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OBJECTIVES: The predominant determinant of an unfavorable prognosis among Systemic Lupus Erythematosus (SLE) patients resides in the irreversible organ damage. This prospective cohort study aimed to identify the additional value of anti-nucleosome antibodies on organ damage accumulation in SLE patients. METHODS: Based on the Chinese SLE Treatment and Research group (CSTAR) registry, demographic characteristics, autoantibodies profiles, and clinical manifestations were collected at baseline. Follow-up data were collected by reviewing clinical records. RESULTS: Of 2481 SLE patients with full follow-up data, 663 (26.7%) were anti-nucleosome antibodies positive and 1668 (68.0%) were anti-dsDNA antibodies positive. 764 (30.8%) patients developed new organ damage during a mean follow-up of 4.31 ± 2.60 years. At baseline, patients with positive anti-nucleosome antibodies have a higher rate of lupus nephritis (50.7% vs 36.2%, p < .001). According to the multivariable Cox regression analysis, both anti-nucleosome (HR = 1.30, 95% CI, 1.09-1.54, p < .001) and anti-dsDNA antibodies (HR=1.68, 95% CI, 1.38-2.05, p < .001) were associated with organ damage accumulation. Anti-nucleosome (HR = 2.51, 95% CI, 1.81-3.46, p < .001) and anti-dsDNA antibodies (HR = 1.69, 95% CI, 1.39-2.06, p < .001) were independent predictors for renal damage. Furthermore, the combination of the two antibodies can provide more accurate information about renal damage in overall SLE patients (HR = 3.19, 95% CI, 2.49-4.10, p < .001) and patients with lupus nephritis at baseline (HR = 2.86, 95% CI, 2.29-3.57, p < .001). CONCLUSION: Besides anti-dsDNA antibodies, anti-nucleosome antibodies can also provide information about organ damage accrual during follow-up. The ability of co-positivity of anti-nucleosome and anti-dsDNA antibodies in predicting renal damage may lead to additional benefits in the follow-up of these patients.
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Anticuerpos Antinucleares , Lupus Eritematoso Sistémico , Nefritis Lúpica , Nucleosomas , Humanos , Femenino , Masculino , Adulto , Nucleosomas/inmunología , Estudios Prospectivos , Anticuerpos Antinucleares/inmunología , Anticuerpos Antinucleares/sangre , Nefritis Lúpica/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/complicaciones , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Adulto Joven , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Sistema de Registros , China , Riñón/inmunología , Riñón/patología , Análisis Multivariante , Estudios de SeguimientoRESUMEN
Background: Nearly half of the Systemic lupus erythematosus (SLE) patients develop lung involvement. The study assessed the extent of pulmonary involvement among SLE patients and to identify the associated factors in the population. Methodology: This retrospective cohort study was conducted at Aseer Hospital and Khamis Myshat Hospital in the Southern region of Saudi Arabia. The study spanned from January 1, 2016, to June 3, 2023. Patient inclusion criteria encompassed individuals who received a definitive diagnosis and classification as per American College of Rheumatology criteria, while patients under 18 years of age and those with mixed connective tissue diseases were exclude. Results: A total of 247 participants were included. 41.7% (n=103) aged 41 years and older, 95.1% (n = 235) were females. Around 10.10% had diabetes mellitus and 17.00% had hypertension and hypothyroidism. Lupus Nephritis was in 15.40%. Chest involvement was reported in 21.9%, in the form of pleuritis (6.10%), pleural effusion (4.00%), and lupus pneumonitis (4.00%), interstitial lung disease (4.00%), pulmonary embolism (3.60%) of individuals, and pulmonary hemorrhage (2.80%). The respiratory symptoms reported by SLE were; dyspnea, cough, and chest pain each having a prevalence of around 18.0%. Palpitations have a relatively high occurrence at 13.80%. Meanwhile, hemoptysis (blood coughing) has a lower prevalence of 1.20%, and fever is reported at 2.80%. Having chronic kidney disease and hypertension were significantly associated with having pulmonary involvement; (χ2=3.308, p=0.027) and (χ2=7.782, Fisher's p=0.002) respectively. The seropositivity for antiphospholipid Abs, anti-CCP, and antids-DNA were significantly associated with pulmonary involvement (χ2=3.239, =p=0.049), (χ2=4.621, Fisher's p=0.023), and (χ2=8.248, p=0.010) respectively. Conclusion: The study found that 21.9% of SLE patients experience chest involvement, with varying degrees of pulmonary symptoms. Factors such as chronic kidney disease, hypertension, antiphospholipid antibodies, Anti-CCP positivity, and seropositivity for Anti-dsDNA were found to be significant associations with lung involvement, contributing to our understanding of SLE.
