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Ole Petter Rekvig - One of the best experts on this subject based on the ideXlab platform.
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nephritogenic Antibodies bind in glomeruli through interaction with exposed chromatin fragments and not with renal cross reactive antigens
2011Co-Authors: Janne Erikke Mjelle, Ole Petter Rekvig, J Van Der Vlag, Kristin A FentonAbstract:Cross-reactivity of anti-double stranded DNA (Anti-dsDNA) Antibodies with glomerular antigens has been postulated as a key factor in the development of lupus nephritis. Because no direct proof has been presented on Anti-dsDNA Antibodies binding in vivo to glomerular structures, we have analysed the binding of potentially nephritogenic Anti-dsDNA Antibodies to α-actinin and laminin. By enzyme-linked immunosorbent assay and surface plasmon resonance (SPR) analyses, we demonstrate that monoclonal Antibodies (mAbs) bind both double-stranded DNA and α-actinin at high affinity. However, when added to nephritic kidney sections they did not bind to such structures, but rather to nucleosome-containing structures within the mesangial matrix or the glomerular basement membranes (GBMs). Nucleosomes, anti-nuclear Antibodies and complexes of them were tested for their binding to glomerular components such as agrin, perlecan and laminin using SPR analysis. Nucleosomes bound to laminin, marginally to agrin, but not to pe...
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Alpha-actinin-binding Antibodies in relation to systemic lupus erythematosus and lupus nephritis
2006Co-Authors: Andrea Becker-merok, Kaia Haugbro, Ole Petter Rekvig, Manar Kalaaji, Cathrin Nikolaisen, Kirsten Nilsen, Johannes C NossentAbstract:This study investigated the overall clinical impact of anti-α-actinin Antibodies in patients with pre-selected autoimmune diseases and in a random group of anti-nuclear antibody (ANA)-positive individuals. The relation of anti-α-actinin Antibodies with lupus nephritis and anti-double-stranded DNA (Anti-dsDNA) Antibodies represented a particular focus for the study. Using a cross-sectional design, the presence of Antibodies to α-actinin was studied in selected groups, classified according to the relevant American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE) ( n = 99), rheumatoid arthritis (RA) ( n = 68), Wegener's granulomatosis (WG) ( n = 85), and fibromyalgia (FM) ( n = 29), and in a random group of ANA-positive individuals ( n = 142). Renal disease was defined as (increased) proteinuria with haematuria or presence of cellular casts. Sera from SLE, RA, and Sjøgren's syndrome (SS) patients had significantly higher levels of anti-α-actinin Antibodies than the other patient groups. Using the geometric mean (± 2 standard deviations) in FM patients as the upper cutoff, 20% of SLE patients, 12% of RA patients, 4% of SS patients, and none of the WG patients were positive for anti-α-actinin Antibodies. Within the SLE cohort, anti-α-actinin antibody levels were higher in patients with renal flares ( p = 0.02) and correlated independently with Anti-dsDNA antibody levels by enzyme-linked immunosorbent assay ( p < 0.007) but not with other disease features. In the random ANA group, 14 individuals had anti-α-actinin Antibodies. Of these, 36% had SLE, while 64% suffered from other, mostly autoimmune, disorders. Antibodies binding to α-actinin were detected in 20% of SLE patients but were not specific for SLE. They correlate with Anti-dsDNA antibody levels, implying in vitro cross-reactivity of Anti-dsDNA Antibodies, which may explain the observed association with renal disease in SLE.
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nephritogenic lupus Antibodies recognize glomerular basement membrane associated chromatin fragments released from apoptotic intraglomerular cells
2006Co-Authors: Manar Kalaaji, Elin Mortensen, L Jorgensen, Randi Olsen, Ole Petter RekvigAbstract:Antibodies to dsDNA represent a classification criterion for systemic lupus erythematosus. Subpopulations of these Antibodies are involved in lupus nephritis. No known marker separates nephritogenic from non-nephritogenic Anti-dsDNA Antibodies. It is not clear whether specificity for glomerular target antigens or intrinsic antibody-affinity for dsDNA or nucleosomes is a critical parameter. Furthermore, it is still controversial whether glomerular target antigen(s) is constituted by nucleosomes or by non-nucleosomal glomerular structures. Previously, we have demonstrated that Antibodies eluted from murine nephritic kidneys recognize nucleosomes, but not other glomerular antigens. In this study, we determined the structures that bind nephritogenic autoAntibodies in vivo by transmission electron microscopy, immune electron microscopy, and colocalization immune electron microscopy using experimental Antibodies to dsDNA, to histones and transcription factors, or to laminin. The data obtained are consistent and point at glomerular basement membrane-associated nucleosomes as target structures for the nephritogenic autoAntibodies. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling or caspase-3 assays demonstrate that lupus nephritis is linked to intraglomerular cell apoptosis. The data suggest that nucleosomes are released by apoptosis and associate with glomerulus basement membranes, which may then be targeted by pathogenic anti-nucleosome Antibodies. Thus, apoptotic nucleosomes may represent both inducer and target structures for nephritogenic autoAntibodies in systemic lupus erythematosus.
