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Objective In evaluation of systemic lupus erythematosus (SLE), anti–double-stranded DNA antibodies (anti-dsDNA) play a significant role in diagnosis, monitoring SLE activity, and assessing prognosis. However, evaluations of the performance and limitations for recently developed methods for anti-dsDNA assessment are sparse. Methods Specimens used for antinuclear antibody testing (n = 129) were evaluated for anti-dsDNA assay comparability across 4 medical centers in the United States. The methods compared were Werfen Quanta Lite dsDNA, Zeus Scientific dsDNA Enzyme Immunoassay, Bio-Rad multiplex immunoassay (MIA) dsDNA, ImmunoConcepts Crithidia, and Bio-Rad Laboratories Crithidia. Results For quantitative anti-dsDNA measurements, Spearman's correlation coefficient was highest between Zeus and Werfen (ρ = 0.86; CI, 0.81-0.90; P <.0001). Comparison of MIA to Werfen or Zeus yielded similar results to each other (ρ = 0.58; CI, 0.44-0.68; P <.0001; and ρ = 0.59; CI, 0.46-0.69; P <.0001, respectively), but lower than the correlation between Zeus and Werfen. Positive concordance between assays ranged from 31.4% to 97.1%, and negative concordance between assays ranged from 58.5% to 100%. The detection of anti-dsDNA in those with SLE diagnosis ranged from 50.9% to 77.4% for quantitative assays and 15.1% to 24.5% for Crithidia assays. Conclusion Current quantitative anti-dsDNA assays are not interchangeable for patient follow-up. Crithidia -based assays demonstrate high negative concordance and lack positive concordance among the methods. [ABSTRACT FROM AUTHOR]

Abstract Backgrounds Progranulin (PGRN) is a growth factor-like molecule with diverse roles in homeostatic and pathogenic processes including the control of immune and inflammatory responses. Pathogenic inflammation is a hallmark of systemic lupus erythematosus (SLE) and elevated serum levels of PGRN has been evaluated as a biomarker of disease activity in SLE. However, the role of PGRN in SLE has not been fully investigated. This study is aimed to determine the potential involvements of PGRN in SLE. Methods Wild type (WT) and PGRN knockout (PGRN-/-) C57BL/6 mice received intraperitoneal injection of pristane for induction of a murine model of SLE. Sera were collected every biweekly and levels of anti-dsDNA antibody, IgG, and inflammatory factors were measured. Mice were sacrificed 5 months later and the renal lesions, as well as the proportions of T cell subtypes in the spleen were analyzed. Results Following exposure to pristane, PGRN-/- mice generated significantly lower levels of anti-dsDNA antibody and IgG relative to WT mice. PGRN-/- mouse kidneys had less IgG and collagen deposition compared with WT mice after pristane injection. Conclusion The results indicate that PGRN participates in inflammatory response and renal damage in pristane induced SLE models, suggesting that PGRN mediates the onset of SLE.

The goal of this study is to develop a rapid diagnostic test for rheumatic disease and systemic lupus erythematosus (SLE) screening. A novel rapid vertical flow assay (VFA) was engineered and used to assay anti-nuclear (ANA) and anti-dsDNA (αDNA) autoantibodies from systemic lupus erythematosus (SLE) patients and healthy controls (HCs). Observer scores and absolute signal intensities from the VFA were validated via ELISA. The rapid point-of-care VFA test that was engineered demonstrated a limit of detection of 0.5 IU/mL for ANA and αDNA autoantibodies in human plasma with an inter-operator CV of 19% for ANA and 12% for αDNA. Storage stability was verified over a three-month period. When testing anti-dsDNA and ANA levels in SLE and HC serum samples, the duplex VFA revealed 95% sensitivity, 72% specificity and an 84% ROC AUC value in discriminating disease groups, comparable to the gold standard, ELISA. The rapid αDNA/ANA duplex VFA can potentially be used in primary care clinics for evaluating patients or at-risk subjects for rheumatic diseases and for planning follow-up testing. Given its low cost, ease, and rapid turnaround, it can also be used to assess SLE prevalence estimates. [ABSTRACT FROM AUTHOR]

Abstract Background Lupus nephritis (LN) is a crucial organ involvement in systemic lupus erythematosus (SLE). Patients with LN have higher morbidity and mortality rates than those without. Among all patients with LN, 20–40% had delayed onset, but the data for patients with juvenile-onset SLE (jSLE), who have a higher percentage of LN than patients with adult-onset SLE (aSLE), were limited. This study aimed to determine the risk factors for subsequent LN in patients with jSLE. Methods A retrospective cohort study was conducted between 2008 and 2018 in a single tertiary medical centre. Patients with diagnosed jSLE were reviewed. We investigated those without LN at diagnosis and whether they developed LN afterward. The primary outcome was the development of subsequent LN. Clinical manifestations at diagnosis, serial laboratory data, and treatments were reviewed during follow-up periods. Results Among the 48 patients with jSLE without initial LN, 20 developed subsequent LN later (Group 1), whereas 28 remained free of LN (Group 2). There was no difference in the percentage of initial manifestations except for more discoid rashes in Group 2 patients. In the Cox regression model, elevated average anti-double-stranded DNA (dsDNA) antibody, low average serum complements, and high average erythrocyte sedimentation rate (ESR) levels during follow-up were predictors of subsequent LN. After adjusting for these factors in multivariable analyses, only high average anti-dsDNA antibody and high average ESR levels remained predictive of subsequent LN. For every 100 IU/ml increase in anti-dsDNA antibody, the risk for subsequent LN in jSLE increases by 1.29 times (hazard ratio = 1.29, 95% confidence interval 1.055–1.573). Conclusion Persistently high anti-dsDNA antibody and ESR levels during the follow-up period were risk factors for subsequent LN in patients with jSLE.

Objective: This study aimed to identify which disease activity parameters may be risk factors for preterm birth (PB) and low birth weight (LBW) in patients with systemic lupus erythematosus (SLE). We also analyzed the extent to which these parameters affected PB and LBW. Methods: We collected the SLE Disease Activity Index (SLEDAI), the rate of lupus low disease activity state (LLDAS) attainment, complement levels, and the titer of anti-double stranded DNA (dsDNA) antibody as disease activity parameters. We retrospectively analyzed the associations of these parameters with PB and LBW. Results: Sixty pregnancies were included in this study. C3 levels and anti-dsDNA antibody titers at conception were strongly associated with PB (p = 0.03 and p = 0.01, respectively), whereas C3 and CH50 levels were associated with LBW (p = 0.02 and p = 0.03, respectively). A logistic regression analysis showed that the cutoff values of C3 and anti-dsDNA antibody for PB were 62.0 mg/dl and 5.4 IU/ml, respectively. The cutoff values of C3 and CH50 for LBW were 87.0 mg/dl and 41.8 U/ml, respectively. The risk of PB or LBW was increased when divided by the cutoff value, and the combination of these cutoff values showed a significantly higher risk of PB and LBW (p = 0.01 and p < 0.01, respectively). Conclusions: PB and LBW are strongly associated with disease activity parameters in patients with SLE. Therefore, strictly monitoring and controlling these disease activity parameters, with or without clinical manifestation, is important for women who want to become mothers. [ABSTRACT FROM AUTHOR]

