The engagement of histone lysine methyltransferases with nucleosomes: structural basis, regulatory mechanisms, and therapeutic implications

Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs' roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.

Histone Variant H2A.Z Enhances the Stability of Nucleosomes under the Effect of Salt Ions / 中国生物化学与分子生物学报

In eukaryotes, the basic structural unit of chromatin is the nucleosome, and genomic DNA iscompressed in chromatin. The presence of nucleosomes usually inhibits the biological processes that occuron the DNA templates, such as transcription, replication, repair, and recombination,. The histonevariant H2A.Z can regulate the structure of chromatin and affect the transcription process of genes, but itsdetailed regulation mechanism remains unclear. In this paper, the method of Förster resonance energytransfer (FRET) was used to detect the influence of sodium chloride, potassium chloride, manganesechloride, calcium chloride and magnesium chloride on the dissociation of nucleosomes. Then, the stabilitydifferences between the nucleosomes containing the histone variant H2A. Z and the conventionalnucleosomes were compared under the action of salt ions. Widom 601 DNA sequence was labeled withdual fluorescence Cy3 and Cy5, and the dissociation of nucleosomes was reflected by the change offluorescence signal value. FRET results showed that the dissociation speed of nucleosomes containing thehistone variant H2A. Z under the action of sodium chloride, potassium chloride, manganese chloride, calcium chloride and magnesium chloride is slower than that of canonical nucleosomes, and the influenceof calcium chloride, manganese chloride and magnesium chloride on dissociation is more obvious thansodium chloride, potassium chloride. The results of electrophoresis analysis showed that the dissociationrate of nucleosomes containing histone variant H2A. Z was significantly lower than that of canonicalnucleosomes at 75℃. Fluorescence thermal shift (FTS) was used to further analyze the stability ofnucleosomes containing histone variant H2A.Z. It was found that the fluorescence signals of the two typesof nucleosomes showed two distinct growth periods, and the fluorescence signals generated in thedissociation process of the two types of nucleosomes showed two distinct growth periods. The temperaturecorresponding to the first increasing period of fluorescence signal in the dissociation process of H2A. Z-containing nucleosome is significantly higher than that in the dissociation process of the canonicalnucleosome, which indicated that the dissociation and denaturation temperature of the H2A.Z / H2B dimerin the nucleosome is higher than that of the canonical H2A / H2B dimer, and the H2A. Z-containingnucleosomes have high thermal stability. The results indicated that the structure of nucleosomes containingthe histone variant H2A.Z is more stable than that of canonical nucleosomes.

Utility of anti-C1q and anti-nucleosome antibodies in systemic lupus erythematosus and lupus nephritis in southwestern Colombia / Utilidad de los anticuerpos anti-C1q y anti-nucleosomas en el lupus eritematoso sistémico y la nefritis lúpica en el suroccidente colombiano

ABSTRACT Introduction: Lupus nephritis (LN) is one of the most prevalent and severe complications of systemic lupus erythematosus (SLE), requiring reliable urine and serum biomarkers to evaluate it. Anti-nucleosome and anti-C1q antibodies are associated with LN in several geographic regions. Also, southwest Colombia has a heterogeneous ethnicity, which motivated the evaluation of the frequency and relationship of such markers with LN in this region. Methods: A cross-sectional study was conducted in a health centre in south-west Colombia in 84 patients diagnosed with SLE (57 without LN; 27 with LN) between 2016 and 2018. Demographic and clinical and laboratory features, including anti-dsDNA, complement, and anti-C1q and anti-nucleosome antibodies were compared in these patients. ELISA immunoassays were performed to measure the antibodies of interest in blood samples. Statistical analysis was carried out using STATA14 software (StataCorp, College Station, Texas, USA). Quantitative variables were summarised as means or medians and compared with Mann-Whitney or Two-sample t test. Categorical variables were shown as proportions, and compared with Chi-squared or Fisher's exact test. Correlation analysis between quantitative variables was calculated using Spearman's correlation. Results: Of all 84 patients, 27 patients had LN, of which 16 (59.2%) had a positive test for anti-nucleosome antibodies and 10 (37%) for anti-C1q antibodies. An association was found between anti-C1q and proliferative forms of LN and newly diagnosed LN. A correlation was found between anti-nucleosome and anti-C1q antibodies, and anti-dsDNA and low serum complement concentrations. Conclusion: Although both markers were found in variable percentages in SLE patients and seem not to be specific markers of LN in our population, anti-C1q was associated with proliferative forms of LN and de novo LN.