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critical comparative analyses of anti α actinin and glomerulus bound Antibodies in human and murine lupus nephritis
2006Co-Authors: Manar Kalaaji, Janne Erikke Mjelle, Gunnar Sturfelt, Hans Nossent, Ole Petter RekvigAbstract:Objective. Although anti-double-stranded DNA (Anti-dsDNA) Antibodies are important in lupus nephritis, the question regarding which glomerular structures (a-actinin, nucleosomes, or others) are recognized by nephritogenic Anti-dsDNA Antibodies is still controversial. In this study, we determined which glomerular structures are recognized by monoclonal and in vivo-bound nephritogenic Antibodies. Methods. Western blotting was used to analyze the ability of nephritogenic Anti-dsDNA Antibodies to recognize glomerular and nucleosomal structures. Sera from patients with lupus nephritis, sera from random antinuclear antibody-positive patients, and paired Antibodies from sera and kidney eluates from nephritic (NZB X NZW)F-1 mice were analyzed for activity against proteins identified by monoclonal nephritogenic Antibodies, and against a-actinin, dsDNA, nucleosomes, histone H1, heparan sulfate, DNase I, and type IV collagen. Immunoelectron microscopy was used to determine the glomerular localization of a-actinin and in vivo-bound autoAntibodies in nephritic (NZB X NZW)F-1 mouse kidneys. Results. Anti-alpha-actinin Antibodies were observed in human and murine lupus nephritis sera and in sera from patients without systemic lupus erythematosus and were not detected in kidney eluates from nephritic mice. Antibodies to dsDNA and histone H1 were detected in all eluates. Western blot analyses revealed that nephritogenic Anti-dsDNA Antibodies recognized a 32-kd band, identified as histone H1. Competitive enzyme-linked immunosorbent assay demonstrated that nephritogenic monoclonal Antibodies, and dominant Antibodies eluted from nephritic kidneys, cross-reacted with dsDNA and H1. This cross-reactive anti-H1 specificity was largely absent in sera from those mice. Immunoelectron microscopic analysis of nephritic (NZB X NZW)F-1 mouse kidneys revealed that Antibodies eluted from kidneys, but not anti-alpha-actinin Antibodies, bound to distinct nephritis-associated electron-dense structures linked to glomerular basement membranes. Conclusion. Cross-reactive Anti-dsDNA/anti-histone H1 Antibodies, but not anti-alpha-actinin Antibodies, are central among those deposited in nephritic glomeruli. (Less)
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anti dsdna Antibodies and disease classification in antinuclear antibody positive patients the role of analytical diversity
2004Co-Authors: Kaia Haugbro, Johannes C Nossent, T W Winkler, Yngve Figenschau, Ole Petter RekvigAbstract:Background: The presence of "anti-DNA Antibodies in abnormal titres" is a well established criterion for SLE classification, but there is no agreement on the performance of this test. Objective: To study the correlation between clinical findings and five different solid and solution phase anti-DNA antibody assays. Methods: 158 consecutively collected ANA positive sera were studied in a double blind fashion. Anti-DNA Antibodies were determined by different solid phase assays (ssDNA-, dsDNA- specific ELISA, EliA Anti-dsDNA assay, Crithidia luciliae assay), and by an experimental solution phase anti-DNA assay using biotinylated pUC18 plasmid, human, calf thymus, and E coli DNA. Antibody affinity was determined by surface plasmon resonance. Clinical data were obtained independently of the laboratory analyses and later related to the Anti-dsDNA findings. Results: Anti-dsDNA Antibodies were most frequently detected by ELISA, but were not specific for SLE as they were present in up to 30% of other disease groups. Those detected by the Crithidia luciliae assay were predictive for SLE, while Antibodies binding in solution phase ELISA using the pUC18 correlated strongly with the Crithidia luciliae assay. Surface plasmon resonance analysis showed that antibody binding to pUC18 was not due to higher relative affinity for dsDNA in general, but apparently to specificity for that plasmid DNA. Serum samples from three patients with lupus nephritis were positive in both pUC18 solution phase and Crithidia luciliae assays. Conclusions: Assay principle selection is decisive for the detection of clinically significant anti-DNA Antibodies. Revision of the anti-DNA antibody criterion in the SLE classification may be needed.