The goal of this study is to develop a rapid diagnostic test for rheumatic disease and systemic lupus erythematosus (SLE) screening. A novel rapid vertical flow assay (VFA) was engineered and used to assay anti-nuclear (ANA) and anti-dsDNA (αDNA) autoantibodies from systemic lupus erythematosus (SLE) patients and healthy controls (HCs). Observer scores and absolute signal intensities from the VFA were validated via ELISA. The rapid point-of-care VFA test that was engineered demonstrated a limit of detection of 0.5 IU/mL for ANA and αDNA autoantibodies in human plasma with an inter-operator CV of 19% for ANA and 12% for αDNA. Storage stability was verified over a three-month period. When testing anti-dsDNA and ANA levels in SLE and HC serum samples, the duplex VFA revealed 95% sensitivity, 72% specificity and an 84% ROC AUC value in discriminating disease groups, comparable to the gold standard, ELISA. The rapid αDNA/ANA duplex VFA can potentially be used in primary care clinics for evaluating patients or at-risk subjects for rheumatic diseases and for planning follow-up testing. Given its low cost, ease, and rapid turnaround, it can also be used to assess SLE prevalence estimates.

Background: Lupus nephritis (LN) is a crucial organ involvement in systemic lupus erythematosus (SLE). Patients with LN have higher morbidity and mortality rates than those without. Among all patients with LN, 20–40% had delayed onset, but the data for patients with juvenile-onset SLE (jSLE), who have a higher percentage of LN than patients with adult-onset SLE (aSLE), were limited. This study aimed to determine the risk factors for subsequent LN in patients with jSLE. Methods: A retrospective cohort study was conducted between 2008 and 2018 in a single tertiary medical centre. Patients with diagnosed jSLE were reviewed. We investigated those without LN at diagnosis and whether they developed LN afterward. The primary outcome was the development of subsequent LN. Clinical manifestations at diagnosis, serial laboratory data, and treatments were reviewed during follow-up periods. Results: Among the 48 patients with jSLE without initial LN, 20 developed subsequent LN later (Group 1), whereas 28 remained free of LN (Group 2). There was no difference in the percentage of initial manifestations except for more discoid rashes in Group 2 patients. In the Cox regression model, elevated average anti-double-stranded DNA (dsDNA) antibody, low average serum complements, and high average erythrocyte sedimentation rate (ESR) levels during follow-up were predictors of subsequent LN. After adjusting for these factors in multivariable analyses, only high average anti-dsDNA antibody and high average ESR levels remained predictive of subsequent LN. For every 100 IU/ml increase in anti-dsDNA antibody, the risk for subsequent LN in jSLE increases by 1.29 times (hazard ratio = 1.29, 95% confidence interval 1.055–1.573). Conclusion: Persistently high anti-dsDNA antibody and ESR levels during the follow-up period were risk factors for subsequent LN in patients with jSLE. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by diverse serological autoantibodies. Anti-dsDNA antibodies are involved in multiple organ damage, especially the kidney, skin, and central nervous system. Anti-dsDNA antibodies play a pivotal role in SLE, and researchers have developed therapeutic strategies targeting these antibodies. Approaches to reduce anti-dsDNA antibodies via B cell targeted biologics against B cell surface antigens, B cell survival factors, or Bruton's tyrosine kinase have effectively eliminated B cells. However, their non-specific depletion hampers normal immune system functioning and limits the therapeutic benefits. Thus, scientists have attempted anti-dsDNA antibodies or lupus-specific strategies, such as the immature dendritic cell vaccine and immunoadsorption. Recently, synthetic mimic peptides (hCDR1, pCONs, DWEYS, FISLE-412, and ALW) that directly block anti-dsDNA autoantibodies have attracted attention, which could ameliorate lupus, decrease the serological autoantibody titer, reduce the deposition of renal autoantibodies, and improve pathological performance. These potent small peptide molecules are well tolerated, non-toxic, and non-immunogenic, which have demonstrated a benign safety profile and are expected to be hopeful candidates for SLE management. In this review, we clarify the role of anti-dsDNA antibodies in SLE, mainly focus on the current strategies targeting anti-dsDNA antibodies, and discuss their potential clinical value. [ABSTRACT FROM AUTHOR]

Anti-double-stranded DNA antibodies (anti-dsDNA) serve as a crucial serological indicator for systemic lupus erythematosus (SLE). Chemiluminescent immunoassay (CIA) is mainly used in clinical diagnosis of SLE, but suffers from low specificity, partially because the use of dsDNA antigens of varied sources in current CIA kits that sometimes led to controversial results. On the basis that anti-dsDNA in healthy individuals tend to selectively bind with dsDNA originating from pathogens, whereas pathogenic anti-dsDNA in SLE patients bind all forms of dsDNA, here we proposed the use of dsDNA fragment derived from human genome as antigen (synthesized via PCR using the human genomic DNA as the template). A magnetic bead-based immunofluorescence assay (IFA) was thus developed for SLE diagnosis, which exhibited improved sensitivity and specificity over CIA using the WHO reference reagent (15/174) as standard. For clinical serum sample analysis (n = 590), IFA exhibited an accuracy of 71.9% that was higher than CIA (65.3%). Crucially, the IFA results exhibited stronger correlations with the activity of SLE, renal involvement, and its prognosis. Besides the improved clinical diagnosis, the proposed IFA also holds great promise in assay standardization due to the high homogeneity of the synthetic dsDNA. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: Bacterial translocation across the gut barrier has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), though underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utilizing lupus model mice and blood samples from untreated SLE patients., Methods: Bacterial translocation was evaluated using nonselective cultured mesenteric lymph nodes (MLNs) from B6SKG mice, a lupus model characterized by impaired TCR signalling and gut dysbiosis. The relationships of detected pathobionts with autoantibody production were examined using in vivo experiments, enzyme-linked immunosorbent assay, immunoblotting, and epitope mapping., Results: Culture-based bacterial profiling in MLNs demonstrated that Lactobacillus murinus was enriched in B6SKG mice with elevated anti-dsDNA IgG levels. Subcutaneous injection of heat-killed L. murinus induced anti-dsDNA IgG production without altering T- or B cell subset composition. Immunoblotting and mass spectrometry analysis identified a peptide ATP-binding cassette (ABC) transporter as a molecular mimicry antigen, with its cross-reactivity in lupus mice confirmed by serological assays and in vivo immunization. The L. murinus ABC transporter exhibited surface epitopes that were cross-reactive with sera from lupus mice and patients. The ABC transporter from R. gnavus, known for its pathogenic role in lupus patients, had a similar epitope sequence to that of the L. murinus ABC transporter and reacted with lupus sera., Conclusion: ABC transporters from gut bacteria can serve as cross-reactive antigens that may promote anti-dsDNA antibody production in genetically susceptible mice. These findings underscore the role of commensal-derived molecular mimicry and bacterial translocation in lupus pathogenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lupus Nephritis (LN) in patients with Systemic Lupus Erythematosus (SLE) is one of the most serious and prevalent manifestations. The procedure of renal biopsy is harmful and accompanied by potential hazards. Therefore, introducing reliable biomarkers to predict LN is exceedingly worthwhile. In the present study, we compared the diagnostic values of circulating autoantibodies against dsDNA, C1q, C3b, SSA, SSB, and Sm alone or in combination to predict LN. This study evaluated the abovementioned autoantibodies in 40 healthy controls (HCs) and 95 SLE patients with different kidney involvements, including absent (n = 40), inactive (n = 20), and active (n = 35) LN using EIA method. The frequency and odds ratio of anti-dsDNA (71.4%, OR = 4.2), anti-C1q (62.9%, OR = 5.1), and the simultaneous existence of anti-C1q and anti-dsDNA (51.4%, OR = 6) antibodies were significantly higher in the active LN group compared with both inactive and absent LN groups. Moreover, the levels of anti-C1q and anti-dsDNA antibodies positively correlated with disease activity in patients with SLE. The prevalence of these autoantibodies was associated with the severity of LN biopsies. These data suggest that anti-C1q and anti-dsDNA antibodies and also their simultaneous presence may be valuable diagnostic biomarkers for LN prediction in patients with SLE. [ABSTRACT FROM AUTHOR]