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Objective: The presence of urinary autoantibodies in patients with systemic lupus erythematosus (SLE) has been confirmed by several studies; however, the significance of their presence in urine remains unclear. This study aims to further investigate the association between urine autoantibodies and disease activity as well as organ involvement in SLE. Methods: This cross-sectional study included 89 SLE patients. Data collected included anti-nuclear antibody (ANA), anti-ENA antibodies, and anti-dsDNA antibody levels in both serum and urine, complement (C) 3, C4 levels in serum, SLE disease activity index-2000 (SLEDAI-2000), renal domains of SLEDAI (RSLEDAI) and non-renal SLEDAI (NRSLEDAI). Results: The rate of positive urine ANA (uANA) was 33.3% (29/87) among the enrolled patients. Compared to the uANA negative group, the positive group exhibited significantly higher SLEDAI-2000 scores (7.85 ± 5.88 vs. 18.69 ± 6.93, p < 0.001), RSLEDAI scores [0 (0, 4.0) vs. 12.0 (8.0, 16.0), p < 0.001], and NRSLEDAI [4 (2.0, 8.0) vs. 6.0 (4.0, 9.5), p = 0.038]. Patients with positive urine anti-Sm antibody demonstrated significantly elevated SLEDAI-2000 scores compared to those who were negative (25.0 ± 8.80 vs. 10.09 ± 6.63, p < 0.001). Similarly, they also had higher RSLEDAI [16.0 (12.0, 16.0) vs. 4.0 (0, 8.0), p < 0.001] and NRSLEDAI [9.5 (6.0, 13.5) vs. 4.0 (3.0, 8.0), p = 0.012], as well as a greater prevalence of renal involvement compared to their negative counterparts (100% vs. 58.2, p = 0.022). There was a positive correlation between uANA titer and both SLEDAI-2000 (rs = 0.663, p < 0.001) and RSLEDAI (rs = 0.662, p < 0.001). The serum anti-dsDNA antibody level did not exhibit a significant correlation with RSLEDAI (rs = 0.143, p = 0.182). Conversely, the urine anti-dsDNA antibody level demonstrated a significant positive correlation with RSLEDAI (rs = 0.529, p < 0.001). Conclusion: Urine ANA is associated with both global SLEDAI and RSLEDAI scores. Urine anti-Sm antibody is associated with an increased incidence of renal involvement in SLE. The urine anti-dsDNA antibody level, rather than the serum anti-dsDNA antibody level, exhibits a significant association with RSLEDAI in SLE.
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The basic initiative related to this study is derived from the fact that systemic lupus erythematosus (SLE) is a unique and fertile system science subject. We are, however, still far from understanding its nature. It may be fair to indicate that we are spending more time and resources on studying the complexity of classified SLE than studying the validity of classification criteria. This study represents a theoretical analysis of current instinctual SLE classification criteria based on "the causality principle." The discussion has its basis on the radical scientific traditions introduced by Robert Koch and Louis Pasteur. They announced significant changes in our thinking of disease etiology through the implementation of the modern version of "the causality principle." They influenced all aspects of today's medical concepts and research: the transformation of medical science from studies of symptoms to study their causes, relevant for monosymptomatic diseases as for syndromes. Their studies focused on bacteria as causes of infectious diseases and on how the immune system adapts to control and prevent contagious spreading. This is the most significant paradigm shift in the modern history of medicine and resulted in radical changes in our view of the immune system. They described acquired post-infection immunity and active immunization by antigen-specific vaccines. The paradigm "transformation" has a great theoretical impact also on current studies of autoimmune diseases like SLE: symptoms and their cause(s). In this study, the evolution of SLE classification and diagnostic criteria is discussed from "the causality principle" perspective, and if contemporary SLE classification criteria are as useful as believed today for SLE research. This skepticism is based on the fact that classification criteria are not selected based on cogent causal strategies. The SLE classification criteria do not harmonize with Koch's and Pasteur's causality principle paradigms and not with Witebsky's Koch-derived postulates for autoimmune and infectious diseases. It is not established whether the classification criteria can separate SLE as a "one disease entity" from "SLE-like non-SLE disorders"-the latter in terms of SLE imitations. This is discussed here in terms of weight, rank, and impact of the classification criteria: Do they all originate from "one basic causal etiology"? Probably not.