RESUMEN Introducción: La nefritis lúpica (NL), una de las complicaciones más frecuentes y graves del lupus eritematoso sistémico (LES), requiere biomarcadores confiables de orina y suero para su evaluación. Los anticuerpos anti-nucleosoma y anti-C1q se asocian con la NL en varias regiones geográficas. En el suroccidente colombiano se asienta una etnia heterogénea, lo que motivó la evaluación de la frecuencia y la relación de dichos marcadores con NL en dicha región. Métodos: Realizamos un estudio transversal en un centro de salud en el suroccidente de Colombia, con 84 pacientes diagnosticados con LES (57 sin NL; 27 con NL) entre los anos 2016 y 2018. Se compararon las características demográficas, clínicas y de laboratorio, incluidos los anticuerpos anti-dsDNA, complemento, anti-C1q y anti-nucleosomas entre estos pacientes. Se realizaron inmunoensayos ELISA para medir los anticuerpos de interés en muestras de sangre. El análisis estadístico se llevó a cabo con el software Stata v.14 (Stata-Corp, College Station, Texas, EE. UU.). Las variables cuantitativas se resumieron como medias o medianas y se compararon con la prueba t de Mann-Whitney o Two-sample t test; las variables categóricas se mostraron como proporciones y se compararon con Chi-cuadrado o con la prueba exacta de Fisher. Para el análisis de correlaciones entre variables cuantitativas se calculó el coeficiente de correlación de Spearman. Resultados: Entre los 84 pacientes, 27 presentaban LN, de los cuales 16 (59,2%) tuvieron una prueba positiva para anticuerpos anti-nucleosoma y 10 (37%) para anticuerpos anti-C1q. Se encontró una asociación entre anti-C1q y formas proliferativas de NL, así como formas recientemente diagnosticadas de NL. Hubo una correlación entre los anticuerpos anti-nucleosoma y anti-C1q y el anti-dsDNA y las bajas concentraciones de complemento sérico. Conclusión: Aunque los 2 marcadores se encontraron en porcentajes variables de pacientes con LES y no parecen ser marcadores específicos de NL en nuestra población, la presencia de anti-C1q se asoció con formas proliferativas de NL y NL de novo.

Phase-separation in chromatin organization

The organization of chromatin into different types of compact versus open states provides a means to fine tune generegulation. Recent studies have suggested a role for phase-separation in chromatin compaction, raising new possibilities for regulating chromatin compartments. This perspective discusses some specific molecular mechanismsthat could leverage such phase-separation processes to control the functions and organization of chromatin

Origin of RNA Polymerase II pause in eumetazoans: Insights from Hydra

Multicellular organisms have evolved sophisticated mechanisms for responding to various developmental,environmental and physical stimuli by regulating transcription. The correlation of distribution of RNAPolymerase II (RNA Pol II) with transcription is well established in higher metazoans, however genome-wideinformation about its distribution in early metazoans, such as Hydra, is virtually absent. To gain insights intoRNA Pol II-mediated transcription and chromatin organization in Hydra, we performed chromatin immunoprecipitation (ChIP)-coupled high-throughput sequencing (ChIP-seq) for RNA Pol II and Histone H3. Strikingly, we found that Hydra RNA Pol II is uniformly distributed across the entire gene body, as opposed to itscounterparts in bilaterians such as human and mouse. Furthermore, correlation with transcriptome datarevealed that the levels of RNA Pol II correlate with the magnitude of gene expression. Strikingly, thecharacteristic peak of RNA Pol II pause typically observed in bilaterians at the transcription start sites (TSSs)was not observed in Hydra. The RNA Pol II traversing ratio in Hydra was found to be intermediate to yeastand bilaterians. The search for factors involved in RNA Pol II pause revealed that RNA Pol II pausingmachinery was most likely acquired first in Cnidaria. However, only a small subset of genes exhibited thepromoter proximal RNP Pol II pause. Interestingly, the nucleosome occupancy is highest over the subset ofpaused genes as compared to total Hydra genes, which is another indication of paused RNA Pol II at thesegenes. Thus, this study provides evidence for the molecular basis of RNA Pol II pause early during theevolution of multicellular organisms.

