anti-DNA Antibodies Research Articles

Self-DNA at the Epicenter of SLE: Immunogenic Forms, Regulation, and Effects.

Self-reactive B cells generated through V(D)J recombination in the bone marrow or through accrual of random mutations in secondary lymphoid tissues are mostly purged or edited to prevent autoimmunity. Yet, 10–20% of all mature naïve B cells in healthy individuals have self-reactive B cell receptors (BCRs). In patients with serologically active systemic lupus erythematosus (SLE) the percentage increases up to 50%, with significant self-DNA reactivity that correlates with disease severity. Endogenous or self-DNA has emerged as a potent antigen in several autoimmune disorders, particularly in SLE. However, the mechanism(s) regulating or preventing anti-DNA antibody production remain elusive. It is likely that in healthy subjects, DNA-reactive B cells avoid activation due to the unavailability of endogenous DNA, which is efficiently degraded through efferocytosis and various DNA-processing proteins. Genetic defects, physiological, and/or pathological conditions can override these protective checkpoints, leading to autoimmunity. Plausibly, increased availability of immunogenic self-DNA may be the key initiating event in the loss of tolerance of otherwise quiescent DNA-reactive B cells. Indeed, mutations impairing apoptotic cell clearance pathways and nucleic acid metabolism-associated genes like DNases, RNases, and their sensors are known to cause autoimmune disorders including SLE. Here we review the literature supporting the idea that increased availability of DNA as an immunogen or adjuvant, or both, may cause the production of pathogenic anti-DNA antibodies and subsequent manifestations of clinical disease such as SLE. We discuss the main cellular players involved in anti-DNA responses; the physical forms and sources of immunogenic DNA in autoimmunity; the DNA-protein complexes that render DNA immunogenic; the regulation of DNA availability by intracellular and extracellular DNases and the autoimmune pathologies associated with their dysfunction; the cytosolic and endosomal sensors of immunogenic DNA; and the cytokines such as interferons that drive auto-inflammatory and autoimmune pathways leading to clinical disease. We propose that prevention of DNA availability by aiding extracellular DNase activity could be a viable therapeutic modality in controlling SLE.

Corrigendum: Akkermansia muciniphila as a Model Case for the Development of an Improved Quantitative RPA Microbiome Assay.

[This corrects the article DOI: 10.3389/fcimb.2018.00237.].

Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell-Targeted Nanoparticles Loaded With Interleukin-2 and Transforming Growth Factor β.

To develop a nanoparticle (NP) platform that can expand both CD4+ and CD8+ Treg cells in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE). Poly(lactic-co-glycolic acid) (PLGA) NPs encapsulating interleukin-2 (IL-2) and transforming growth factor β (TGFβ) were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 × DBA/2)F1 (BDF1) mice. The peripheral frequency of Treg cells was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-double-stranded DNA antibody levels by enzyme-linked immunosorbent assay. Kidney disease was defined as the presence of proteinuria or renal histopathologic features. Anti-CD2/CD4 antibody-coated, but not noncoated, NPs encapsulating IL-2 and TGFβ induced CD4+ and CD8+ FoxP3+ Treg cells in vitro. The optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Treg cells was determined in in vivo studies in mice without lupus and then tested in BDF1 mice with lupus. The administration of anti-CD2/CD4 antibody-coated NPs encapsulating IL-2 and TGFβ resulted in the expansion of CD4+ and CD8+ Treg cells, a marked suppression of anti-DNA antibody production, and reduced renal disease. This study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGFβ can expand both CD4+ and CD8+ Treg cells in vivo and suppress murine lupus. This approach, which enables the expansion of Treg cells in vivo and inhibits pathogenic immune responses in SLE, could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Treg cell function associated with IL-2 deficiency.