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Enfermedades Autoinmunes , Enfermedades Transmisibles , Lupus Eritematoso Sistémico , Humanos , Anticuerpos Antinucleares , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/etiologíaRESUMEN
OBJECTIVE: Topoisomerase I (topo I) is a highly conserved enzyme which is known to reduce torsional stress at double-stranded (ds) DNA. Torsional stress induced by supercoiling of dsDNA requires either very long dsDNA existing in genomic DNA or circulation as presented in plasmid DNA. To enable DNA relaxation, topo I induce a transient single-strand break followed by stress-relieving rotation of the released DNA strand. Our group found by serendipity that the topo I inhibitor irinotecan is able to suppress murine systemic lupus erythematosus (SLE), an autoimmune disease which is characterized by the existence of pathogenic anti-dsDNA antibodies (abs). As a possible mechanism we demonstrated in the absence of immunosuppression an increased binding of anti-dsDNA abs to long genomic or circulated plasmid dsDNA modified with topo I. RESULTS: Here we show that this effect requires active site tyrosine of topo I which is known to facilitate DNA relaxation activity. Moreover, topo I enhanced anti-dsDNA abs binding to short linear oligonucleotides down to a size of 42 bp. Since oligonucleotides of such length are devoid of torsional stress and relaxation respectively, our results suggest a new and unknown function for the enzyme topo I.
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ADN-Topoisomerasas de Tipo I , Lupus Eritematoso Sistémico , Animales , Ratones , ADN-Topoisomerasas de Tipo I/genética , ADN-Topoisomerasas de Tipo I/metabolismo , Oligonucleótidos , Anticuerpos Antinucleares/metabolismo , ADN/genéticaRESUMEN
Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA-anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Células Endoteliales/patología , Glomérulos Renales/patología , Autoanticuerpos , Lupus Eritematoso Sistémico/patologíaRESUMEN
OBJECTIVES: This study aimed to compare the YHLO chemiluminescence immunoassay (CLIA) with the Crithidia luciliae immunofluorescence test (CLIFT) to detect anti-dsDNA antibodies and its correlation with disease activity in systemic lupus erythematosus (SLE). METHOD: In total, 208 patients diagnosed with SLE, 110 other autoimmune patients, 70 infectious disorders patients, and 105 healthy people were enrolled in this study. Serum samples were tested using CLIA in a YHLO chemiluminescence system and CLIFT. RESULTS: The overall agreement between YHLO CLIA and CLIFT was 76.9% (160/208), with a moderate correlation (kappa = 0.530, p < 0.001). The sensitivity of YHLO CLIA and CLIFT were 58.2% and 55.3%, respectively. The specificity of YHLO CLIA and CLIFT were 95.1% and 99.3%, respectively. The sensitivity of YHLO CLIA was increased to 66.8% with a specificity of 93.6% when the cut-off value was set at 24 IU/mL. Spearman's correlation coefficient between the quantitative results of YHLO CLIA and the titers of CLIFT was 0.59 (p < .01). A significant correlation was found between the anti-dsDNA results detected by YHLO CLIA and the SLE Disease Activity Index 2000 (SLEDAI-2K). Spearman's correlation coefficient between YHLO CLIA and SLEDAI-2K (r = 0.66, p < .01) was higher than that of CLIFT (r = 0.60, p < .01). CONCLUSIONS: Good correlation and agreement were found between YHLO CLIA and CLIFT. In addition, there was a significant correlation between YHLO CLIA and the SLE Disease Activity Index, which was superior to that of CLIFT. The YHLO chemiluminescence system is recommended for the assessment of disease activity.
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Crithidia , Lupus Eritematoso Sistémico , Humanos , Sensibilidad y Especificidad , Luminiscencia , Anticuerpos Antinucleares , Técnica del Anticuerpo Fluorescente , Inmunoensayo , Ensayo de Inmunoadsorción Enzimática/métodosRESUMEN
Anti-double-stranded DNA antibodies (anti-dsDNA) are considered a specific marker for systemic lupus erythematosus (SLE). Though the Farr technique was once the reference method for their detection, it has been almost entirely replaced by more recently developed assays. However, there is still no solid evidence of the commutability of these methods in terms of diagnostic accuracy and their correlation with the Crithidia luciliae immunofluorescence test (CLIFT). Anti-dsDNA antibody levels were measured in 80 subjects: 24 patients with SLE, 36 disease controls drawn from different autoimmune rheumatic diseases (14 systemic sclerosis, 10 Sjögren's syndrome, nine autoimmune myositis, three mixed connective tissue disease), 10 inflammatory arthritis and 10 apparently healthy blood donors by eight different methods: fluorescence enzyme immunoassay, microdot array, chemiluminescent immunoassay (two assays), multiplex flow immunoassay, particle multi-analyte technology immunoassay and two CLIFT. At the recommended manufacturer cut-off, the sensitivity varied from 67% to 92%, while the specificity ranged from 84% to 98%. Positive agreement among CLIFT and the other assays was higher than negative agreement. Mean agreement among methods assessed by the Cohen's kappa was 0.715, ranging from moderate (0.588) to almost perfect (0.888). Evaluation of the concordance among quantitative values by regression analysis showed a poor correlation index (mean r2, 0.66). The present study shows that current technologies for anti-dsDNA antibody detection are not fully comparable. In particular, their different correlation with CLIFT influences their positioning in the diagnostic algorithm for SLE (either in association or sequentially). Considering the high intermethod variability, harmonization and commutability of anti-dsDNA antibody testing remains an unachieved goal.