Picking a nucleosome lock: Sequence- and structure-specific recognition of the nucleosome

The nucleosome presents a formidable barrier to DNA-templated transcription by the RNA polymerase IImachinery. Overcoming this transcriptional barrier in a locus-specific manner requires sequence-specificrecognition of nucleosomal DNA by ‘pioneer’ transcription factors (TFs). Cell fate decisions, in turn, dependon the coordinated action of pioneer TFs at cell lineage-specific gene regulatory elements. Although it isalready appreciated that pioneer factors play a critical role in cell differentiation, our understanding of thestructural and biochemical mechanisms by which they act is still rapidly expanding. Recent research hasrevealed novel insight into modes of nucleosome-TF binding and uncovered kinetic principles by whichnucleosomal DNA compaction affects both TF binding and residence time. Here, we review progress and arguethat these structural and kinetic studies suggest new models of gene regulation by pioneer TFs.

Role of nucleosome positioning in 3D chromatin organization and loop formation

We present a physics-based polymer model that can investigate 3D organization of chromatin accounting for DNA elasticity,DNA-bending due to nucleosomes, and 1D organization of nucleosomes along DNA. We find that the packing density ofchromatin oscillates between densities corresponding to highly folded and extended configurations as we change thenucleosome organization (length of linker DNA). We compute the looping probability of chromatin and show that thepresence of nucleosomes increases the looping probability of the chain compared to that of a bare DNA. We also show thatlooping probability has a large variability depending on the nature of nucleosome organization and density of linker histones.

The CBX family of proteins in transcriptional repression and memory

For mammals to develop properly, master regulatory genes must be repressed appropriately in a heritable manner. This review concerns the Polycomb Repressive Complex 1 (PRC1) family and the relationshipbetween the establishment of repression and memory of the repressed state. The primary focus is on the CBXfamily of proteins in PRC1 complexes and their role in both chromatin compaction and phase separation.These two activities are linked and might contribute to both repression and memory.

Identification of nucleosome positioning using support vector machine method based on comprehensive DNA sequence feature / 生物医学工程学杂志

In this article, based on z-curve theory and position weight matrix (PWM), a model for nucleosome sequences was constructed. Nucleosome sequence dataset was transformed into three-dimensional coordinates, PWM of the nucleosome sequences was calculated and the similarity score was obtained. After integrating them, a nucleosome feature model based on the comprehensive DNA sequences was obtained and named CSeqFM. We calculated the Euclidean distance between nucleosome sequence candidates or linker sequences and CSeqFM model as the feature dataset, and put the feature datasets into the support vector machine (SVM) for training and testing by ten-fold cross-validation. The results showed that the sensitivity, specificity, accuracy and Matthews correlation coefficient (MCC) of identifying nucleosome positioning for were 97.1%, 96.9%, 94.2% and 0.89, respectively, and the area under the receiver operating characteristic curve (AUC) was 0.980 1. Compared with another z-curve method, it was found that our method had better identifying effect and each evaluation performance showed better superiority. CSeqFM method was applied to identify nucleosome positioning for other three species, including , and . The results showed that AUCs of the three species were all higher than 0.90, and CSeqFM method also showed better stability and effectiveness compared with iNuc-STNC and iNuc-PseKNC methods, which is further demonstrated that CSeqFM method has strong reliability and good identification performance.