Abstract IA22: Autoimmune rheumatic diseases and cancer

Abstract Some rheumatic disease autoantibodies are powerful markers of subgroups of patients who have distinct disease phenotypes and trajectories. Of particular interest are markers of several disease subgroups in whom cancer and rheumatic disease onset are clustered together in time. For example, a subgroup of scleroderma patients have coincident onset of cancer and scleroderma. This is observed in scleroderma patients with autoantibodies against RNA polymerase-3 (POLR3), and more recently with autoantibodies recognizing the minor spliceosome. In autoimmune myopathies, temporal clustering of diagnosis of cancer and myositis is associated with autoantibodies to NXP2 and components of the TIF1 complex. Interestingly, although the incidence of cancer is higher in patients with these autoantibodies, most patients with these autoantibodies do not manifest cancer, even with extended periods of follow-up. These observations provide an important opportunity to investigate the potential mechanisms which operate at the cancer-immune interface during development of rheumatic diseases. In cancers from anti-POLR3-positive scleroderma patients with a short scleroderma-cancer interval, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to POLR3 but not in eight patients without these antibodies. 3 antibody-positive patients had somatic mutations in POLR3A; 5 patients had loss of heterozygosity at the POLR3A locus. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations sparked cellular immunity and cross-reactive humoral immune responses. In a larger scleroderma cohort (>2300 patients), the incidence of cancer in various autoantibody subgroups was compared to data from the Surveillance, Epidemiology and End Results (SEER) Program. An increase in cancer incidence in scleroderma patients with POLR3 autoantibodies was observed compared to the general population; strikingly, patients with anti-centromere autoantibodies had a lower cancer incidence than observed in the general population. The finding that distinct serologic subgroups have different cancer risks suggests that cancer immunity may be a common principle across the scleroderma spectrum, with cancer emergence influenced by the effectiveness of the different immune responses. For example, in scleroderma patients with anti-centromere antibodies, cancer emergence may be inhibited, while inhibition of cancer emergence may only be partial for anti-POLR3. Prior studies in small cohorts of breast cancer patients have demonstrated that anti-centromere antibodies may be present, and may associate with improved disease-free and overall survival. Additionally, recent data also suggest that anti-DNA antibodies can have direct anti-cancer effects in cells with DNA repair defects, possibly explaining the decreased risk of breast and other cancers observed among patients with SLE.Taken together, these data suggest that at least some patients with autoimmune rheumatic diseases such as scleroderma may represent natural cancer immunoediting in humans. In the simplest model, somatic mutations in autoantigens in different cancers initiate an immune response to the mutated autoantigen, which spreads to include the wild type version, and exerts both an anti-cancer effect as well as causes damage or dysfunction of normal tissues. Understanding the mechanisms underlying the range of efficacies of the anti-cancer effects in different patients and subgroups may provide important insights into how the anti-cancer immune response in autoimmune diseases might be more effectively harnessed therapeutically. Citation Format: Livia Casciola-Rosen, Ami Shah, Antony Rosen. Autoimmune rheumatic diseases and cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA22.

Intravenous immune globulin therapy of lupus nephritis: use of pathogenic anti-DNA-reactive IgG

The authors have recently shown that antibodies with anti-idiotype (Id) specificity to pathogenic Ids of lupus nephritis may occasionally occur in several intravenous immune globulin (IVIG) preparations because they are present in healthy donors and the healthy relatives of SLE patients. In the present study, the authors purified these anti-Ids and treated two SLE patients with nephritis in parallel with conventional high-dose IVIG management with a commercial preparation (IVIG 6) in three controls for two months. Because pathogenic Ids of anti-DNA molecules, such as both 8.12 and F4 Ids, show a cationic mobility in isoelectric focusing, a commercial preparation of IVIG (11) was absorbed on a Sepharose column coupled with DC-305-39 myeloma protein, namely an 8.12+ and F4+ cationic IgG. Infusion of the eluate (EL-11) induced a prompt resolution of proteinuria levels and an evident decrease of serum levels of anti-DNA antibodies in both patients, whereas in the three controls, proteinuria and anti-DNA antibodies were scarcely reduced. In addition, plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha were also significantly influenced by both treatments. The mean values of both cytokines increased significantly after 1 h and then progressively declined over the next 48 h. It was of interest, however, that the increased TNF-alpha in the two EL-11-treated patients was significantly lower than in the three controls. The data suggest that reduction of active lupus nephritis by enriched specific anti-Id molecules is the result of two (or perhaps more) mechanisms: suppression of pathogenic idiotypes at the cellular level and improvement in the mesangium of the secretion of anti-inflammatory cytokines, such as IL-6, whose defective function is related to the autoimmune disorder.