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Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Síndrome de Sjögren , Humanos , Anticuerpos Antinucleares , Lupus Eritematoso Sistémico/diagnósticoRESUMEN
Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.
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Anexina A1 , Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Anticuerpos Antinucleares , Autoanticuerpos , Inmunoglobulina G , Anexina A1/metabolismo , ADNRESUMEN
BACKGROUND: The role of sialylated and de-sialylated (de-SIA) IgG anti-dsDNA antibodies in experimental mouse lupus remains unclear. AIM OF THE STUDY: To examine how sialylated and de-SIA IgG anti-dsDNA antibodies affect lupus mouse proteinuria and possible mechanisms. METHODS: Blood was serially obtained from pristane-induced female BALB/c lupus mice to assess correlations between alpha-2,6-sialic cid (SIA) ratios of serum IgG anti-dsDNA and proteinuria. Kidney C3 staining was correlated with blood IgG anti-dsDNA. Sialylated IgG anti-dsDNA with its de-SIA form was administered to determine the effect on lupus proteinuria and in vitro consequences. RESULTS: We observed that the SIA contents of IgG anti-dsDNA were lower in Week 16/1+ (Week 16 with 1 + proteinuria) and W24/2 + mice than those in W16 (no proteinuria) and W24/1 + mice, respectively (P < 0.005 for both). C3 staining densities in the kidney correlated inversely with the α-2,6-SIA content of plasma IgG anti-dsDNA (r = -0.660). Highly sialylated A52L1 IgG anti-dsDNA injection mitigated lupus proteinuria significantly from PBS injection; however, its de-SIA form worsened proteinuria (aggravation of proteinuria: the latter vs. the former [sialylated A52L1 IgG anti-dsDNA] with an infinite odds ratio). Highly sialylated A52L1 IgG anti-dsDNA resulted in higher interleukin (IL)-10/IL-12 ratios, higher transforming growth factor-ß1 levels, and lower tumor necrosis factor-α levels in sera than its de-SIA from. CONCLUSION: We concluded that a low SIA/serum IgG anti-dsDNA ratio indicated a high severity of nephritis in pristane-induced lupus mice. Highly sialylated IgG anti-dsDNA, in contrast to the de-SIA form, alleviated the severity of lupus proteinuria.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Animales , Anticuerpos Antinucleares , ADN , Femenino , Inmunoglobulina G , Ratones , Ratones Endogámicos BALB C , ProteinuriaRESUMEN
OBJECTIVE: To study the association of α2,6-sialic acid (SIA) content in serum IgG anti-dsDNA with human systemic lupus erythematosus disease activity index (SLEDAI) and the effect of sialylated and desialylated (deSIA) IgG anti-dsDNA on lupus B cells. METHODS: Blood from lupus patients was collected to determine the ratio of SIA in isolated IgG anti-dsDNA over serum IgG anti-dsDNA (SIA/IgG anti-dsDNA) ratios, which were plotted against SLEDAI using a receiver-operating-characteristics curve. Lupus B cells were cultured in vitro with chimeric sialylated IgG anti-dsDNA and its deSIA form. Culture supernatants were assayed for anti-inflammatory IL-10 and SIA/IgG anti-dsDNA ratios, which were compared among different pre-treatment groups using t-tests. RESULTS: The area-under-the-curve (AUC) for anti-dsDNA levels against SLEDAI was 0.791 positively (95% confidence interval [C.I.]: 0.699-0.884) and SIA/IgG anti-dsDNA ratios against SLEDAI yielded an AUC of 0.705 inversely (95% C.I: 0.601-0.809): not significantly different. SIA/IgG anti-dsDNA ratios discriminated significantly between patients without and patients with proteinuria (p = .046). SIA/IgG anti-dsDNA ratios correlated significantly and positively with serum C3c and C4 levels. Pre-treatment with IgG anti-dsDNA and its immune complexes (dsDNA/IgG anti-dsDNA IC) induced higher IL-10 from lupus B cells than medium pre-treatment (most p < .01 from day 2 to day 5 culture). DeSIA IgG anti-dsDNA IC induced lower IL-10 (p < .05) and lower SIA/IgG anti-dsDNA ratios (p < .001) from lupus B cells than medium and dsDNA pre-treatment. CONCLUSION: α2,6-SIA/IgG anti-dsDNA ratios inversely forecasted SLEDAI scores. Possible mechanisms may be due to the different effects of sialylated and deSIA IgG anti-dsDNA on lupus B cells in terms of IL-10 secretion and SIA/IgG anti-dsDNA ratios.