H3K27me3 Signal in the Cis Regulatory Elements Reveals the Differentiation Potential of Progenitors During Drosophila Neuroglial Development / 基因组蛋白质组与生物信息学报·英文版

Drosophila neural development undergoes extensive chromatin remodeling and precise epigenetic regulation. However, the roles of chromatin remodeling in establishment and maintenance of cell identity during cell fate transition remain enigmatic. Here, we compared the changes in gene expression, as well as the dynamics of nucleosome positioning and key histone modifications between the four major neural cell types during Drosophila neural development. We find that the neural progenitors can be separated from the terminally differentiated cells based on their gene expression profiles, whereas nucleosome distribution in the flanking regions of transcription start sites fails to identify the relationships between the progenitors and the differentiated cells. H3K27me3 signal in promoters and enhancers can not only distinguish the progenitors from the differentiated cells but also identify the differentiation path of the neural stem cells (NSCs) to the intermediate progenitor cells to the glial cells. In contrast, H3K9ac signal fails to identify the differentiation path, although it activates distinct sets of genes with neuron-specific and glia-related functions during the differentiation of the NSCs into neurons and glia, respectively. Together, our study provides novel insights into the crucial roles of chromatin remodeling in determining cell type during Drosophila neural development.

Association of anti-nuclesome and anti C1q antibodies with lupus nephritis in an Egyptian cohort of patients with systemic lupus erythematosus

Abstract Introduction: Anti-nucleosome and anti-C1q antibodies demonstrated an association with the development of glomerulonephritis in systemic lupus erythematosus (SLE). Some investigators have proposed that monitoring anti- C1q and anti-nucleosome antibodies might be valuable for making predictions about lupus nephritis (LN) and assessment of disease activity as a non-invasive biological marker of renal disease. Objectives: The current study was proposed to investigate the presence of anti-C1q and anti-nucleosome antibodies in the sera of Egyptian patients with SLE and their association with LN. Methods: Eighty patients with SLE were included. Patients were classified into, a LN group including 40 cases with active LN (based on the results of renal biopsy and renal SLEDAI≥4) and a non renal SLE group including 40 patients (with no clinical or laboratory evidence of renal involvement that were attributed in the past or present to SLE). They were subjected to full medical history taking, clinical examination, routine laboratory investigations, measurement of antinuclear antibody (ANA), anti-ds DNA, anti-C1q & anti-nucleosome antibodies. Results: Anti-C1q antibody showed a statistically significant association with the presence of vasculitis and nephritis while anti-nucleosome antibody didn't show a significant association with the presence of any clinical features. Double positivity of anti-nucleosome and anti-C1q antibodies showed a statistically significant association with the presence of vasculitis and photosensitivity, high ECLAM score, elevated ESR, low serum albumin and low C3 levels. Conclusion: Serum anti-C1q antibody has a significant association with LN while double positive antibodies have a significant association with vasculitis and low C3 levels in Egyptian patients with SLE.

Role of HMGN1 in epithelial-mesenchymal transition of kidney tubules in diabetic nephropathy mice / 中华内分泌代谢杂志

Objective This study aimed to investigate the renal expression change of high mobility of nucleosome binding protein 1 ( HMGN1) in epithelia-mesenchymal transition ( EMT) process, and to study the effect of HMGN1 on renal fibrosis in the diabetic nephropathy mice model. Methods 20 C57BL/6 mice were randomly divided into control group, model group, benazepril group, and insulin group. After 8 weeks of drug intervention, blood, urine and kidney tissue samples were taken from mice. The routine physiological and biochemical indexes were detected. Renal structure and fibrosis were detected by HE and Sirius red staining, respectively. Immunohistochemistry and in situ hybridization were used to investigate the protein and mRNA expression levels of HMGN1, CD68, F4/80,α-smooth muscle actin (α-SMA) , and E-cadherin in renal tissue. Results Blood glucose, renal index, and urinary albumin to creatinine ratio ( UACR) were significantly higher in the model group than those in the normal group. In the model group, HE staining showed glomerular hypertrophy and interstitial inflammatory cell infiltration, and Sirius red showed collagen deposition in the renal tissue. Compared with normal group, HMGN1, CD68, F4/80 positive cell counts andα-SMA protein expression were all increased, while E-cadherin protein expression was downregulated in the model group ( all P<0.05) . The above indexes were not improved significantly in the benazepril group. And after intervention of insulin, the expression levels of CD68 positive cell count andα-SMA protein were decreased and the expression levels of E-cadherin protein were increased compared with the model group ( all P<0.05) . The correlation analysis showed that the level of HMGN1 was correlated with CD68, F4/80, α-SMA, E-cadherin and collagen protein, while CD68 and f4/80 were correlated withα-SMA, collagen protein and blood glucose, respectively ( all P<0. 05 ) . Conclusion HMGN1 is involved in the progression of diabetic nephropathy fibrosis, and its underlying mechanism might be related to the macrophage-mediated EMT process.