John Nerges - One of the best experts on this subject based on the ideXlab platform.
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safety tolerability and lack of antibody responses after administration of a pfcsp dna malaria vaccine via needle or needle free jet injection and comparison of intramuscular and combination intramuscular intradermal routes
2002Co-Authors: Judith E Epstein, Yupin Charoenvit, Ruobing Wang, Edward J Gorak, Nicole Freydberg, Oluwatoyin Osinowo, Thomas L Richie, Erin L Stoltz, Fernando Trespalacios, John NergesAbstract:Introduction of a new vaccine requires choosing a delivery system that provides safe administration and the desired level of immunogenicity. The safety, tolerability, and immunogenicity of three monthly 2.5-mg doses of a PfCSP DNA vaccine were evaluated in healthy volunteers as administered intramuscularly (IM) by needle, IM by jet injection (Biojector®) or IM/intradermally (ID) by jet injection. Vaccine administration was well-tolerated. Adverse events were primarily mild and limited to the site of injection (98%). Jet injections (either IM or ID) were associated with approximately twice as many adverse events per immunization as needle IM, but nevertheless were strongly and consistently preferred in opinion polls taken during the study. No volunteers had clinically significant biochemical or hematologic changes or detectable Anti-dsDNA Antibodies. In conclusion, the injection of Plasmodium falciparum circumsporozoite (PfCSP) DNA vaccine appeared to be safe and well-tolerated when administered by any of ...
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safety tolerability and lack of antibody responses after administration of a pfcsp dna malaria vaccine via needle or needle free jet injection and comparison of intramuscular and combination intramuscular intradermal routes
2002Co-Authors: Judith E Epstein, Yupin Charoenvit, Ruobing Wang, Edward J Gorak, Nicole Freydberg, Oluwatoyin Osinowo, Thomas L Richie, Erin L Stoltz, Fernando Trespalacios, John NergesAbstract:Introduction of a new vaccine requires choosing a delivery system that provides safe administration and the desired level of immunogenicity. The safety, tolerability, and immunogenicity of three monthly 2.5-mg doses of a PfCSP DNA vaccine were evaluated in healthy volunteers as administered intramuscularly (IM) by needle, IM by jet injection (Biojector or IM/intradermally (ID) by jet injection. Vaccine administration was well-tolerated. Adverse events were primarily mild and limited to the site of injection (98%). Jet injections (either IM or ID) were associated with approximately twice as many adverse events per immunization as needle IM, but nevertheless were strongly and consistently preferred in opinion polls taken during the study. No volunteers had clinically significant biochemical or hematologic changes or detectable Anti-dsDNA Antibodies. In conclusion, the injection of Plasmodium falciparum circumsporozoite (PfCSP) DNA vaccine appeared to be safe and well-tolerated when administered by any of the three modes of delivery. However, despite improved antibody responses following both jet injection and ID delivery in animal models, no Antibodies could be detected in volunteers by immunofluorescence antibody test (IFAT) or enzyme-linked immunosorbent assay (ELISA) after DNA vaccination.
Judith E Epstein - One of the best experts on this subject based on the ideXlab platform.