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Lupus Eritematoso Sistémico , Ácido N-Acetilneuramínico , Anticuerpos Antinucleares , ADN , Humanos , Inmunoglobulina G , Interleucina-10 , Proyectos PilotoRESUMEN
Objective: The significance of anti-dense fine speckles 70 (DFS70) antibodies in systemic lupus erythematosus (SLE) is still unclear, especially in lupus nephritis (LN) patients. We investigated the prevalence, clinical and pathological relevance of anti-DFS70 antibodies in LN patients. Methods: Anti-DFS70 antibodies were measured using enzyme-linked immunosorbent assays in 377 biopsy-proven LN patients, 268 non-LN SLE patients, 232 chronic kidney disease (CKD) patients, and 78 healthy individuals (HI). Demographic, clinical, and pathological parameters were compared between LN patients with and without anti-DFS70 antibodies. Stepwise multivariable logistic regression was performed to identify covariates associated with anti-DFS70 antibodies. Results: The prevalence of anti-DFS70 antibodies in LN (19.6%) was comparable to non-LN SLE patients (19.8%, P=0.9630), but was significantly higher than CKD patients (13.4%, P=0.0468) and HI (9.0%, P=0.0252). Using multivariable logistic regression analysis, the titer of anti-double-stranded DNA (dsDNA) antibodies (adjusted odds ratio=1.002, 95% confidence interval 1.001-1.003, P=0.004) was associated with positive anti-DFS70 antibodies in LN patients. In addition, anti-DFS70 antibodies were more prevalent in proliferative LN (22.0%, 68/309) compared to membrane LN patients (10.2%, 6/59, P=0.0376). Furthermore, LN patients with positive anti-DFS70 antibodies had significantly higher activity index (AI) compared to patients who were negative (8.0 vs 6.0, P=0.0131). However, the chronicity index was similar between the groups (3.0 vs 3.0, P=0.8412). Conclusion: Anti-DFS70 antibodies were not associated with LN development in SLE patients but were associated with anti-dsDNA antibodies, proliferative LN, and renal AI. This suggests their potential to serve as a non-histological biomarker for LN subclass and activity status.
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Proteínas Adaptadoras Transductoras de Señales/inmunología , Anticuerpos Antinucleares/sangre , Nefritis Lúpica/inmunología , Factores de Transcripción/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Anticuerpos Antinucleares/biosíntesis , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Riñón/patología , Modelos Logísticos , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/diagnóstico , Masculino , Persona de Mediana Edad , Factores de Transcripción/metabolismoRESUMEN
Anti-double stranded DNA (dsDNA) antibodies play an important role in the diagnosis, classification and management of systemic lupus erythematosus (SLE), an autoimmune disease characterized by heterogeneous clinical manifestations and a wide range of autoantibodies, which makes the diagnosis quite challenging. In the absence of diagnostic criteria, classification criteria have been used for many decades. The first classification criteria for SLE were formulated in 1971 by the American College of Rheumatology (ACR), followed by two revisions in 1982 and 1997. In order to improve their clinical performance and to reflect new knowledge on autoantibodies, new classification criteria for SLE were issued in 2012 by the Systemic Lupus International Collaborating Clinics (SLICC). These criteria proposed to classify only patients that have at least one immunologic criterion, overcoming SLE classification based solely on clinical manifestations. In 2019, the European League Against Rheumatism (EULAR)/ACR proposed new criteria that aimed to maintain the high specificity of the ACR criteria with a sensitivity close to the SLICC 2012 criteria. These 2019 criteria reinforced the importance of autoantibodies in SLE diagnosis, assigning the highest score (6 points) to anti-dsDNA antibodies in the fully weighted scoring of the disease. The current criteria require the use of an anti-dsDNA assay with at least 90% specificity, such as the Crithidia luciliae immunofluorescence test (CLIFT) or FARR assay. However, the criteria do not comment on all the tests currently widely used in clinical laboratories. Neither do they consider the technological evolutions, nor standardization issues. Since strict adherence to any of the classification criteria, including the serological items, could lead to possible misclassification of SLE and/or delayed diagnosis, test characteristics of the distinct immunoassays should be taken into consideration.