A Case of MPO-ANCA Positive Systemic Lupus Erythematosus Developed into Acute Kidney Injury

During the course of treatment for rheumatoid arthritis, anti-DNA antibody was detected, and systemic lupus erythematosus was diagnosed, who was subsequently treated with abatacept—and remission was achieved. Rebound of elevated anti-DNA antibody and urinary abnormalities were noted with MPO-ANCA positivity. Renal biopsy revealed lupus nephritis; followed by the development of rapidly progressive glomerulonephritis, which required apheresis (double filtration plasmapheresis) therapy, although no response was achieved. However, plasma exchange therapy was highly effective. These results suggest that MPO-ANCA-positive lupus nephritis can become severe and require intensive treatment in accordance with the treatment for severe vasculitis.

Leptospirosis as Unusual Trigger of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder of an unknown origin. The role of leptospirosis as a triggering factor for SLE is unknown. This paper reports an uncommon case of SLE following a leptospira infection. A 29-year-old female was referred due to fevers, myalgia, and facial edema with rash. Laboratory investigations revealed a hepatic dysfunction, significantly raised lactate dehydrogenase with marked leukopenia and thrombocytopenia. A diagnosis of leptospirosis was confirmed. The patient was treated with antibiotic therapy for leptospirosis. She developed dyspnea after one week. The echocardiogram revealed global hypokinesia with a decreased ejection fraction. A positivity of antinuclear, anti-DNA, and anti-Smith antibodies, together with clinical and laboratory improvement by steroid therapy, led to the diagnosis of SLE. This case highlights the presence of concurrent SLE and leptospirosis. As the symptoms of SLE are similar to leptospirosis, accurate diagnosis through high suspicion is essential for appropriate treatment.

Anti-DNA antibody detected by Farr assay in six patients with rheumatoid arthritis

Anti-DNA antibody detected by Farr assay in six patients with rheumatoid arthritis

Dnase1l3 deletion causes aberrations in length and end-motif frequencies in plasma DNA

Circulating DNA in plasma consists of short DNA fragments. The biological processes generating such fragments are not well understood. DNASE1L3 is a secreted DNASE1-like nuclease capable of digesting DNA in chromatin, and its absence causes anti-DNA responses and autoimmunity in humans and mice. We found that the deletion of Dnase1l3 in mice resulted in aberrations in the fragmentation of plasma DNA. Such aberrations included an increase in short DNA molecules below 120 bp, which was positively correlated with anti-DNA antibody levels. We also observed an increase in long, multinucleosomal DNA molecules and decreased frequencies of the most common end motifs found in plasma DNA. These aberrations were independent of anti-DNA response, suggesting that they represented a primary effect of DNASE1L3 loss. Pregnant Dnase1l3-/- mice carrying Dnase1l3+/- fetuses showed a partial restoration of normal frequencies of plasma DNA end motifs, suggesting that DNASE1L3 from Dnase1l3-proficient fetuses could enter maternal systemic circulation and affect both fetal and maternal DNA fragmentation in a systemic as well as local manner. However, the observed shortening of circulating fetal DNA relative to maternal DNA was not affected by the deletion of Dnase1l3 Collectively, our findings demonstrate that DNASE1L3 plays a role in circulating plasma DNA homeostasis by enhancing fragmentation and influencing end-motif frequencies. These results support a distinct role of DNASE1L3 as a regulator of the physical form and availability of cell-free DNA and may have important implications for the mechanism whereby this enzyme prevents autoimmunity.

From the Literature

From the Literature

Autoantibodies in HIV-infected patients: Cross site-specific hydrolysis of H1 histone and myelin basic protein.

Histones act as damage-associated molecules, while anti-DNA antibodies are directed against histone-DNA nucleosomal complexes. Myelin basic protein (MBP) plays an important role in the pathogenesis of multiple sclerosis. Autoantibodies (Abs) with enzymatic activities are the distinctive feature of some autoimmune and viral diseases. Abzymes with proteolytic activity against different proteins specifically hydrolyze only these specific proteins. Using chromatography of IgGs on columns with immobilized H1 histone and then by chromatography of the fraction having an affinity for the histone (eluted upon loading) on MBP Sepharose, the anti-MBP antibodies were obtained. Anti-H1 antibodies were obtained using these columns in reverse order. IgGs against H1 and MBP effectively hydrolyze both H1 histone and MBP but no other control proteins. Using the MALDI mass spectrometry, the cleavage sites of H1 histone and MBP by abzymes against these proteins are found. The hydrolysis of MBP by anti-MBP IgGs occurs at four clusters (22 sites of the hydrolysis) locating at four known antigenic determinants of MBP. Anti-H1 Abs hydrolyze MBP only at one cluster (11 sites of the hydrolysis); this cluster is only partially overlapped with one of the four MBP clusters. Anti-H1 antibodies hydrolyze H1 at five sites of one cluster of the protein when anti-MBP IgGs cleavage this histone at two clusters containing 17 sites of the cleavage. Anti-H1 and anti-MBP abzymes are the first examples of Abs possessing not only with cross-complexing but also with catalytic cross-reactivity. The existence of cross-reactivity of abzymes against histones and MBP represent great danger to humans. © 2018 BioFactors, 45(2):211-222, 2019.