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safety tolerability and lack of antibody responses after administration of a pfcsp dna malaria vaccine via needle or needle free jet injection and comparison of intramuscular and combination intramuscular intradermal routes
2002Co-Authors: Judith E Epstein, Yupin Charoenvit, Ruobing Wang, Edward J Gorak, Nicole Freydberg, Oluwatoyin Osinowo, Thomas L Richie, Erin L Stoltz, Fernando Trespalacios, John NergesAbstract:Introduction of a new vaccine requires choosing a delivery system that provides safe administration and the desired level of immunogenicity. The safety, tolerability, and immunogenicity of three monthly 2.5-mg doses of a PfCSP DNA vaccine were evaluated in healthy volunteers as administered intramuscularly (IM) by needle, IM by jet injection (Biojector or IM/intradermally (ID) by jet injection. Vaccine administration was well-tolerated. Adverse events were primarily mild and limited to the site of injection (98%). Jet injections (either IM or ID) were associated with approximately twice as many adverse events per immunization as needle IM, but nevertheless were strongly and consistently preferred in opinion polls taken during the study. No volunteers had clinically significant biochemical or hematologic changes or detectable Anti-dsDNA Antibodies. In conclusion, the injection of Plasmodium falciparum circumsporozoite (PfCSP) DNA vaccine appeared to be safe and well-tolerated when administered by any of the three modes of delivery. However, despite improved antibody responses following both jet injection and ID delivery in animal models, no Antibodies could be detected in volunteers by immunofluorescence antibody test (IFAT) or enzyme-linked immunosorbent assay (ELISA) after DNA vaccination.
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safety tolerability and lack of antibody responses after administration of a pfcsp dna malaria vaccine via needle or needle free jet injection and comparison of intramuscular and combination intramuscular intradermal routes
2002Co-Authors: Judith E Epstein, Yupin Charoenvit, Ruobing Wang, Edward J Gorak, Nicole Freydberg, Oluwatoyin Osinowo, Thomas L Richie, Erin L Stoltz, Fernando Trespalacios, John NergesAbstract:Introduction of a new vaccine requires choosing a delivery system that provides safe administration and the desired level of immunogenicity. The safety, tolerability, and immunogenicity of three monthly 2.5-mg doses of a PfCSP DNA vaccine were evaluated in healthy volunteers as administered intramuscularly (IM) by needle, IM by jet injection (Biojector®) or IM/intradermally (ID) by jet injection. Vaccine administration was well-tolerated. Adverse events were primarily mild and limited to the site of injection (98%). Jet injections (either IM or ID) were associated with approximately twice as many adverse events per immunization as needle IM, but nevertheless were strongly and consistently preferred in opinion polls taken during the study. No volunteers had clinically significant biochemical or hematologic changes or detectable Anti-dsDNA Antibodies. In conclusion, the injection of Plasmodium falciparum circumsporozoite (PfCSP) DNA vaccine appeared to be safe and well-tolerated when administered by any of ...
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safety tolerability and humoral immune responses after intramuscular administration of a malaria dna vaccine to healthy adult volunteers
2000Co-Authors: Kevin M Coonan, Richard C Hedstrom, Yupin Charoenvit, Martha Sedegah, Judith E Epstein, Sanjai Kumar, Ruobing Wang, Denise L Doolan, Jason D Maguire, Suezanne E ParkerAbstract:DNA-based vaccines are considered to be potentially revolutionary due to their ease of production, low cost, long shelf life, lack of requirement for a cold chain and ability to induce good T-cell responses. Twenty healthy adult volunteers were enrolled in a Phase I safety and tolerability clinical study of a DNA vaccine encoding a malaria antigen. Volunteers received 3 intramuscular injections of one of four different dosages (20, 100, 500 and 2500 μg) of the Plasmodium falciparum circumsporozoite protein (PfCSP) plasmid DNA at monthly intervals and were followed for up to twelve months. Local reactogenicity and systemic symptoms were few and mild. There were no severe or serious adverse events, clinically significant biochemical or hematologic changes, or detectable Anti-dsDNA Antibodies. Despite induction of excellent CTL responses, intramuscular DNA vaccination via needle injection failed to induce detectable antigen-specific Antibodies in any of the volunteers.
Anisur Rahman - One of the best experts on this subject based on the ideXlab platform.