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Anti-dsDNA antibodies are a hallmark of systemic lupus erythematosus and are highly associated with its exacerbation. Cumulative evidence has suggested that somatic hypermutation contributes to the high-affinity reactivity of anti-dsDNA antibodies. Our previous study demonstrated that these antibodies are generated from germline precursors with low-affinity ssDNA reactivity through affinity maturation and clonal expansion in patients with acute lupus. This raised the question of whether such precursors could be subjected to immune tolerance. To address this, we generated a site-directed knock-in (KI) mouse line, G9gl, which carries germline-reverted sequences of the VH-DH-JH and Vκ-Jκ regions of patient-derived, high-affinity anti-dsDNA antibodies. G9gl heterozygous mice had a reduced number of peripheral B cells, only 27% of which expressed G9gl B-cell receptor (BCR). The remaining B cells harbored non-KI allele-derived immunoglobulin heavy (IgH) chains or fusion products of upstream mouse VH and the KI gene, suggesting that receptor editing through VH replacement occurred in a large proportion of B cells in the KI mice. G9gl BCR-expressing B cells responded to ssDNA but not dsDNA, and exhibited several anergic phenotypes, including reduced surface BCR and shortened life span. Furthermore, G9gl B cells were excluded from germinal centers (GCs) induced by several conditions. In particular, following immunization with methylated bovine serum albumin-conjugated bacterial DNA, G9gl B cells occurred at a high frequency in memory B cells but not GC B cells or plasmablasts. Collectively, multiple tolerance checkpoints prevented low-affinity precursors of pathogenic anti-dsDNA B cells from undergoing clonal expansion and affinity maturation in GCs.
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Anticuerpos Antinucleares , Lupus Eritematoso Sistémico , Animales , Linfocitos B , Células Germinativas , Humanos , Tolerancia Inmunológica/genética , Cadenas Pesadas de Inmunoglobulina/genética , Lupus Eritematoso Sistémico/genética , Ratones , Receptores de Antígenos de Linfocitos BRESUMEN
Objective: Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk. Approach and Results: Eighty SLE patients were included. Extensive clinical/analytical evaluation was performed, including cardiovascular disease parameters (endothelial function, proatherogenic dyslipidemia, and carotid intima-media thickness). Gene and protein expression profiles were evaluated in monocytes from patients diagnosed positive or negative for anti-dsDNA antibodies by using NanoString and cytokine arrays, respectively. NETosis and circulating inflammatory profile was assessed in both neutrophils and plasma. Positivity and persistence of anti-dsDNA antibodies in SLE patients were associated to endothelial dysfunction, proatherogenic dyslipidemia, and accelerated atherosclerosis. In parallel, anti-dsDNA antibodies were linked to the aberrant activation of innate immune cells, so that anti-dsDNA(+) SLE monocytes showed distinctive gene and protein expression/activity profiles, and neutrophils were more prone to suffer NETosis in comparison with anti-dsDNA(−) patients. Anti-dsDNA(+) patients further displayed altered levels of numerous circulating mediators related to inflammation, NETosis, and cardiovascular risk. In vitro, Ig-dsDNA promoted NETosis on neutrophils, apoptosis on monocytes, modulated the expression of inflammation and thrombosis-related molecules, and induced endothelial activation, at least partially, by FcR (Fc receptor)-binding mechanisms. Conclusions: Anti-dsDNA antibodies increase the cardiovascular risk of SLE patients by altering key molecular processes that drive a distinctive and coordinated immune and vascular activation, representing a potential tool in the management of this comorbidity.
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Anticuerpos Antinucleares/sangre , Enfermedades Cardiovasculares/inmunología , ADN/inmunología , Células Endoteliales/inmunología , Inmunoglobulina G/sangre , Leucocitos/inmunología , Lupus Eritematoso Sistémico/inmunología , Adulto , Apoptosis , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico por imagen , Enfermedades Cardiovasculares/genética , Células Cultivadas , Técnicas de Cocultivo , Estudios Transversales , Citocinas/genética , Citocinas/metabolismo , Células Endoteliales/metabolismo , Trampas Extracelulares/metabolismo , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Leucocitos/metabolismo , Lípidos/sangre , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/genética , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Estrés Oxidativo , Estudios Retrospectivos , Medición de Riesgo , Transducción de SeñalRESUMEN
Pathogens such as the Epstein Barr virus (EBV) have long been implicated in the etiology of systemic lupus erythematosus (SLE). The Epstein Barr virus nuclear antigen I (EBNA-1) has been shown to play a role in the development of anti-nuclear antibodies characteristic of SLE. One mechanism by which EBV may play a role in SLE is molecular mimicry. We previously generated two monoclonal antibodies (mAbs) to EBNA-1 and demonstrated that they cross-react with double-stranded DNA (dsDNA). In the present study, we demonstrate that these mAbs have pathogenic potential. We show that they can bind to isolated rat glomeruli and that binding can be greatly diminished by pretreatment of glomeruli with DNase I, suggesting that these mAbs bind dsDNA in the kidney. We also demonstrate that these antibodies can deposit in the kidney when injected into mice and can induce proteinuria and elicit histopathological alterations consistent with glomerulonephritis. Finally, we show that these antibodies can cross-react with laminin and collagen IV in the extracellular matrix suggesting that direct binding to the glomerular basement membrane or mesangial matrix may also contribute to the antibody deposition in the kidney. In summary, our results indicate that EBNA-1 can elicit antibodies that cross-react with dsDNA, that can deposit in the kidney, and induce kidney damage. These results are significant because they support the role of a viral protein in SLE and lupus nephritis.