Peptide ALW (ALWPPNLHAWVP) targeting anti-dsDNA antibodies has shown promising therapeutic effects in alleviating lupus nephritis, but is potentially limited by poor stability and non-kidney targeting. We recently developed a D-form modified ALW, called D-ALW, which has the capacity to widely inhibit pathogenic polyclonal anti-dsDNA antibody reactions. Further modification of D-ALW using PEG-PLGA nanoparticles to enhance good kidney-targeting ability and extend half-life. Here, we demonstrate that the D-form modified ALW maintains higher binding and inhibition efficiencies and achieves higher stability. Most importantly, D-ALW nanoparticles exhibit excellent kidney-targeting ability and prolong the half-life of the peptides in BALB/c mice. Additionally, compared to D-ALW, D-ALW nanoparticles significantly reduce the glomerular deposition of IgG and C3, improve renal histopathologies, such as glomerular proliferation and inflammatory cells infiltration, and markedly prolong lifespan in MRL/lpr lupus-prone mice. Overall, these results establish that the D-ALW nanoparticles offer synergistic benefits in both safety and efficacy, providing long-term renal preservation and treatment advantages in lupus nephritis. • Poor stability and non-kidney targeting hampered the effect of peptide ALW. • D-ALW improves proteases resistance and binding affinity to anti-dsDNA antibodies. • D-ALW nanoparticles possessed high renal retention of peptide. • D-ALW nanoparticles largely prolonged the lifespan of MRL/lpr mice. [ABSTRACT FROM AUTHOR]

Objective　 To investigate the clinical application value of anti-dsDNA antibody, complement C3 and other laboratory indicators in patients with systemic lupus erythematosus (SLE) with renal injury. Methods　The clinical data of 296 SLE patients were retrospectively analyzed. The differences of autoantibodies and other laboratory indicators between SLE with renal injury group and without renal injury group were compared, and the immunological indicators of SLE renal injury were found. Results　The positive rates of serum anti-dsDNA, anti-nucleosome and anti-histone antibodies in SLE with renal injury group were significantly higher than those in without renal injury group, serum renal function indexes such as urea, creatinine and uric acid, electrolytes such as potassium, chlorine and calcium ion were significantly higher than those in without renal injury group, and the levels of immunoglobulin IgG, IgA and complement C3 were significantly lower than those in without renal injury group (P < 0.05). Conclusion　Anti-dsDNA, anti-nucleosome, anti-histone autoantibodies, complement C3 and other laboratory indicators may be associated with renal injury in SLE patients. [ABSTRACT FROM AUTHOR]

Objectives Apolipoprotein A-1 (ApoA-1) is a protein fraction of the high-density lipoproteins with anti-inflammatory and antioxidant properties that play a major role in reverse cholesterol transport. The presence of anti-ApoA-1 IgG has been reported in SLE to be variably associated with disease activity or cardiovascular events (CVEs). We assessed the clinical performance of anti-ApoA-1 IgG and of antibodies directed against its immunodominant F3L1 peptide (F3L1 IgG) in a well-characterized Swiss SLE cohort study. Methods A total of 354 biological samples and interviews from 176 individuals were studied. SLEDAI, clinical characteristics, anamnestic CVEs and therapy details were recorded. Sera were tested for the presence of anti-ApoA-1 IgG, anti-F3L1 IgG, anti-dsDNA IgG and aPL. Results Anti-ApoA-1 and anti-F3L1 IgG positivity was associated with higher SLEDAI, mostly due to concomitant positivity of dsDNA IgG and low complement. Variations in time of anti-ApoA-1 IgG correlated positively with variations of anti-dsDNA IgG and inversely to variations of C3 levels. No cross-reactivity was found between anti-ApoA-1 and anti-dsDNA IgG. Positivity for anti-Apo-A1 IgG was more frequent in individuals receiving 10 mg/day or more of prednisone. We did not find any significant association between anti-ApoA-1 IgG positivity and CVEs. Conclusion Anti-ApoA-1 and anti-F3L1 IgG in SLE correlate strongly with laboratory markers of activity, particularly with the presence and titre of dsDNA IgG. These results confirm and extend previous findings and support the use of anti-ApoA1 IgG in the clinical setting. Their role in CVEs deserves further investigation. [ABSTRACT FROM AUTHOR]

This study aimed to compare the test results of anti-double-stranded DNA (anti-dsDNA) antibodies obtained using chemiluminescent immunoassay (CIA) and enzyme-linked immunosorbent assay (ELISA), and investigate predictors of inconsistent results. This retrospective study included 502 patients who underwent CIA and ELISA to determine their anti-dsDNA antibody values within a year. We compared the diagnostic power for SLE, disease activity, and predictive power for lupus nephritis (LN). A multivariate analysis was performed to determine the predictors of inconsistencies. CIA and ELISA were moderately correlated in terms of their consistency (Cronbach’s α = 0.571), and yielded comparably favorable results in terms of SLE diagnostic power and SLE disease activity. However, if the patient had LN, CIA displayed higher predictive power than ELISA (0.620 vs. 0.555, p = 0.026). Compared with the CIA/ELISA double-positive group, the inconsistent group had lower anti-C1q circulating immune complexes (CIC) antibody values (OR: 0.42, 95% CI: 0.18–0.94, p = 0.036), and lower SLEDAI scores (≥4) (OR: 0.33, 95% CI: 0.14–0.79, p = 0.013). Anti-dsDNA antibody detection with CIA exhibited higher predictability for diagnosing LN than did ELISA. In the event of inconsistencies between anti-dsDNA methods, SLE disease activity and CIC test values should be considered simultaneously.

Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective. These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE. Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE. By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane. These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells. In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes. Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells. Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE. A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE. This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them.