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relationship between anti dsdna anti nucleosome and anti alpha actinin Antibodies and markers of renal disease in patients with lupus nephritis a prospective longitudinal study
2009Co-Authors: Jessica Manson, Pauline Rogers, Lesley J Mason, Jo H M Berden, Johan Van Der Vlag, David Dcruz, David A Isenberg, Anisur RahmanAbstract: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. Methods Renal disease activity was monitored by measuring urine protein/creatinine ratio (PCR), serum albumin and a composite outcome of renal remission. At each time point, antinucleosome and anti-α-actinin Antibodies were measured by enzyme-linked immunosorbent assay. High-avidity Anti-dsDNA Antibodies were measured using the Farrzyme assay. We analysed relationships between levels of the three Antibodies and between antibody levels and renal outcome measures over time. Results Levels of anti-nucleosome and Anti-dsDNA were positively correlated with each other (r = 0.6, P = 0.0001) but neither correlated with anti-α-actinin level. At baseline, mean anti-nucleosome levels were higher in patients with LN than in healthy controls (0.32 versus 0.01, P < 0.001). The same was true for Anti-dsDNA Antibodies (0.50 versus 0.07, P < 0.001) but not for anti-α-actinin (0.33 versus 0.29). Over the follow-up period, anti-nucleosome and Anti-dsDNA levels associated positively with urine PCR (P = 0.041 and 0.051, respectively) and negatively with serum albumin (P = 0.027 and 0.032, respectively). Both anti-nucleosome and Anti-dsDNA levels were significantly lower during renal remission than when renal disease was active (P = 0.002 and 0.003, respectively). However, there was no relationship between anti-α-actinin levels and urine PCR, serum albumin or remission status. Conclusions This prospective longitudinal clinical study is the first to compare levels of anti-nucleosome, Anti-dsDNA and antiα-actinin Antibodies in the same patients with SLE. Our results support the concept that, in the majority of patients, antinucleosome Antibodies play a major role in pathogenesis of LN, in contrast to anti-α-actinin Antibodies.
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b cell depletion therapy in systemic lupus erythematosus effect on autoantibody and antimicrobial antibody profiles
2006Co-Authors: G Cambridge, M J Leandro, Marius Teodorescu, Jessica Manson, Anisur Rahman, D A Isenberg, J C W EdwardsAbstract:Objective Autoantibody production in patients with systemic lupus erythematosus (SLE) is associated with abnormalities of B cell function and phenotype. Clinical responses to B cell depletion therapy (BCDT), based on rituximab, are encouraging. Therefore, we undertook this study to investigate the effect of BCDT on antibody profiles. Methods Serial sera from 16 patients with active, refractory SLE were assayed for antinucleosome Antibodies, anti–double-stranded DNA (Anti-dsDNA), anti–extractable nuclear antigen, anti–tetanus toxoid, and Antibodies to pneumococcal capsular polysaccharide for at least 1 year following BCDT. Anti-dsDNA Antibodies derived from the VH4.34 immunoglobulin germ line gene (9G4+) were also measured. Results All patients achieved peripheral B cell depletion and improved clinically for at least 3 months. Antinucleosome and Anti-dsDNA Antibodies decreased to a mean ± SD of 64 ± 37% and 38 ± 33% of baseline values, respectively, by 6–8 months post-BCDT. Levels of other autoAntibodies and antimicrobial Antibodies were generally unchanged. In the 9 of 16 patients who were still well at 1 year, Anti-dsDNA Antibodies fell to 42 ± 36% of baseline values at 6–8 months and to 37 ± 33% at 10–14 months. In patients who had disease flares within 1 year of BCDT, levels of these Antibodies decreased to 60 ± 40% and 83 ± 93% of baseline values at 6–8 months and at 10–14 months, respectively. Circulating Anti-dsDNA Antibodies were positive for 9G4 expression in 4 of 6 patients tested, and flares in 2 of these patients were accompanied by rises in 9G4+ Anti-dsDNA Antibodies. Conclusion These observations suggest that B cell clones committed to producing antinucleosome and Anti-dsDNA Antibodies, including the VH4.34 subpopulation of Anti-dsDNA Antibodies, have a relatively rapid turnover compared with B cell clones producing other Antibodies. There was also a trend toward a greater and more sustained decrease in Anti-dsDNA Antibodies in patients with clinical benefit lasting >1 year.