Optimización del algoritmo diagnóstico de anticuerpos antinucleares / Optimization of the diagnostic algorithm of antinuclear antibodies

Introducción: La prueba de anticuerpos antinucleares es una poderosa herramienta en el diagnóstico de las enfermedades reumáticas. Los anticuerpos antinucleares se determinan en el laboratorio por un algoritmo o secuencia que se inicia con prueba de cribado y sigue con la identificación de las especificidades antinucleares más comunes. Pero, ¿cómo interpretar los resultados discordantes entre los dos niveles de estudio de anticuerpos antinucleares? Objetivo: Determinar las especificidades antinucleares menos frecuentes en pacientes positivos de cribado de ANA y negativos de las especificidades más comunes. Métodos: Estudio prospectivo de 88 pacientes consecutivos remitidos para la detección rutinaria de ANA con resultado positivo de cribado por ensayo inmuno-adsorbente ligado a enzima (ELISA) pero negativo de anticuerpos anti-ADN de doble cadena (dc, IgG) y anti-antígenos nucleares extraíbles comunes (ENAc). Las muestras séricas correspondientes fueron evaluadas por inmunofluorescencia indirecta sobre células de carcinoma epidermoide laríngeo humano (IFI-HEp-2) y por ELISA para la detección individual de ANA específicos. Resultados: La prueba de ANA por IFI/HEp-2 resultó positiva en 56/88 (63,6 por ciento) y las especificidades antinucleares se detectaron en 57/88 (64,8 por ciento) muestras, en el orden decreciente de Anti-Nucs: 16/88 (18,2 por ciento); anti-centrómero (CENP-B): 15/88 (17,0 por ciento); -histona: 15/88 (17 por ciento); -PM/Scl: 13/88 (14,8 por ciento); -ADNsc: 11/88 (12,5 por ciento) y -ENAc individuales: 8/88 (9,1 por ciento). La sensibilidad de la IFI-HEp-2 para las especificidades antinucleares fue de 0,83 (IC95 por ciento: 0,72-0,93). De los pacientes negativos de subserología (26/31), 83,9 por ciento no tenían antecedentes de enfermedad reumática asociada a ANA. Conclusiones: La mayoría de los pacientes con resultados discordantes entre el primer y segundo nivel de ANA fueron positivos de especificidades antinucleares menos comunes, pero de reconocido valor diagnóstico(AU)

Introduction: The antinuclear antibody test is a powerful tool for diagnosing rheumatic diseases. Antinuclear antibodies are determined in the laboratory by an algorithm or sequence that starts with a screening test and continues with the identification of the most common antinuclear specificities. But how to interpret the discordant results between the two levels of study of antinuclear antibodies? Objective: To determine the less frequent antinuclear specificities in positive patients of ANA screening and negative of the most common specificities. Methods: A prospective study was done on 88 consecutive patients referred for the routine ANA screening with a positive result of screening by enzyme-linked immunosorbent assay (ELISA) but negative for anti-double-stranded DNA (dc, IgG) and common extractable anti-nuclear antigens (ENAc). The corresponding serum samples were evaluated by indirect immunofluorescence on human laryngeal epidermoid carcinoma cells (IFI-HEp-2) and by ELISA for the individual detection of specific ANA. Results: The ANA test by IFI / HEp-2 was positive in 56/88 (63.6 percent) and the antinuclear specificities were detected in 57/88 (64.8 percent) samples, in decreasing Anti-Nucs order: 16/88 (18.2 percent); anti-centromere (CENP-B): 15/88 (17.0 percent); -histona: 15/88 (17 percent); -PM / Scl: 13/88 (14.8 percent); -ADNsc: 11/88 (12.5 percent) and -ENAc individual: 8/88 (9.1 percent). The sensitivity of IFI-HEp-2 for antinuclear specificities was 0.83 (95 percent CI: 0.72-0.93). No history of rheumatic disease associated with ANA was read in (26/31) 83.9 percent patients with negative subserology. Conclusions: The majority of patients with discordant results between the first and second level of ANA were positive of less common antinuclear specificities, but of recognized diagnostic value(AU)