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Herein, a simple and selective electrochemical method was developed for sulfadimethoxine detection based on the triggered cleavage activity of nuclease P1 by the formation of aptamer and sulfadimethoxine conjugate. After probe DNA was immobilized on gold electrode surface, aptamer DNA labeled with biotin at its 5′-terminal was then captured on electrode surface through the hybridization reaction between probe DNA and aptamer DNA. The formed double-stranded DNA (dsDNA) can block the digestion activity of Nuclease P1 towards the single-stranded probe DNA. Then, the anti -dsDNA antibody was further modified on electrode surface based on the specific interaction between dsDNA and antibody. Due to the electrostatic repulsion effect and steric-hindrance effect, a weak electrochemical signal was obtained at this electrode. However, in the presence of sulfadimethoxine, it can interact with aptamer DNA, and then the formation of dsDNA can be blocked. As a result, the probe DNA at its single-strand state can be digested by Nuclease P1, which leads to the failure of the immobilization of anti -dsDNA antibody. At this state, a strong electrochemical signal was obtained. Based on the change of the electrochemical signal, sulfadimethoxine can be detected with linear range of 0.1–500 nmol/L. The detection limit was 0.038 nmol/L. The developed method possesses high detection selectivity and sensitivity. The applicability of this method was also proved by detecting sulfadimethoxine in veterinary drug and milk with satisfactory results. Image 1 • Electrochemical method was developed for sulfadimethoxine detection. • Aptamer was employed to specific recognition of sulfadimethoxine. • Signal improvement can be achieved after the formation of aptamer-target conjugate. • Sulfadimethoxine in veterinary drug and milk was detected. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective. These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE. Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE. By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane. These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells. In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes. Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells. Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE. A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE. This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them. [ABSTRACT FROM AUTHOR]

Background: Viral infection is implicated in development of autoimmunity. Parvovirus B19 (B19V) nonstructural protein, NS1, a helicase, covalently modifies self double-stranded deoxyribonucleic acid (dsDNA) and induces apoptosis. This study tested whether resulting apoptotic bodies (ApoBods) containing virally modified dsDNA could induce autoimmunity in an animal model.Methods: BALB/c mice were inoculated with (1) pristane-induced, (2) B19V NS1-induced, or (3) staurosporine-induced ApoBods. Serum was tested for dsDNA autoantibodies by Crithidia luciliae staining and enzyme-linked immunosorbent assay. Brain, heart, liver, and kidney pathology was examined. Deposition of self-antigens in glomeruli was examined by staining with antibodies to dsDNA, histones H1 and H4, and TATA-binding protein.Results: The B19V NS1-induced ApoBod inoculation induced dsDNA autoantibodies in a dose-dependent fashion. Histopathological features of immune-mediated organ damage were evident in pristane-induced and NS1-induced ApoBod groups; severity scores were higher in these groups than in staurosporine-treated groups. Tissue damage was dependent on NS1-induced ApoBod dose. Nucleosomal antigens were deposited in target tissue from pristane-induced and NS1-induced ApoBod inoculated groups, but not in the staurosporine-induced ApoBod inoculated group.Conclusions: This study demonstrated proof of principle in an animal model that virally modified dsDNA in apoptotic bodies could break tolerance to self dsDNA and induce dsDNA autoantibodies and end-organ damage. [ABSTRACT FROM AUTHOR]

Background Systemic lupus erythematosus (SLE) disease has been shown to be associated with the generation of multiple auto-antibodies. Among these, anti-dsDNA antibodies (anti-DNAs) are specific and play a pathogenic role in SLE. Indeed, anti-DNA+ SLE patients display a worse disease course. The generation of these pathogenic anti-DNAs has been attributed to the interaction between aberrant T helper (Th) cells and autoimmune B cells. Thus, in this study we have investigated whether CCR6+Th cells have the ability to differentiate SLE patients based on anti-DNA status, and if their distribution has any correlation with disease activity. Methods We recruited 25 anti-DNA+ and 25 anti-DNA− treatment-naive onset SLE patients, matched for various clinical characteristics in our nested matched case-control study. CCR6+ Th cells and their additional subsets were analyzed in each patient by flow cytometry. Results Anti-DNA+ SLE patients specifically had a higher percentage of Th cells expressing CCR6 and CXCR3. Further analysis of CCR6+ Th cell subsets showed that anti-DNA+ SLE patients had elevated proportions of Th9, Th17, Th17.1 and CCR4/CXCR3 double-negative (DN) cells. However, the proportions of CCR6− Th subsets, including Th1 and Th2 cells, did not show any association with anti-DNA status. Finally, we identified a correlation between CCR6+ Th subsets and clinical indicators, specifically in anti-DNA+ SLE patients. Conclusions Our data indicated that CCR6+ Th cells and their subsets were elevated and correlated with disease activity in anti-DNA+ SLE patients. We speculated that CCR6+ Th cells may contribute to distinct disease severity in anti-DNA+ SLE patients.

Background. Systemic lupus erythematosus (SLE) disease has been shown to be associated with the generation of multiple auto-antibodies. Among these, anti-dsDNA antibodies (anti-DNAs) are specific and play a pathogenic role in SLE. Indeed, anti- DNA+ SLE patients display a worse disease course. The generation of these pathogenic anti-DNAs has been attributed to the interaction between aberrant T helper (Th) cells and autoimmune B cells. Thus, in this study we have investigated whether CCR6+ Th cells have the ability to differentiate SLE patients based on anti-DNA status, and if their distribution has any correlation with disease activity. Methods. We recruited 25 anti-DNA+ and 25 anti-DNA- treatment-naive onset SLE patients, matched for various clinical characteristics in our nested matched case-control study. CCR6+ Th cells and their additional subsets were analyzed in each patient by flow cytometry. Results. Anti-DNA+ SLE patients specifically had a higher percentage of Th cells expressing CCR6 and CXCR3. Further analysis of CCR6C Th cell subsets showed that anti-DNA+ SLE patients had elevated proportions of Th9, Th17, Th17.1 and CCR4/CXCR3 double-negative (DN) cells. However, the proportions of CCR6+ Th subsets, including Th1 and Th2 cells, did not show any association with anti-DNA status. Finally, we identified a correlation between CCR6C Th subsets and clinical indicators, specifically in anti-DNA+ SLE patients. Conclusions. Our data indicated that CCR6C Th cells and their subsets were elevated and correlated with disease activity in anti-DNA+ SLE patients. We speculated that CCR6C Th cells may contribute to distinct disease severity in anti-DNA+ SLE patients. [ABSTRACT FROM AUTHOR]

SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4−CD8− T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases.