Clinical significance of anti-DNA/N-methyl-D-aspartate receptor 2 antibodies in de novo and post-steroid cases with neuropsychiatric systemic lupus erythematosus.

Anti-DNA/N-methyl-D-aspartate receptor 2 (NR2) antibodies (anti-DNA/NR2 antibodies) are a subset of anti-DNA autoantibodies that cross-react with the extracellular domain of the GluN2A/GluN2B subunits of NR2. These antibodies induce apoptosis of hippocampus neurons and psychiatric disorder in mice and humans. Neuropsychiatric system lupus erythematosus (NPSLE) can develop after initiation of corticosteroids (post-steroid neuropsychiatric manifestation: PSNP) or before treatment (de novo NPSLE); however, pathophysiological differences between these subtypes remain unclear. The objective of this study was to clarify the prevalence of anti-DNA/NR2 antibodies in patients with NPSLE. This study involved a cohort of patients with NPSLE admitted to our hospital. NPSLE patients were classified into two groups, de novo NPSLE and PSNP-SLE. Serum anti-DNA antibodies and anti-DNA/NR2 antibodies were measured by enzyme-linked immunosorbent assays. Serum samples were obtained from 24 patients with de novo NPSLE, 25 with PSNP-SLE and 76 healthy controls (HC). The level of anti-DNA/NR2 antibodies in patients with de novo NPSLE and PSNP-SLE were also higher than those in HC. Positive correlation between anti-DNA antibodies and anti-DNA/NR2 antibodies were found in PSNP-SLE, but was not significant in de novo NPSLE. The levels of anti-DNA/NR2 antibodies in PSNP-SLE were similar to those in de novo NPSLE. Anti-DNA/NR2 antibodies in PSNP-SLE were suggested as a dominant subset of anti-DNA antibodies, indicating that anti-DNA/NR2 antibodies may be a predictive factor in PSNP-SLE.

Antibody Epitope Specificity for dsDNA Phosphate Backbone Is an Intrinsic Property of the Heavy Chain Variable Germline Gene Segment Used.

Analysis of protein sequences by the informational spectrum method (ISM) enables characterization of their specificity according to encoded information represented with defined frequency (F). Our previous data showed that F(0.367) is characteristic for variable heavy chain (VH) domains (a combination of variable (V), diversity (D) and joining (J) gene segments) of the anti-phosphocholine (PC) T15 antibodies and mostly dependent on the CDR2 region, a site for PC phosphate group binding. Because the T15 dsDNA-reactive U4 mutant also encodes F(0.367), we hypothesized that the same frequency may also be characteristic for anti-DNA antibodies. Data obtained from an analysis of 60 spontaneously produced anti-DNA antibody VH domain sequences supported our hypothesis only for antibodies, which use V gene segment in germline configuration, such as S57(VH31), MRL-DNA22, and VH11, members of the VH1 (J558) and VH7 (S107) gene families. The important finding is that out of seven V gene segments used by spontaneous anti-DNA antibodies, F(0.367) is only expressed by the germline configuration of these three V gene segments. The data suggest that antibody specificity for the phosphate group moiety delineated as F(0.367) is the intrinsic property of the V germline gene segments used, whereas paratope/epitope interaction with antigens bearing this epitope, such as PC or dsDNA, requires corresponding antibody VH conformation that is susceptible to somatic mutation(s).

Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors.

Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.

Cytosolic Internalization of Anti-DNA Antibodies by Human Monocytes Induces Production of Pro-inflammatory Cytokines Independently of the Tripartite Motif-Containing 21 (TRIM21)-Mediated Pathway.