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is α actinin a target for pathogenic anti dna Antibodies in lupus nephritis
2004Co-Authors: Lesley J Mason, Chaim Putterman, Anisur Rahman, C T Ravirajan, David A IsenbergAbstract:Objective Following recent reports that pathogenic murine anti-DNA Antibodies bind to α-actinin, it was obviously of interest to assess the ability of human pathogenic anti–double-stranded DNA (Anti-dsDNA) Antibodies to bind this antigen. Both human monoclonal anti-DNA Antibodies and Antibodies affinity purified from the sera of patients with systemic lupus erythematosus (SLE) were investigated. Methods An enzyme-linked immunosorbent assay was established to measure immunoglobulin binding to α-actinin. Antibodies binding dsDNA were purified from the sera of SLE patients who either had active renal disease or had never had renal disease. Serum samples were selected at times when the patients' sera exhibited high IgG binding to dsDNA. The binding of supernatants from 3 high-affinity human Anti-dsDNA IgG hybridomas (RH14, B3, and DIL-6) and 7 human IgM anti-DNA hybridomas was also investigated. Results A greater proportion of Anti-dsDNA IgG–binding Antibodies purified from patients with renal disease bound to α-actinin than did those purified from the sera of patients without renal disease. The specificity of binding to the 100-kd α-actinin molecule was confirmed by Western blotting. The pathogenic human Antibodies RH14 and B3 bound strongly to α-actinin, while nonpathogenic DIL-6 bound very weakly. RT84, the IgM antibody that binds dsDNA with the highest affinity, exhibited the greatest binding to α-actinin. Conclusion The results of our study support the findings of previous studies using murine anti-DNA monoclonal Antibodies, which suggest that pathogenic Anti-dsDNA Antibodies cross-react with α-actinin.
Chaim Putterman - One of the best experts on this subject based on the ideXlab platform.
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urinary lipocalin 2 is associated with renal disease activity in human lupus nephritis
2007Co-Authors: Milena Pitashny, Noa Schwartz, Xiaoping Qing, Bernard Hojaili, Cynthia Aranow, Meggan Mackay, Chaim PuttermanAbstract:Objective Pathogenic monoclonal anti–double-stranded DNA (Anti-dsDNA) Antibodies up-regulate the expression of lipocalin-2 in glomerular mesangial cells. This study was undertaken to investigate whether polyclonal Anti-dsDNA Antibodies promote the local secretion of lipocalin-2 in the kidneys of patients with systemic lupus erythematosus (SLE), and whether urinary lipocalin-2 represents a marker of kidney involvement in SLE. Methods Hispanic, African American, and white patients with SLE and normal healthy control subjects from affiliated hospitals of the Albert Einstein College of Medicine were recruited for this cross-sectional study. Patients were classified based on the presence of active renal disease according to the SLE Disease Activity Index (SLEDAI). Correlations of clinical and laboratory data with urinary and serum levels of lipocalin-2 were assessed. Results Among SLE patients, urinary lipocalin-2 levels were significantly higher in those with lupus nephritis (LN) (median 17.1 ng/mg creatinine, interquartile range [IQR] 10.3–45.4; n = 32) than in those without LN (median 11.2 ng/mg creatinine, IQR 3.1–20.3; n = 38) (P = 0.023). Compared with the values in normal controls (median 4 ng/ml, IQR 0–11.1; n = 14), urinary levels of lipocalin-2 in SLE patients were significantly higher (non-normalized median 19.3 ng/ml, IQR 8–34.2) (P = 0.004). The presence of lipocalin-2 in the urine of patients with LN correlated significantly with the renal SLEDAI score (r = 0.452, P = 0.009), but not with extrarenal disease activity. Conclusion The high prevalence of LN in SLE patients and the prognostic significance of kidney disease support the need for identifying early biomarkers to assess the risk of nephritis development and for following up patients with established disease. These findings indicate that urinary lipocalin-2 is a potential marker of the presence and severity of renal involvement in adult patients with SLE.
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Anti-alpha-actinin Antibodies: A new marker of lupus nephritis
2007Co-Authors: Yves Renaudineau, Chaim Putterman, Bisram Deocharan, Sandrine Jousse, Eric Renaudineau, Pierre YouinouAbstract:Abstract The exact role of anti-ds (double stranded) DNA Antibodies in the pathogenesis of kidney injury in lupus nephritis remains a focus of continuing investigation. One theory explaining the pathogenicity of Anti-dsDNA Antibodies in lupus nephritis is direct cross-reactivity with renal antigens. Several years ago, α-actinin was identified as a major cross-reactive target for pathogenic Anti-dsDNA Antibodies in murine SLE. Indeed, binding of a nephritogenic murine Anti-dsDNA antibody was stronger to the α-actinin derived from a lupus prone mouse mesangial cell line as compared to α-actinin in a non-autoimmune mouse mesangial cell line. Furthermore, we recently showed that immunization of non-autoimmune mice with α-actinin induces anti-chromatin Antibodies, glomerular IgG deposition and proteinuria. In humans, anti-α-actinin autoAntibodies (Ab) were associated with Anti-dsDNA Ab in SLE. In those patients, anti-α-actinin rather than Anti-dsDNA Ab were significantly associated with glomerulonephritis and disease activity. The anti-α-actinin reactivity was associated with high avidity Anti-dsDNA Ab. Moreover, the anti-α-actinin response was related to the actin-binding site of α-actinin. Taken together, these studies indicate that detection of anti-α-actinin Ab, in association with Anti-dsDNA Ab, may constitute a new marker in lupus nephritis.