It is necessary and useful to explore prevalence of various systemic autoimmune rheumatic diseases ( SARDs) in patients with suspicion of having SARDs and to characterize antinuclear antibodies ( ANA) profile for identifying different populations ( SARDs and non- SARDs). A total of 5024 consecutive patients with available medical records were investigated, whose sera had been tested for ANA profile, including ANA, anti-ds DNA and anti-extractable nuclear antigen ( ENA) antibodies, between 31 January 2012 and 26 March 2014. Only 594 (11.8%) patients were diagnosed with SARDs of those suspected with SARDs. The prevalence of systemic lupus erythematosus ( SLE) was highest (3.2%), followed by rheumatoid arthritis ( RA) (2.5%), primary Sjögren's syndrome ( pSS) (1.7%), ankylosing spondylitis ( AS) (1.5%), etc. Of females, SLE also showed the highest prevalence (6%), while of males, AS showed the highest prevalence (1.9%). The prevalence of most SARDs was closely associated with age, except mixed connective tissue disease ( MCTD), and the variation characteristics among different age groups were different among various SARDs. The prevalence of ANA was significantly increased in most SARD patients [especially in SLE, systemic sclerosis ( SSc) and MCTD]. For anti- ENA antibodies, in contrast to some autoantibodies associated with multiple SARDs (e.g. anti- SSA, SSB, nRNP), others were relatively specific for certain diseases, such as anti-ds DNA, Sm, histone, nucleosome and Rib-P for SLE, anti- SCL-70 for SSc and anti-Jo-1 for polymyositis/dermatomyositis ( PM/ DM). Of note, ANA profile appeared to be of little significance for AS, ANCA-associated vasculitis ( AAV), polymyalgia rheumatic ( PMR), adult-onset Still's disease ( ASD) and Behcet's disease ( BD). The younger were more likely to have the presence of anti-ds DNA, Sm, histone or Rib-P for SLE, and anti- SSA for RA or MCTD. No significant differences for frequencies of ANA and anti- ENA autoantibodies were found between sexes in most SARDs, with the exception of RA and AS. The present study suggests that, of patients with SARDs-like clinical manifestations, the proportion of those with true SARDS is small, for most of whom tests for autoantibodies are necessary and useful to help make a prompt and precise diagnosis. [ABSTRACT FROM AUTHOR]

Introduction B cell receptor (BCR) -mediated signals are enhanced when CD72 expression is deficient on B cells in autoimmune diseases. The significance of soluble CD72 (sCD72) has not been elucidated. Methods Soluble CD72 was analyzed in the serum of 159 SLE patients, 40 rheumatoid arthritis (RA) patients, and 100 healthy individuals. Correlations between sCD72 and SLE disease activity (SLEDAI) were assessed. Results Soluble CD72 was found increased in SLE patients, when compared to both RA patients and healthy individuals (20.2 ± 1.2 ng/ml; 10.6 ± 4.6 ng/ml and 7.2 ± 3.3 ng/ml; p < 0.001). Soluble CD72 level was significantly higher in SLE patients with renal involvement than in patients without (31.8 ± 2.3 ng/ml vs 13.9 ± 0.9 ng/ml; p < 0.001) and also with the presence of auto-antibodies. Conclusion Soluble CD72 is significantly increased in SLE patients mainly in those with renal involvement. Increased sCD72 may become a potential biomarker for renal involvement in SLE. [ABSTRACT FROM AUTHOR]

In drug-induced lupus (DIL), symptoms similar to those of systemic lupus erythematosus (SLE) usually resolve after discontinuation of the offending drug. A 41-year-old-woman with a history of ulcerative colitis presented with polyarthritis and myositis and was positive for anti-double stranded (ds) DNA IgG antibody. After discontinuation of mesalazine, the symptoms resolved, and the antibody titer decreased. The patient was diagnosed with DIL. Six months later, lupus myocarditis developed. After treatment with glucocorticoids, cyclophosphamide, intravenous immunoglobulin, and an intra-aortic balloon pump, she showed dramatic improvement. Patients with DIL and an immunological predisposition, such as anti-dsDNA antibodies, may have SLE and should be carefully monitored.

Recent evidence implicated an important role of Th17 cells in the pathogenesis of systemic lupus erythematosus (SLE). However, the association between dynamic changes of Th17 cell frequency and clinical parameters in SLE patients receiving clinical managements remains unknown. Here, we sought to evaluate their correlation in Chinese new-onset SLE patients with standard therapy. We found that the frequency of Th17 cells was higher in SLE patients than that in healthy controls and could be decreased by standard care. In consistent, the level of serum IL-6, IL-1β, IL-23, and Stat3 activity was elevated in SLE patients and down-regulated by disease treatment. Of note, the frequency of Th17 cells was correlated with SLEDAI and serum C3 in SLE patients. The changes of Th17 cell frequency were associated with those of SLEDAI and serum C3 in SLE patients between pretreatment and posttreatment. Further, the Th17 cell frequency was positively correlated with serum anti-dsDNA antibody in SLE patients. The changes of Th17 cell frequency were associated with those of serum anti-dsDNA antibody in SLE patients. Our findings showed that dynamic frequencies of Th17 cells were closely correlated with clinical parameters in SLE patients receiving standard treatment, which could facilitate the efficient management and development of novel therapeutics for SLE. [ABSTRACT FROM AUTHOR]

Objectives: To determine the serum levels of anti-dsDNA, anti-histone, and anti-nucleosome antibodies after laparoscopic ovarian electrocauterization in patients with polycystic ovarian syndrome (PCOS). Methods: Our study was performed on 35 patients with PCOS resistant to medical therapy, 35 patients with unexplained infertility, and 35 healthy fertile individuals. Patients with PCOS underwent laparoscopic electrocauterization while those with unexplained infertility underwent diagnostic laparoscopy. Serum levels of anti-dsDNA, anti-histone, and anti-nucleosome antibodies were measured at baseline and 1 month after operation and were compared between groups. Result: Baseline characteristics were similar between groups. Patients with PCOS had significantly higher levels of anti-dsDNA compared to unexplained infertility ( p < 0.001) and control groups ( p = 0.001). Anti-histone antibodies were higher in PCOS group compared to control group ( p = 0.001). In those patients suffering from PCOS, anti-histone antibody increased significantly 1 month after ovarian electrocauterization ( p = 0.017). Similarly, serum levels of anti-nucleosome antibodies increased significantly 1 month after operation ( p < 0.001). Conclusion: Laparoscopic ovarian electrocauterization in patients with PCOS results in increased levels of anti-histone and anti-nucleosome antibodies. Anti-dsDNA, anti-histone, and anti-nucleosome antibodies also increase after diagnostic laparoscopy in those with unexplained infertility. Patients with PCOS have higher levels of anti-dsDNA and anti-histone antibodies compared to those with unexplained infertility and healthy fertile subjects. [ABSTRACT FROM AUTHOR]

In order to evaluate Fas and Bcl-2 expressions in CD14+ monocytes, to measure soluble CD14 serum levels and to analyze the relationships with lupus nephritis and disease activity, we enrolled 41 patients with juvenile systemic lupus erythematosus (JSLE) and 27 healthy volunteers. Disease activity was determined by SLEDAI score. Peripheral monocytes were stained for CD14, Fas and Bcl-2 molecules, and cellular expressions were determined by flow cytometry. Soluble CD14 levels were measured by a quantitative ELISA kit. JSLE patients, those with active disease and those with nephritis, presented significantly reduced expressions of Fas and Bcl-2 proteins in CD14+ monocytes compared with healthy controls. Significant inverse correlations between percentages of CD14+Fas+ cells, SLEDAI score and anti-dsDNA antibodies were observed. JSLE patients had soluble CD14 levels similar to controls, although sCD14 levels positively correlated with ESR, but not with SLEDAI score. JSLE patients with nephritis also presented sCD14 levels similar to controls. In conclusion, the reduced expressions of Fas and Bcl-2 proteins in CD14+ monocytes from JSLE patients depict that monocyte apoptotic mechanisms may be important in lupus pathogenesis. [ABSTRACT FROM PUBLISHER]