Anti-DNA autoantibodies are a hallmark of systemic lupus erythematosus (SLE). A subset of anti-DNA IgG autoantibodies is cell-internalizable; thus they can enter living cells in the form of free IgG. However, the contribution made by the Fc region of internalized free-form IgG to the cytokine response has not been studied, despite the recent discovery of tripartite motif-containing 21 (TRIM21), a cytosolic Fc receptor involved in immune signaling. This study used an internalizable IgG anti-DNA antibody (3D8) to examine the cytokine responses of human monocytes to the Fc region of cytosolic free IgG. Internalization of 3D8 IgG and a 3D8 single-chain variable fragment-Fc (scFv-Fc) induced production of IL-8 and TNF-α via activation of NF-κB. By contrast, a 3D8 scFv (comprising variable domains alone) did not. This suggests Fc-dependent cytokine signaling. A 3D8 IgG-N434D mutant that is not recognized by TRIM21 induced greater production of cytokines than 3D8 IgG. Moreover the amounts of cytokines induced by 3D8 IgG in TRIM21-knockdown THP-1 cells were higher than those in control cells, indicating that cytokine signaling is not mediated by TRIM21. The results suggest the existence of a novel Fc-dependent signaling pathway that is activated upon internalization of IgG antibodies by human monocytes.

Follicular Helper T Cells in Systemic Lupus Erythematosus.

CD4+ follicular helper T (Tfh) cells constitute a subset of effector T cells that participate in the generation of high-affinity humoral responses. They express the chemokine receptor CXCR5 and produce the cytokine IL-21, both of which are required for their contribution to germinal center formation. Uncontrolled expansion of Tfh cells is observed in various mouse models of systemic autoimmune diseases and in patients with these diseases. In particular, the frequency of circulating Tfh is correlated with disease activity and anti-DNA antibody titer in patients with systemic lupus erythematosus. Recent studies reveal functional diversity within the Tfh population in both humans and mice. We will summarize here the molecular mechanisms for Tfh cell generation, survival and function in both humans and mice, and the relationship between Tfh cells and autoimmune disease in animal models and in patients.

Preeclampsia without hypertension occurring at 17 weeks of amenorrhea; a case report and review of literature

In general, the term "preeclampsia" refers to the presence of hypertension associated with proteinuria occurring after 20 weeks of gestation in a previously non-proteinuric and normotensive woman. A 24-year-old woman, known to be non-hypertensive, carried two pregnancies and lost two babies. In 2011, as she was carrying the third (twin) pregnancy at 17 weeks of amenorrhea, she was admitted to the hospital for an 8-kilogram excess weight gain between two antenatal visits spaced 4 weeks apart. The clinical examination revealed 140 mmHg systolic blood pressure and 80 mm Hg diastolic blood pressure. The following days, the systolic blood pressure ranged between 110 and 120 mm Hg. Furthermore, the presence of bilateral and symmetrical pitting edema of the lower limbs was reported. The laboratory assessment upon admission showed the following results, proteinuria; 3.3 g/24 h, total albumin; 1.7 g/dL, total protein; 5.4 g/dL and total calcium was 75 g/L. The test results for HIV serology, HBs antigen and HCV antibodies as well as antinuclear and native anti-DNA antibodies were negative. The treatment consisted of iron, folic acid and calcium supplementation. Cesarean section was scheduled for the 38th week. The immediate aftermath was simple. Formula feeding was recommended for the newborns and ramipril 1.25 mg was initiated in the mother once daily. The evolution was marked by a progressive reduction in proteinuria around 500 mg/24 h six months after delivery, and below 200 mg/24 h one year later. Pre-eclampsia before 20 weeks of gestation is rare. Hypertension, which is its main clinical sign, may be exceptionally absent at this stage.

Akkermansia muciniphila as a Model Case for the Development of an Improved Quantitative RPA Microbiome Assay.