Significance of anti-nucleosome antibody, anti-C1q antibody and anti-double stranded DNA antibody in diagnosis of lupus nephritis / 吉林大学学报(医学版)

Objective:To investigate the clinical and laboratory characteristics of lupus nephritis(LN) patients by detecting the anti-nucleosome antibodies, anti-C1q antibodies and anti-double stranded antibodies(anti-ds DNA), and to clarify the risk factors of LN in the patients with systemic lupus erythematosus(SLE),and the significance of three kinds of antibodies in diagnosis of LN.Methods:A total of 120 SLE patients were selected and divided into LN group(n=60) and non-LN group(n=60).The ANAS data of 120 patients were retrospectively analyzed,the levels of anti-C1q antibodies were measured.The clinical symptoms and laboratory data of the patients with positive anti-dsDNA,-nucleosome and-C1q antibodies (3-pos group)and negative three kinds of antibodies(non 3-pos group) were analyzed in LN group.Results:The positive rate of anti-C1q antibody of the patients in LN group (40.00%) was higher than that in non-LN group (21.67%) (χ2=4.728, P=0.03).The positive rate of anti-dsDNA antibody in LN group was 66.67%, and it was 46.67% in non-LN group;the positive rates of the patients had significant difference between two groups (χ2=4.887, P=0.027).The positive rate of anti-nucleosome antibody in LN group was 58.33%, and it was 40.00% in non-LN group;the positive rates of the patients had significant difference between two groups (χ2=4.034, P=0.045).The positive rates of U1-snRNP, SmD1 and other antibodies Jo-1, SSA/Ro60kD, SSA/Ro52kD, SSB, ScL-70, CENP-B,and P0 had no significant differences between two groups(P>0.05).The levels of C3 and C4 and hemoglobinin of the patients in 3-pos group were higher than those innon 3-pos group (P0.05).The clinical symptoms were not statistically significant in 3-pos and non 3-pos groups (P>0.05).Conclusion:The anti-nucleosome, anti-C1q and anti-dsDNA antibodies are the risk factors of SLE complicated with LN;the positive antibodies can improve the diagnostic rate of LN.The 3-pos patients have more severe damage in complements and blood system with higher renal disease activities.

Diagnostic value of anti-nucleosome antibody for juvenile systemic lupus erythematosus / 临床检验杂志

Objective To evaluate the diagnostic value of anti-nucleosome antibody for juvenile systemic lupus erythematosus (JSLE).Methods Fifty-four patients with JSLE,28 patients with non-JSLE and 26 healthy children were chosen in this study.antinuclear antibody(ANA),anti-nucleosome antibody (AnuA),anti-dsDNA antibody,anti-histone antibody (AHA) and anti-Sm antibody were detected by ELISA or western-blot method.The relevant clinical data were collected and analyzed.Results For diagnosis of JSLE,the sensitivity and specificity of AnuA was 77.78％ and 96.30％.The sensitivity of AnuA combined with ANA,anti-dsDNA and antiSm was higher than that of single detection.AnuA usually associated with fever,oral/nasal pharyngeal ulcer,lung damage,lymphocyte absolute value,urine protein and C3 level.Conclusion AnuA can be used as a serum marker for JSLE diagnosis.The detection of AnuA combined with anti-dsDNA and anti-Sm should be more helpful for diagnosis of JSLE.