Objective: This was an open-labeled, prospective, control study to determine the efficacy of methotrexate (MTX) for improving serological abnormalities in patients with systemic lupus erythematosus (SLE). Methods: Thirty patients with a low serum complement and/or high anti-double-stranded DNA (dsDNA) antibody levels during a prednisolone taper received MTX orally at a dose of 7.5 mg/week over 12-18 months (MTX group). Eighteen SLE patients were selected as controls (control group). At the time of entrance into the study, all patients were receiving <15 mg/day of prednisolone. The C3, C4, and immunoglobulin (Ig)G, IgA, and IgM levels were measured using a turbidimetric immunoassay. The anti-dsDNA antibody level was measured using the Farr assay. Results: Significant increases in C3 and C4 levels and significant decreases in anti-dsDNA antibody, IgG, IgA, and IgM levels from baseline were observed for 3-18 months after the trial in the MTX group but not in the control group. At the end of the study, C3 and/or C4 levels in 96.7 % of the MTX patients and 33.3 % of the control patients were normalized or elevated ( p = 0.0001), and anti-dsDNA antibody levels were normalized or lowered in 24 of the 26 MTX patients (92.3 %) and in 50.0 % of the control patients ( p = 0.0022). In addition, a significant reduction in SLE Disease Activity Index (SLEDAI) score and a prednisolone-sparing effect were observed for the MTX group but not the control group. A significant increase in mean corpuscular volume of red blood cells, which is indicative of an anti-folic-acid metabolic disorder induced by MTX, was observed only for patients in the MTX group. Five patients (16.7 %) discontinued MTX treatment because of disease flare, and another three (10.0 %) discontinued due to treatment side effects. Conclusion: MTX appears to be effective for improving serological abnormalities frequently observed before disease flares in SLE patients on a prednisolone taper. [ABSTRACT FROM AUTHOR]

Abstract: Background: Automated interpretations systems for anti-nuclear antibody (ANA), anti-double stranded DNA antibody (dsDNAab), and anti-neutrophil cytoplasmic antibody (ANCA) assessment by indirect immunofluorescence (IIF) have been recently introduced. The aim of this study was to compare the diagnostic performance of the automated IIF reading system AKLIDES with both traditional visual interpretation of IIF by laboratory experts and confirmatory tests. Methods: Visual and automated autoantibody interpretations of IIF findings using AKLIDES pattern recognition algorithms were performed for ANA on HEp-2 cells (n=182), dsDNAab on Crithidia luciliae (n=44) and ANCA on human neutrophils (n=46). All serum samples tested by IIF for ANCA and dsDNAab were also assessed with the corresponding enzyme-linked immunosorbent assays (ELISAs). Out of the 182 sera tested for ANA by IIF, 116 were also assessed for antibodies to extractable nuclear antigens (ENA) by ELISA and dot immunoassay (DIA). Results: ANA testing showed an excellent agreement between visual and AKLIDES reading (98.9%). The overall agreement of dsDNAab testing on C. luciliae substrate slides was 91.0%, whereas ANCA showed a concordance of 89.1%. There was a remarkable agreement of AKLIDES findings for dsDNAab with confirmatory tests. Conclusion: Visual and automated interpretations of IIF findings for ANA, ANCA, and dsDNAab demonstrated a good agreement when assessing patients with suspected autoimmune diseases. Automated interpretation systems such AKLIDES may improve laboratory efficiency and support standardization of IIF in clinical laboratories. [Copyright &y& Elsevier]

Our previous study demonstrated that activated lymphocyte derived DNA (ALD-DNA) could function as an autoantigen to induce production of anti-double-stranded DNA (anti-dsDNA) antibodies in syngeneic BALB/c mice. Here we carefully evaluated the potential role of T cells in the induction of anti-dsDNA antibody. We demonstrated that ALD-DNA could effectively induce production of anti-dsDNA antibodies in vivo and in vitro. In contrast, ALD-DNA could not induce the generation of anti-dsDNA antibodies in nude mice. We further showed that in vivo depletion of CD3+ T cells blocked the induction of anti-dsDNA antibodies in BALB/c mice. Notably, we demonstrated that CD4+ but not CD8+ T cells conferred ALD-DNA to induce anti-dsDNA antibodies. Finally, we demonstrated that adoptive transfer of CD4+ T cells could rescue ALD-DNA induced anti-dsDNA antibodies in nude mice. Our results suggested that T helper cells were required for ALD-DNA to induce anti-dsDNA antibodies. These findings could further our understanding about the immunogenic properties of DNA and throw new light on SLE pathogenesis. [ABSTRACT FROM PUBLISHER]

Background: We examined the relationship between antinuclear antibody (ANA) data and the presence of anti-double stranded DNA antibodies (anti-dsDNA). Methods: De-identified demographic, ANA and anti-dsDNA data were available for 30,196 individuals aged ≥20 years, whose sera were submitted sequentially to our laboratory. When multiple sera were received for the same subject, data from the earliest sample were used. Anti-dsDNA frequency was stratified by ANA titer and pattern, sample referral source, and by the patient's age, gender, and diagnosis. Results: For sera with ANA titer ≥256 and an accompanying diagnosis of systemic lupus erythematosus, anti-dsDNA frequency was 53.7%, 35.3%, and 37.5% for homogeneous, speckled, or multiple ANA patterns, respectively. Among remaining sera with ANA titer ≥256, anti-dsDNA frequency was highest for the homogeneous pattern (15.9%). Anti-dsDNA frequency was three-fold higher among sera submitted by rheumatologists compared with other providers. However, its relative distribution by ANA pattern and titer was similar between these groups. Patient age and gender had no significant effect on anti-dsDNA frequency after ANA data were taken into account. Conclusions: ANA pattern and titer, together with the diagnosis submitted with the serum sample, can be used to guide decisions for reflexive anti-dsDNA testing in a clinical laboratory setting. [ABSTRACT FROM AUTHOR]