Changes in the population levels of specific bacterial species within the gut microbiome have been linked to a variety of illnesses. Most assays that determine the relative abundance of specific taxa are based on amplification and sequencing of stable phylogenetic gene regions. Such lab-based analysis requires pre-analytical sample preservation and storage that have been shown to introduce biases in the characterization of microbial profiles. Recombinase polymerase amplification (RPA) is an isothermal nucleic acid amplification method that employs commercially available, easy-to-use freeze-dried enzyme pellets that can be used to analyze specimens rapidly in the field or clinic, using a portable fluorometer. Immediate analysis of diverse bacterial communities can lead to a more accurate quantification of relative bacterial abundance. In this study, we discovered that universal bacterial 16S ribosomal DNA primers give false-positive signals in RPA analysis because manufacturing host Escherichia coli DNA is present in the RPA reagents. The manufacturer of RPA reagents advises against developing an RPA assay that detects the presence of E. coli due to the presence of contaminating E. coli DNA in the reaction buffer (www.twistdx.co.uk/). We, therefore, explored four strategies to deplete or fragment extraneous DNA in RPA reagents while preserving enzyme activity: metal-chelate affinity chromatography, sonication, DNA cleavage using methylation-dependent restriction endonucleases, and DNA depletion using anti-DNA antibodies. Removing DNA with anti-DNA antibodies enabled the development of a quantitative RPA microbiome assay capable of determining the relative abundance of the physiologically-important bacterium Akkermansia muciniphila in human feces.

DNA Damage and Deficiencies in the Mechanisms of Its Repair: Implications in the Pathogenesis of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a perplexing and potentially severe disease, the pathogenesis of which is yet to be understood. SLE is considered to be a multifactorial disease, in which genetic factors, immune dysregulation, and environmental factors, such as ultraviolet radiation, are involved. Recently, the description of novel genes conferring susceptibility to develop SLE even in their own (monogenic lupus) has raised the interest in DNA dynamics since many of these genes are linked to DNA repair. Damage to DNA induces an inflammatory response and eventually triggers an immune response, including those targeting self-antigens. We review the evidence that indicates that patients with SLE present higher levels of DNA damage than normal subjects do and that several proteins involved in the preservation of the genomic stability show polymorphisms, some of which increase the risk for SLE development. Also, the experience from animal models reinforces the connection between DNA damage and defective repair in the development of SLE-like disease including characteristic features such as anti-DNA antibodies and nephritis. Defining the role of DNA damage response in SLE pathogenesis might be strategic in the quest for novel therapies.

Antibodies to extractable nuclear antigens (ENAS) in systemic lupus erythematosus patients: correlations with clinical manifestations and disease activity.

The aim was to explore possible correlations of antibodies to extractable nuclear antigens (ENA) with clinical manifestations and disease activity indices in systemic lupus erythematosus (SLE) patients. A total of 70 consecutive SLE patients (64 females) were included. Disease activity was assessed by SLE activity index (SLEDAI), and British Isles Lupus Assessment Group (BILAG). Anti-Ro/SSA correlated positively with, headache (r=0.24, p=0.04), blurring of vision (r=0.25, p=0.03) and SLEDAI (r=0.25, p=0.04) and negatively with C3 (r=-0.35, p=0.003). Anti-Ro/SSA correlated with anti La/SSB antibodies (r=0.69, p<0.001), but not with anti-DNA, anti-RNP and anti-Sm antibodies. Anti-La/SSB antibodies correlated with headache (r=0.26, p=0.03), SLEDAI (r=0.25, p=0.03) and negatively with C3 (r=-0.34, p=0.004). Anti-La/SSB did not correlate with anti-RNP or anti-Sm antibodies. Anti-Sm antibodies correlated with disease duration (r=0.34, p=0.003), 24 hours urinary proteins (r=0.31, p=0.008), SLEDAI (r=0.31, p=0.009), BILAG renal score (r=0.29, p=0.02) and negatively with age at onset (r=-0.27, p=0.02), WBCs (r=-0.29, p=0.014) and C4 (r=-0.25, p=0.049). In multivariate analyses, anti-Ro/SSA antibodies remained associated with headache, blurring of vision and C3 and anti-La/SSB antibodies remained associated with C3 and with headache. Anti-Sm antibodies were independently associated with disease duration and total SLEDAI scores, while anti-RNP antibodies remained significantly associated with BILAG mucocutaneous scores only. Antibodies to ENAs are associated with clinical aspects of SLE and may play a role in the assessment of disease activity. Insight into these ENAs may lead to new approaches to diagnostic testing, accurate evaluation of disease activity and lead to target approach for SLE.