Research progress of the negative effects of extracellular histone / 基础医学与临床

Histones can be released into the extracellular space,and lead to lethal sepsis, ischemia reperfusion injury, trauma, pancreatitis, coagulation and thrombosis.In addition, the increase of serum histone is related to the pathological and pathophysiological process of autoimmune diseases, nervous system diseases and tumors.Therefore, extracellular histone can be used as biomarkers and therapeutic targets for a variety of human diseases.

Identificación de predictores serológicos de recaída en pacientes con lupus eritematoso sistémico: estudio prospectivo de 12 meses / Identification of relapse aerological predictors in patients with systemic lupus erythematous: a prospective study of 12 months

Introducción: las investigativos efectuadas no han tenido éxito en la búsqueda de biomarcadores serológicos o clínicos suficientemente confiables para predecir las recaídas en el lupus eritematoso sistémico (LES). Objetivo: definir el valor predictivo de las especificidades de anticuerpos antinucleares para la recaída del LES y de la nefritis lúpica. Métodos: estudio analítico, observacional, longitudinal y prospectivo en 120 pacientes adultos con LES inactivo (SLEDAI-2K ≤ 5 puntos). La presencia basal de siete especificidades antinucleares, C3 y C4 bajos se correlacionaron con la ocurrencia de recaída del LES (incrementos en la puntuación de SLEDAI-2K ≥ 4) y de la nefritis lúpica mediante análisis univariado. Las variables más valiosas fueron evaluadas adicionalmente como predictoras con un modelo de regresión logística multivariada para calcular los odds ratio (OR). Resultados: las recaídas del LES y de la nefritis lúpica se observaron en 51 (42,5 por ciento) y 29 (24,2 por ciento) de los pacientes, respectivamente. En el análisis multivariado emergieron como factores de riesgo para la recaída del LES la presencia de los anticuerpos anti-Nu (OR= 1523,0; p < 0,001) y los anti-DNAdc (OR= 12,1; p= 0,044) y de la nefritis lúpica, los anti-Nu (OR= 92,9; p< 0,001) y el C3 bajo (OR= 7,1; p= 0,007), La sub-representación de los anti-RNP resultó un factor de riesgo para la recaída del LES y de la nefritis lúpica (OR= 0,023; p= 0,009 y OR= 0,1; p= 0,025). Conclusiones: los pacientes con LES positivos de anticuerpos anti-Nu, anti-DNAdc o niveles bajos del C3 presentaron un riesgo mayor de recaída del LES y de la nefritis lúpica en los próximos 12 meses, lo que señala la necesidad de estrechar su monitoreo clínico(AU)

Introduction: the research carried out have not been successful in finding serological biomarkers or sufficiently reliable biomarkers for predicting relapse in systemic lupus erythematosus (SLE). Objective: setermine the predictive value of specific antinuclear antibodies for relapse of SLE and lupus nephritis. Methods: an analytical, observational, longitudinal and prospective study was carried out in 120 adult patients with inactive SLE (SLEDAI-2K ≤ 5 points). The baseline presence of seven antinuclear specificities, low C3 and C4 were correlated with the occurrence of SLE relapse (increases in score SLEDAI-2K ≥ 4) and lupus nephritis by univariate analysis. The most valuable variables were further evaluated as predictors a multivariate logistic regression model to calculate the odds ratio (OR). Results: SLE and lupus nephritis relapses were observed in 51 (42.5 percent) and 29 (24.2 percent) patients, respectively. The presence of anti-Nu (OR= 1523.0, P < 0.001) antibodies and anti-dsDNA (OR= 12.1; p = 0.044) and lupus nephritis, anti-Nu (OR= 92.9; p < 0.001) and low C3 (OR= 7.1; p= 0.007) emerged as risk factors for relapse of SLE in multivariate analysis. The underrepresentation of anti-RNP was a risk factor for relapse of SLE and lupus nephritis (OR = 0.023; p= 0.009; OR = 0.1; p= 0.025). Conclusions: SLE patients with positive anti-Nu, anti-dsDNA and low levels of C3 had a higher risk of relapse of SLE and lupus nephritis in the succeeding 12 months, signaling the need for close clinical monitoring(AU)