Abstract: Background/Objective: Detection of anti-nucleosome antibodies in patients with systemic lupus erythematosus (SLE) has been well established and it is claimed that their presence is associated with disease activity. The objective of this study is to determine the diagnostic value of anti-nucleosome antibodies in the assessment of lupus nephritis and clinically active SLE. Methods: The anti-nucleosome antibodies were evaluated in the serum of 200 Tunisian SLE patients at disease onset by a sensitive immunodot assay. Serum samples from each patient were also tested for ANA and anti-ds DNA antibody by IIF on Hep 2 cells and Crithidia luciliae respectively. During the follow-up, the patients were regularly monitored for clinical parameters. Global SLE activity was measured by the European Consensus Lupus Activity Measurement (ECLAM). Results: The prevalence of anti-nucleosome and anti-dsDNA antibodies was 69% and 63.5% respectively. Anti-nucleosome antibodies were found to be 30.1% positive in SLE patients lacking anti-dsDNA antibody. 79.5% patients had active SLE at the first clinical examination. Anti-nucleosome antibodies were more sensitive than anti-dsDNA antibodies to detect active SLE (78%vs. 71.7%, P =0.19). 52.5% of SLE patients had renal involvement. Among these patients, the rate of anti-nucleosome positivity and anti-dsDNA were 77.1% and 67.6% respectively. The positivity of anti-nucleosome antibodies was significantly higher in patients with renal disease than the subjects without renal disease (P = 0.009). Anti-nucleosome and anti-ds DNA antibodies were significantly correlated with disease activity (P < 0.001 and P < 0.001 respectively). Conclusion: Anti-nucleosome antibody reactivity may be a useful marker in the diagnosis and assessment of active SLE. [Copyright &y& Elsevier]

Objectives. The transmembrane endoplasmic reticulum (ER) protein UNC93B plays an essential role in the normal response to signalling through intracellular Toll-like receptor (TLR)3, TLR7, TLR8 and TLR9. In the current study, we examined the level of UNC93B expression on peripheral B cells from patients with active SLE, and investigated any correlation with SLE pathogenesis. [ABSTRACT FROM PUBLISHER]

Abstract: Autoantibodies against double-stranded DNA (dsDNA) are found in the serum of systemic lupus erythematosus (SLE) patients. However, the mechanism by which anti-dsDNA antibodies (Abs) contribute to the pathogenesis of SLE is not yet fully understood. In this study, we investigated four anti-dsDNA mouse monoclonal autoantibodies that share positively charged amino acids (including arginines) in their complementarity determining regions for their ability to penetrate RAW264.7 macrophage cells, activate NF-κB and stimulate TNF-α production. All four antibodies penetrated into macrophage cells and increased the level of extracellular TNF-α; two also activated NF-κB. The fact that two of four cell-penetrating anti-dsDNA mAbs induced both NF-κB activation and TNF-α production in macrophages suggests that at least some autoantibodies against dsDNA may play a role in the pathogenesis of SLE by penetrating into macrophage cells and nuclei, and subsequently inducing the pro-inflammatory cytokine, TNF-α, by binding to the NF-κB gene and stimulating its transcriptional activity. [Copyright &y& Elsevier]

Patients with rheumatoid arthritis, Crohns disease or spondyloarthritis who are treated with selective TNF- inhibitors may develop autoantibodies, such as antinuclear antibodies (ANAs) and anti-dsDNA antibodies. Various methods have shown that infliximab led to ANAs in 2976.7% and anti-dsDNA antibodies in 1029% of rheumatoid arthritis patients participating in clinical trials. Furthermore, ANAs and anti-dsDNA antibodies have appeared in 1136 and 515% of rheumatoid arthritis patients treated with etanercept and 12.9% and 5.3% of those treated with adalimumab, respectively. Antiphospholipid antibodies, which are mainly detected by means of anticardiolipin assays, have also been found in rheumatoid arthritis patients receiving TNF- blockers. There have been a number of reports of the development of antidrug antibodies, of which those against infliximab lead to infusion reactions and shorter responses to treatment. This has led some authors to conclude that it is necessary to add methotrexate to infliximab in order to reduce the risk of the appearance of anti-idiotype autoantibodies. [ABSTRACT FROM AUTHOR]

Objectives. Toll-like receptor 9 (TLR9) is a pattern-associated receptor functioning in innate immunity that may be involved in the recognition of self-antigens and the production of pathogenic auto-antibodies. Therefore, we examined the expression of TLR9 in systemic lupus erythematosus (SLE) to determine whether TLR9 is involved in the production of pathogenic auto-antibodies. [ABSTRACT FROM PUBLISHER]

The aim of this study is to investigate the prevalence of antinucleosome antibody in systemic lupus erythematosus (SLE) and their association with disease activity and renal involvement. The study included 131 patients with SLE, 74 rheumatoid arthritis, 26 systemic sclerosis, and 50 healthy individuals. Antinucleosome antibody and anti-dsDNA antibody were measured by an enzyme-linked immunosorbent assay (ELISA). Antinuclear antibody was tested by immunofluorescence using HEp-2 cells. Out of 131 SLE patients, 72 (54.9%) were seropositive for antinucleosome antibody, which was significantly higher than only 3 of 74 (4%) patients with rheumatoid arthritis (χ2= 52.82, P < 0.001); none of the patients with systemic sclerosis and 50 healthy individuals were seropositive. The sensitivity and specificity of antinucleosome antibodies in SLE were 83.6% and 70%, respectively. Fifty-one (38.9%) of SLE patients had renal involvement. Among these patients, the rate of antinucleosome positivity and anti-dsDNA were 74.5% and 78.4%, respectively. Antinucleosome antibodies were found to be 31.4% positive in SLE patients lacking anti-dsDNA antibody. Antinucleosome antibodies significantly correlated with disease activity ( r= 0.428, P < 0.001) and anti-dsDNA ( r= 0518, P < 0.001). The positivity of antinucleosome antibodies was significantly higher in patients with renal disease than the subjects without renal disease (χ2= 12.89, P < 0.001). The results of our study have revealed that in SLE patients, antinucleosome antibody could be a useful parameter for the assessment of disease activity or renal involvement. [ABSTRACT FROM AUTHOR]

Abstract: Both spontaneous and chemically induced rodent models of autoimmune nephritis and autoantibody production have been explored to understand mechanisms involved in human systemic lupus erythematosus (SLE). While it has been known for decades that women are more susceptible than men to SLE, mechanisms underlying this female preponderance remain unclear. One chemically induced model involves injection of hydrocarbon oils such as pristane into otherwise normal mouse strains, which results in the development of autoantibodies and inflammation in organs such as kidney and liver. It is unknown whether lupus-like disease induced by chemicals would exhibit a sex bias in disease susceptibility. Here, we show that SJL/J female mice injected with pristane display greater mortality, kidney disease, serum anti-nuclear and anti-dsDNA antibodies than their male siblings. This is the first evidence that a female sex bias exists in a chemically induced lupus model. [Copyright &y& Elsevier]

Increased numbers of apoptotic neutrophils are found in SLE, related to disease activity and levels of anti-dsDNA antibody. The mechanism of increased apoptosis is not clear, but anti-dsDNA antibody has been shown to induce apoptosis in neutrophils from normal subjects and in certain cell lines. In this study, polyclonal anti-dsDNA antibody was isolated from the serum of a patient with active SLE, and was shown to substantially accelerate apoptosis in neutrophils from SLE patients as compared with neutrophils from healthy control or rheumatoid arthritis subjects. [ABSTRACT FROM AUTHOR]