Asunto(s)
Anticuerpos Antinucleares/toxicidad , Anticuerpos Monoclonales/toxicidad , Anticuerpos Antivirales/inmunología , ADN/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Glomérulos Renales/inmunología , Animales , Anticuerpos Antinucleares/inmunología , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/aislamiento & purificación , Colágeno/inmunología , Reacciones Cruzadas/inmunología , Desoxirribonucleasa I , Infecciones por Virus de Epstein-Barr/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/inmunología , Femenino , Membrana Basal Glomerular/inmunología , Membrana Basal Glomerular/metabolismo , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Glomerulonefritis/virología , Células HEK293 , Humanos , Inmunoglobulina G/inmunología , Glomérulos Renales/patología , Laminina/inmunología , Ratones , Ratones Endogámicos BALB C , Imitación Molecular , Proteinuria/inmunología , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: Data on the clinical importance of the detection of anti-dsDNA antibodies in patients with negative indirect immunofluorescence on the HEp-2 cell (IIF) are sparse and are especially not available for all common commercially available assays. This study aimed to assess the clinical significance of anti-dsDNA antibodies determined by the Elia™ dsDNA assay in patients with negative IIF. METHODS: We retrospectively examined the medical records of 234 consecutive subjects with detectable anti-dsDNA antibodies determined by the Elia™ dsDNA assay. RESULTS: A total of 124 subjects with detectable anti-dsDNA autoantibodies were IIF-negative, but yielded positive or borderline results in the Elia™ CTD screen assay for antinuclear antibodies (ANA). Within this group, 6/49 IIF-negative patients (12%) with ANA-associated systemic autoimmune rheumatic disorders (AASARD) and 118/185 subjects (64%) with various other diseases (Non-AASARD) were identified. There was no statistically significant difference with regard to the concentrations of anti-dsDNA antibodies (p=0.53) between the AASARD and the Non-AASARD group. Within the AASARD group, four patients diagnosed with systemic lupus erythematosus (SLE, treated), discoid lupus erythematosus (untreated), indetermined connective tissue disease (untreated) and polymyositis (treated) had positive anti-dsDNA autoantibodies, whereas two patients with treated SLE, thereby one in remission, had borderline concentrations of anti-dsDNA antibodies. CONCLUSIONS: Our findings suggest that the detection of anti-dsDNA antibodies in IIF-negative patients can be of clinical relevance in some cases. Our results further support the combined use of IIF and solid-phase assays in screening algorithms for ANA, in order to avoid overlooking potentially important autoantibody entities.
Asunto(s)
Técnica del Anticuerpo Fluorescente Indirecta , Anticuerpos Antinucleares , Autoanticuerpos , ADN , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Estudios RetrospectivosRESUMEN
One cannot discuss anti-dsDNA antibodies and lupus nephritis without discussing the nature of Systemic lupus erythematosus (SLE). SLE is insistently described as a prototype autoimmune syndrome, with anti-dsDNA antibodies as a central biomarker and a pathogenic factor. The two entities, "SLE" and "The Anti-dsDNA Antibody," have been linked in previous and contemporary studies although serious criticism to this mutual linkage have been raised: Anti-dsDNA antibodies were first described in bacterial infections and not in SLE; later in SLE, viral and parasitic infections and in malignancies. An increasing number of studies on classification criteria for SLE have been published in the aftermath of the canonical 1982 American College of Rheumatology SLE classification sets of criteria. Considering these studies, it is surprising to observe a nearby complete absence of fundamental critical/theoretical discussions aimed to explain how and why the classification criteria are linked in context of etiology, pathogenicity, or biology. This study is an attempt to prioritize critical comments on the contemporary definition and classification of SLE and of anti-dsDNA antibodies in context of lupus nephritis. Epidemiology, etiology, pathogenesis, and measures of therapy efficacy are implemented as problems in the present discussion. In order to understand whether or not disparate clinical SLE phenotypes are useful to determine its basic biological processes accounting for the syndrome is problematic. A central problem is discussed on whether the clinical role of anti-dsDNA antibodies from principal reasons can be accepted as a biomarker for SLE without clarifying what we define as an anti-dsDNA antibody, and in which biologic contexts the antibodies appear. In sum, this study is an attempt to bring to the forum critical comments on the contemporary definition and classification of SLE, lupus nephritis and anti-dsDNA antibodies. Four concise hypotheses are suggested for future science at the end of this analytical study.