Significance of anti-nucleosome antibodies in diagnosis of systemic lupus erythematosus / 国际检验医学杂志

Objective To explore the significance and value of the anti-nucleosome antibodies(AnuA)in the diagnosis of system-ic lupus erythematosus(SLE).Methods The serum AnuA was detected in 177 patients with SLE,138 patients with other rheumat-ic diseases and 56 healthy controls by Western blot.The clinical manifestations,autoantibodies and other test results were recorded in the SLE patients.The AnuA and other autoantibodies were analyzed.Results The positive rate of AnuA in the SLE group was significantly higher than that in the disease control group,AnuA was negative in the healthy control group;the sensitivity of AnuA in the SLE group was 48.6% and the specificity was 95.3%;the sensitivity of AnuA was significantly higher than that of the anti-ds-DNA antibodies and anti-Sm antibodies,the difference had statistical significance (P <0.05).The specificity of AnuA was higher than that of ANA and histone (P <0.05 ).The sensitivity of joint detection of AnuA,anti-ds-DNA and anti-Sm antibodies was 89.8%,which was significantly higher than that of a single index detection.The positive rate of AnuA in the active period of SLE was significantly higher than that of the non-active period,moreover higher than that of the ds-DNA antibodies (P <0.05).Conclu-sion AnuA might participate in the pathogenesis of SLE.The joint detection of autoantibodies including AnuA,etc.has importance significance in the diagnosis,condition judgment and curative efficacy evaluation of SLE.

Autoanticuerpos como biomarcadores de actividad de la enfermedad del lupus eritematoso sistémico / Autoantibodies as biomarkers of disease activity in systemic lupus erythematosus

Hay una necesidad urgente de biomarcadores que permitan identificar y predecir las fases de actividad del lupus eritematoso sistémico (LES) para optimizar el manejo clínico de los pacientes. De la centena de autoanticuerpos presentes en los pacientes con LES muy pocos son candidatos para biomarcadores de actividad clínica de la enfermedad y ninguno se ha establecido como criterio independiente para la toma de decisiones clínicas. Identificar las recaídas del LES es más arte que ciencia. Recientemente se ha señalado que la correlación positiva entre los niveles de autoanticuerpos y la actividad del LES puede estar subvertida por la presencia de autoanticuerpos protectores que se oponen al daño hístico que producen los autoanticuerpos patogénicos. Los anticuerpos anti-nucleosoma, anti-DNA de doble cadena y anti-C1q están asociados a la actividad de la enfermedad evaluada por varios sistemas de puntuación internacionales como el SLEDAI, ECLAM y BILAG, mayormente en estudios transversales. Estos biomarcadores resultan prometedores para el seguimiento clínico de pacientes con LES, pero aún necesitan la validación de estudios controlados multicéntricos de gran escala. Se hizo esta revisión para resumir los retos del descubrimiento y validación de los autoanticuerpos biomarcadores de actividad del LES en el marco de la complejidad funcional de los autoanticuerpos...

There is an urgent need for biomarkers to identify and predict activity phases of systemic lupus erythematosus (SLE) to optimize the patients clinical management. Out of hundreds of autoantibodies present in SLE patients, very few are candidates for biomarkers of clinical disease activity and none has been established as an independent criterion for clinical decision making. Identifying relapse of SLE is more art than science. It has recently been suggested that the positive correlation between autoantibody levels and SLE activity may be subverted by the presence of protective autoantibodies opposed to tissue damage produced by pathogenic autoantibodies. The anti-nucleosome, anti-dsDNA and anti-C1q antibodies are associated with disease activity assessed by several international rating systems such as the SLEDAI, BILAG ECLAM and, partly in cross-sectional studies. These biomarkers are promising for clinical monitoring of SLE patients, but they still need the validation of multi-scale controlled studies. This review was to summarize the challenges of discovery and validation of biomarkers of autoantibodies in SLE activity within the functional complexity of the autoantibodies...