Mizoribine (MZR) is a novel purine synthesis inhibitor that was developed in Japan. We previously reported the efficacy and safety of oral MZR intermittent pulse therapy, which is associated with elevated peak serum MZR levels, in selected patients with lupus nephritis. However, the efficacy and safety of long-term MZR intermittent pulse therapy (administered for over 24 months) in lupus nephritis patients at high risk for relapse has not yet been reported. Our study included five patients with a long history of systemic lupus erythematosus (SLE), including four patients with proliferative lupus nephritis (WHO class IV) and one patient with WHO class II lupus nephritis, in whom remission had been achieved through treatment with high-dose corticosteroids combined with cytotoxic agents. For the most recent flares, all the patients were treated with MZR intermittent pulse therapy without increase in the dose of corticosteroids. MZR was administered at 5–10 mg/kg per day (up to 500 mg) as a single daily dose on two days of the week (Monday and Thursday) for over 24 months. Concomitantly administered corticosteroid dose was gradually reduced or continued unchanged. At presentation, the urinary protein excretion, serum complement hemolytic activity (CH50) and serum anti-dsDNA antibody titer were 1.7±1.0 g/day, 16.6±3.8 U/mL (normal, 23–46 U/mL) and 143.7±151.1 IU/mL (normal,<12.0 IU/mL), respectively. At the latest observation point, after a mean interval of 31 months (24–34 months) after the initiation of MZR pulse therapy, the urinary protein excretion and serum anti-dsDNA antibody titer were significantly decreased (0.3±0.2 g/day and 18.5±19.1 IU/mL, respectively; P<0.05), and the serum CH50 value had returned to within normal range (33.6±7.8 U/mL, P<0.05). Despite the reduced minimum dose of prednisolone required to maintain clinical remission at the time of the post-treatment evaluation after MZR pulse therapy as compared with that at the time of the pretreatment evaluation (9.0±4.5 vs. 17.5±7.9 mg/day; P=0.0656), the calculated flare rate was significantly decreased (0.15±0.2 vs. 0.6±0.11 times per year; P<0.05). The serum creatinine level remained within normal range in all the study participants. Furthermore, the platelet count increased following the MZR pulse therapy in two patients who had suffered from chronic thrombocytopenia. No serious adverse effects were observed. From the view point of the balance between suppression of disease activity and the adverse effects of treatment, we believe that long-term MZR pulse therapy may be the treatment of choice in selected patients with lupus nephritis at high risk for relapse. However, this was only a pilot study conducted on a small number of subjects, without a control group. Further studies to confirm the long-term efficacy and safety of oral MZR intermittent pulse therapy in larger numbers of patients are needed. [ABSTRACT FROM AUTHOR]

Aim: Mizoribine (MZR) is a novel selective inhibitor of inosine mono-phosphatasedehydrogenase that was developed in Japan. We previously re portedthe efficacy and safety of oral MZR pulse therapy, which is associated withelevated peak serum MZR levels, in selected patients with lupus nephritis.However, only limited information is avail able as yet on the optimal peakserum level of MZR that would yield an enhanced clinical efficacy without serious toxicity in patients with lupus nephritis. Methods: A total of 11 patients withclinicallystable lupus nephritis treated with oral MZR pulse therapy combined withlow-dose prednisolone were enrolled in the cross-sectional study. The peakserum concentrations of MZR (as determined by HPLC) and the serum anti-dsDNA antibody titers (as determined by ELISA) were examined in the patients in order to evaluate the correlation between these two parameters. The correlation between the dose of MZR (mg/kg) administered orally as a single daily dose and the peak serum level of the drug was also examined. In two of the patients, serial measurements of the changes in the peak serum levels of MZR and anti-dsDNA titers could be conducted over 10 months. Results: A significant in verse correlation (r = -0.596, p = 0.0116) was observed between the peak serum levels of MZR and the serum anti-dsDNA antibody titers in the study participants, while the dose of prednisolone remained unchanged. The peak level of MZR in the serum was significantly correlated with the single dose of MZR (r = 0.509, p = 0.0371). In the two patients in whom serial measurements were conducted, the first patient who showed a peak serum MZR level of less than 2.5-3.0 mg/ml eventually developed an in crease of the serum anti-dsDNA titer with lypocomplementemia and proteinuria. On the other hand, in the second patient who showed a peak serum MZR level in excess of 4.0 mg/ml, persistently low serum anti-dsDNA titers with normocomplementemia were observed. Conclusion: Although this study is only a preliminary study conducted on a small sample, we speculate from the results that a peak serum level of MZR of at least more than 2.5-3.0 mg/ml is necessary to achieve satisfactory clinical efficacy of the drug for the treatment of lupus nephritis. Further study is needed to confirm these preliminary findings. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the development of clinically overt nephritis in patients with silent lupus nephritis in an effort to determine predictors of onset. Methods: We selected 31 patients with systemic lupus erythematosus (SLE) who were diagnosed as having silent lupus nephritis between 1985 and 1995. Urinalysis, blood cell count, serum creatinine, complement levels, and anti-double-stranded DNA antibody (anti-dsDNA antibody) levels were followed retrospectively for at least 60 months in each patient. Results: During the follow-up period, 8 patients developed clinical renal disease and 23 had no renal impairment. The mean time of overt nephritis onset was 58 months and renal function deteriorated mildly in 3 patients. Although clinical and laboratory findings were not significantly different at SLE onset, patients with overt nephritis showed both persistent elevation of anti-dsDNA antibodies and persistently low levels of serum C3 and CH50 for at least 24 months before the onset of overt nephritis. Conclusions: Although the renal prognosis was relatively favorable, 25.8% of patients developed overt nephritis during the follow-up period. Elevation of anti-dsDNA antibodies with hypocomplementemia was persisted in these patients, suggesting the utility of these factors as predictors of clinical renal involvement in silent lupus nephritis. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We prospectively analyzed the diagnostic sensitivity and specificity as well as the clinical relevance of antinucleosome antibodies in SLE.One hundred and one consecutive SLE patients were followed for 3 years. Three serial serum samples from each patient were tested for antinucleosome antibodies by ELISA (optimum cut-off value 10 U/ml), and for anti-dsDNA antibody (by ELISA and IIF on Crithidia luciliae), and anti-dsDNA avidity (by Scatchard plot analysis). Sera from 100 healthy individuals (HI), 35 patients with systemic sclerosis (SSc), 30 with primary Sjo¨gren's syndrome (SS), 20 with rheumatoid arthritis (RA) and 48 with infectious diseases (ID), were assayed as controls. SLE activity and damage were evaluated using the ECLAM score and the SLICC/ACR index.At baseline, antinucleosome antibodies were found in 87 patients with SLE (86.1%), in 8 patients with SSc (22.8%), in 2 HI (2%), and in 1 ID (2.1%). The sensitivity and specificity of antinucleosome testing for SLE were 86.1% and 95.3%, respectively. The prevalence of antinucleosome antibodies in SLE was significantly higher than that of anti-dsDNA antibodies, with a correlation between them. No relevant relationship was found between antinucleosome antibodies and disease features, including renal involvement, disease activity, and disease damage. During follow-up, no significant variation was observed in antinucleosome level, nor in anti-dsDNA antibody level or avidity.We conclude that antinucleosome antibodies are commonly found in SLE. Low antibody levels can be detected in SSc, whereas medium/high levels are highly specific for SLE. Their clinical relevance during the disease course and utility for monitoring the individual patient seem to be poor. [Copyright &y& Elsevier]