNA, and native DNA. Individual sera often bound to several different epitopes on chromatin, with some epitopes requiring quaternary protein-DNA interactions. These results are consistent with chromatin being a potent immunogenic stimulus in SLE. Taken together with previous studies, we suggest that antibody activity to the (H2A-H2B) -DNA component signals the initial breakdown of immune tolerance whereas responses to (H3-H4)2-DNA and native DNA reflect subsequent global loss of tolerance to chromatin. (J. Clin. Invest. 1994. 94:184-192.)

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Section: Resultsmentioning

confidence: 76%

“…In some studies, the presence of anti-nDNA has been correlated with the severity of disease and the presence of lupus nephritis (25,46,47), especially if changes in antibody levels over time are considered (48,49). In other studies no significant correlation between disease and anti-nDNA was found (50,51 ).…”

Section: Resultsmentioning

confidence: 99%

The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus.

Burlingame¹,

Ml²,

Starkebaum³

et al. 1994

J. Clin. Invest.

289

177

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“…Autoantibodies are thought to have a primary role in the pathogenesis of SLE. Levels of circulating autoantibodies correlate with disease severity in both SLE patients and MRL-Fas lpr mice, with IgG1 and IgG2 being the predominant subclasses found (33,34). These autoantibodies are thought to play a causative role in the occurrence of disease given that a rise in circulating autoantibodies is seen in SLE patients before renal relapses and before any disease is evident in lupus-prone mice (31,35).…”

Section: Discussionmentioning

confidence: 99%

IL-21 Has a Pathogenic Role in a Lupus-Prone Mouse Model and Its Blockade with IL-21R.Fc Reduces Disease Progression

Herber

Brown²,

Liang

et al. 2007

The Journal of Immunology

270

235

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Systemic lupus erythematosus is a complex autoimmune disease characterized by dysregulated interactions between autoreactive T and B lymphocytes and the development of anti-nuclear Abs. The recently described pleiotropic cytokine IL-21 has been shown to regulate B cell differentiation and function. IL-21 is produced by activated T lymphocytes and its interactions with IL-21R are required for isotype switching and differentiation of B cells into Ab-secreting cells. In this report, we studied the impact of blocking IL-21 on disease in the lupus-prone MRL-Faslpr mouse model. Mice treated for 10 wk with IL-21R.Fc fusion protein had reduced proteinuria, fewer IgG glomerular deposits, no glomerular basement membrane thickening, reduced levels of circulating dsDNA autoantibodies and total sera IgG1 and IgG2a, and reduced skin lesions and lymphadenopathy, compared with control mice. Also, treatment with IL-21R.Fc resulted in a reduced number of splenic T lymphocytes and altered splenic B lymphocyte ex vivo function. Our data show for the first time that IL-21 has a pathogenic role in the MRL-Faslpr lupus model by impacting B cell function and regulating the production of pathogenic autoantibodies. From a clinical standpoint, these results suggest that blocking IL-21 in systemic lupus erythematosus patients may represent a promising novel therapeutic approach.

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“…The pathogenetic significance of anti-DNA antibodies has been implicated by their correlation with disease activity (29 -31) and their deposition at sites manifesting histopathologic changes (32)(33)(34)(35). It would be of interest to spec- Our findings demonstrate the binding of anti-DNA antibodies to the HMC cell surface and intracellularly, while no staining was observed within the extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

Mesangial Cell-Binding Anti-DNA Antibodies in Patients with Systemic Lupus Erythematosus

Chan¹,

Leung²,

Ho³

et al. 2002

Journal of the American Society of Nephrology

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ABSTRACT. The mechanisms by which anti-DNA antibodies contribute to the pathogenesis of lupus nephritis (LN) remain to be elucidated. This study investigates the binding of polyclonal anti-DNA immunoglobulins from patients with systemic lupus erythematosus (SLE) to human mesangial cells (HMC) in vitro. Testing of cross-sectional serum samples from 280 LN patients (108 during active disease; 172 during remission), 35 SLE patients without renal involvement, 72 patients with non-lupus primary glomerular diseases, and 37 healthy subjects with a cellular enzyme-linked immunosorbent assay showed significant IgG mesangial cell-binding activity in patients with SLE, particularly those with active LN (P < 0.0001). Significant HMC-binding activity was demonstrated in 83.9%, 42.8%, and 47.1% of patients with active LN, inactive LN, and non-renal SLE, respectively. This was predominantly attributed to binding by anti-DNA antibodies, and immune complex binding accounted for 4.6%, 3.5%, and 2.8% of seropositive samples in the respective groups. Longitudinal studies in 27 LN patients demonstrated correlation between serial levels of anti-DNA antibodies, serum HMC-binding activity, and disease activity in 18 patients (66.7%). Affinity-purified polyclonal IgG anti-DNA antibodies from sera with HMC-binding activity showed significant binding to cultured HMC, and to a lesser extent glomerular and proximal tubular epithelial cells and human umbilical vein endothelial cells, but not tumor cell lines, peritoneal mesothelial cells, bronchial epithelial cells, or fibroblasts. The binding of anti-DNA antibodies to HMC was increased 1.47-fold (P = 0.0059) after the removal of Ig-associated DNA by DNase treatment, but it was unaffected by DNase treatment of HMC membrane. Controlled trypsinization of membrane proteins in HMC resulted in a 1.26-fold (P = 0.0025) increase in their binding by anti-DNA antibodies. In conclusion, subsets of anti-DNA antibodies from patients with SLE are capable of binding to HMC. The association of such binding with renal involvement and disease activity and its modulation by DNA concentration suggest that Ig binding to HMC can be a potential marker for disease activity in selected patients and that the binding of anti-DNA antibodies to HMC may be a pathogenetic mechanism in LN.

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Significance of enzyme linked immunosorbent assay (ELISA) for antibodies to double stranded and single stranded DNA in patients with lupus nephritis: correlation with severity of renal histology.

Cited by 139 publications

References 22 publications

The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus.

The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus.

IL-21 Has a Pathogenic Role in a Lupus-Prone Mouse Model and Its Blockade with IL-21R.Fc Reduces Disease Progression

Mesangial Cell-Binding Anti-DNA Antibodies in Patients with Systemic Lupus Erythematosus

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