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cross reactivity of human lupus anti dna Antibodies with α actinin and nephritogenic potential
2005Co-Authors: Zeguo Zhao, Elena Weinstein, Marina Tuzova, Anne Davidson, Peter Mundel, Paola Marambio, Chaim PuttermanAbstract:Objective Cross-reactivity with kidney antigens is believed to be a critical determinant in the renal pathogenicity of anti–double-stranded DNA (Anti-dsDNA) Antibodies. Murine nephritogenic Anti-dsDNA Antibodies have been shown to cross-react with α-actinin, and anti–α-actinin Antibodies have been found to be deposited in the kidneys of lupus mice with active nephritis. Furthermore, in humans with systemic lupus erythematosus (SLE), it has been found that a greater proportion of polyclonal IgG Anti-dsDNA Antibodies from patients with renal involvement bind to α-actinin than do those from patients without renal disease. We undertook this study to substantiate a direct link between cross-reactive Anti-dsDNA/anti–α-actinin Antibodies and the pathogenesis of lupus nephritis in humans. Methods A panel of 10 Anti-dsDNA and/or anti–α-actinin Antibodies was generated by Epstein-Barr virus transformation of lymphocytes from patients with SLE and was extensively characterized. Antibody binding was studied by enzyme-linked immunosorbent assay and Western blotting. Antibody potential for pathogenicity was assessed by measuring binding to isolated glomeruli and mesangial cells and by evaluation of histologic features of the kidney following injection in vivo. Results All Anti-dsDNA Antibodies isolated also bound α-actinin. Cross-reactive Antibodies bound to mesangial cells and to isolated glomeruli ex vivo. Binding to glomeruli was not inhibited by DNase treatment, but could be abrogated by α-actinin. Furthermore, histopathologic abnormalities seen in mice injected intraperitoneally with a cross-reactive cell line included fusion of podocyte foot processes and subepithelial and subendothelial deposition. Conclusion These studies provide strong support for the hypothesis that α-actinin is a major cross-reactive target for Anti-dsDNA Antibodies in SLE patients. Cross-reactive Anti-dsDNA/anti–α-actinin Antibodies from SLE patients are pathogenic and may contribute to the kidney lesions in lupus nephritis.
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is α actinin a target for pathogenic anti dna Antibodies in lupus nephritis
2004Co-Authors: Lesley J Mason, Chaim Putterman, Anisur Rahman, C T Ravirajan, David A IsenbergAbstract:Objective Following recent reports that pathogenic murine anti-DNA Antibodies bind to α-actinin, it was obviously of interest to assess the ability of human pathogenic anti–double-stranded DNA (Anti-dsDNA) Antibodies to bind this antigen. Both human monoclonal anti-DNA Antibodies and Antibodies affinity purified from the sera of patients with systemic lupus erythematosus (SLE) were investigated. Methods An enzyme-linked immunosorbent assay was established to measure immunoglobulin binding to α-actinin. Antibodies binding dsDNA were purified from the sera of SLE patients who either had active renal disease or had never had renal disease. Serum samples were selected at times when the patients' sera exhibited high IgG binding to dsDNA. The binding of supernatants from 3 high-affinity human Anti-dsDNA IgG hybridomas (RH14, B3, and DIL-6) and 7 human IgM anti-DNA hybridomas was also investigated. Results A greater proportion of Anti-dsDNA IgG–binding Antibodies purified from patients with renal disease bound to α-actinin than did those purified from the sera of patients without renal disease. The specificity of binding to the 100-kd α-actinin molecule was confirmed by Western blotting. The pathogenic human Antibodies RH14 and B3 bound strongly to α-actinin, while nonpathogenic DIL-6 bound very weakly. RT84, the IgM antibody that binds dsDNA with the highest affinity, exhibited the greatest binding to α-actinin. Conclusion The results of our study support the findings of previous studies using murine anti-DNA monoclonal Antibodies, which suggest that pathogenic Anti-dsDNA Antibodies cross-react with α-actinin.