Asunto(s)
Autoinmunidad , Susceptibilidad a Enfermedades/inmunología , Lupus Eritematoso Sistémico/etiología , Animales , Anticuerpos Antinucleares/inmunología , Afinidad de Anticuerpos/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Biomarcadores , ADN/inmunología , Medicina Basada en la Evidencia/métodos , Predisposición Genética a la Enfermedad , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/metabolismo , Investigación , SíndromeRESUMEN
BACKGROUND: Wire-loop lesion (WL) is one of the active lesions of lupus nephritis (LN). However, few reports have focused on the clinicopathological relationships of WL to serological immune abnormality and renal prognosis. METHODS: We enrolled 126 Japanese LN patients subjected to renal biopsy in 11 hospitals from 2000 to 2018. In patients with class III or IV of the International Society of Nephrology/Renal Pathology Society classification, we retrospectively compared clinicopathological findings between those with WL (WL+ group) and without WL (WL- group) to detect factors associated with WL. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate of <60 mL/min/1.73m2 for more than three months. We also compared these findings between those with CKD (CKD+ group) and without CKD (CKD- group) at the last visit to investigate factors associated with renal prognosis. RESULTS: Of 126 patients, 100 (79.4%) were classified as class III or IV. WL was found in 36 (36.0%) of them. Although the renal function did not differ, the WL+ group had a higher titre of serum anti-dsDNA antibodies and lower serum complement 3 levels than the WL- group. Linear regression analysis revealed a significant association only between anti-dsDNA antibodies and WL (ß = 0.27, 95% confidence interval (CI) 0.001-0.100, p = 0.01). Of these patients, 69 were tracked for 59.6 ± 55.1 months. Kaplan-Meier analysis showed no difference in renal prognosis between these groups. Next, the CKD+ group included 15 (22.1%) patients. They were older and had higher frequencies of hypertension and hyperuricaemia, serum creatinine (Cr) level, glomerulosclerosis, interstitial inflammation, interstitial fibrosis and tubular atrophy than the CKD- group at the time of renal biopsy. The frequency of WL was not significantly different. Cox regression analysis revealed significant associations of CKD with hypertension, hyperuricaemia, serum Cr level at the time of renal biopsy clinically and with tubular atrophy histologically. CONCLUSIONS: WL was associated with serum anti-dsDNA antibodies but not with renal prognosis, suggesting that WL reflects immune abnormality but is not an independent factor predictive of renal prognosis in LN.
Asunto(s)
Anticuerpos Antinucleares/sangre , Riñón/patología , Nefritis Lúpica/sangre , Nefritis Lúpica/patología , Adulto , Biopsia , Estudios de Casos y Controles , Complemento C3/inmunología , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Japón/epidemiología , Riñón/inmunología , Riñón/fisiopatología , Nefritis Lúpica/clasificación , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Insuficiencia Renal Crónica/fisiopatología , Estudios RetrospectivosRESUMEN
BACKGROUND: Urinary parameters, anti-dsDNA antibodies and complement tests were explored in patients with childhood-Systemic Lupus Erythematosus (cSLE) early-onset lupus nephritis (ELN) from a large multicenter cohort study. METHODS: Clinical and laboratory features of cSLE cases with kidney involvement at presentation, were reviewed. Disease activity parameters including SLEDAI-2 K scores and major organ involvement at onset and follow up, with accrued damage scored by SLICC-DI, during last follow up, were compared with those without kidney involvement. Autoantibodies, renal function and complement tests were determined by standard methods. Subjects were grouped by presence or absence of ELN. RESULTS: Out of the 846 subjects enrolled, mean age 11.6 (SD 3.6) years; 427 (50.5%) had ELN. There was no significant difference in the ELN proportion, according to onset age, but ELN frequency was significantly higher in non-Caucasians (p = 0.03). Hematuria, pyuria, urine casts, 24-h proteinuria and arterial hypertension at baseline, all had significant association with ELN outcome (p < 0.001). With a similar follow up time, there were significantly higher SLICC-DI damage scores during last follow up visit (p = 0.004) and also higher death rates (p < 0.0001) in those with ELN. Low C3 (chi-square test, p = 0.01), but not C3 levels associated significantly with ELN. High anti-dsDNA antibody levels were associated with ELN (p < 0.0001), but anti-Sm, anti-RNP, anti-Ro, anti-La antibodies were not associated. Low C4, C4 levels, low CH50 and CH50 values had no significant association. High erythrocyte sedimentation rate (ESR) was associated with the absence of ELN (p = 0.02). CONCLUSION: The frequency of ELN was 50%, resulting in higher morbidity and mortality compared to those without ELN. The urinary parameters, positive anti-dsDNA and low C3 are reliable for discriminating ELN.