Pathways In Systemic Lupus Erythematosus Research Articles

Comprehensive study of tumour single nucleotide polymorphism array data reveals significant driver aberrations and disrupted signalling pathways in human hepatocellular cancer.

The authors describe an integrated method for analysing cancer driver aberrations and disrupted pathways by using tumour single nucleotide polymorphism (SNP) arrays. The authors new method adopts a novel statistical model to explicitly quantify the SNP signals, and therefore infers the genomic aberrations, including copy number alteration and loss of heterozygosity. Examination on the dilution series dataset shows that this method can correctly identify the genomic aberrations even with the existence of severe normal cell contamination in tumour sample. Furthermore, with the results of the aberration identification obtained from multiple tumour samples, a permutation-based approach is proposed for identifying the statistically significant driver aberrations, which are further incorporated with the known signalling pathways for pathway enrichment analysis. By applying the approach to 286 hepatocellular tumour samples, they successfully uncover numerous driver aberration regions across the cancer genome, for example, chromosomes 4p and 5q, which harbour many known hepatocellular cancer related genes such as alpha-fetoprotein (AFP) and ectodermal-neural cortex (ENC1). In addition, they identify nine disrupted pathways that are highly enriched by the driver aberrations, including the systemic lupus erythematosus pathway, the vascular endothelial growth factor (VEGF) signalling pathway and so on. These results support the feasibility and the utility of the proposed method on the characterisation of the cancer genome and the downstream analysis of the driver aberrations and the disrupted signalling pathways.

MicroRNA expression profiles of peripheral blood mononuclear cells in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against numerous self-antigens. Evidence underlines the importance of microRNAs (miRNAs) in the pathogenesis of SLE, but the exact etiology of this disease is unknown. Therefore, this study was conducted to explore regulation of abnormal miRNAs in SLE using microarray analysis. Peripheral blood mononuclear cells (PBMCs) from SLE patients and their matched controls were isolated appropriately. Total RNAs from each cell sample were extracted and used for microarray analysis. A total of 29 miRNAs were identified to be down-regulated in PBMCs of SLE patients as compared with healthy controls (P<0.05, fold change>2). No significant up-regulated miRNAs were found in SLE patients. Results of gene ontology analysis indicated that the potential target genes of these miRNAs mainly enriched in the development process, transcription regulator activity, ligand binding, etc. Meanwhile, these putative genes were also found to be involved in diverse signaling transduction pathways, including multiple cancer pathways, Wnt and mitogen-activated protein kinase signaling pathways, etc. This study revealed possible dysregulated biological processes and pathways in SLE that were targeted by the differentially expressed miRNAs, indicating the involvement of these miRNAs in the pathogenesis of SLE.

Autophagy is activated in systemic lupus erythematosus and required for plasmablast development

BackgroundAutophagy has emerged as a critical homeostatic mechanism in T lymphocytes, influencing proliferation and differentiation. Autophagy in B cells has been less studied, but genetic deficiency causes impairment of early...

Genetics of the type I interferon pathway in systemic lupus erythematosus

Genetic studies of systemic lupus erythematosus (SLE) have been successful, identifying numerous risk factors for human disease. While the list is not yet complete, it is clear that important immune system pathways are represented, one of which being type I interferon (IFN). Circulating type I IFN levels are high in SLE patients and this IFN pathway activation is heritable in families with SLE. We summarize our current understanding of the genetics of the type I IFN pathway in SLE, with an emphasis on studies that demonstrate an impact of the SLE-risk alleles upon type I IFN pathway activation in SLE patients. These studies illustrate that variations in type I IFN pathway genes represent a common genetic feature of SLE. By understanding the genetic regulation of type I IFN, we may be able to intervene in a more personalized fashion, based upon the molecular dysregulation present in a given individual.

Genetic interaction between genes involved in NF-κB signaling pathway in systemic lupus erythematosus

Recently, multiple genetic associations have been found between genes involved in nuclear factor-kappaB (NF-κB) signaling pathway and systemic lupus erythematosus (SLE) or other autoimmune diseases. This study was undertaken to replicate some of these associations and further test for genetic interactions among these genes in SLE in a Chinese population. Ten single-nucleotide polymorphisms (SNPs) in NFKB1, REL, inhibitor of κB-like (IκBL), IκB kinase β (IKBKB), tumor necrosis factor receptor associated factor 6 (TRAF6), tumor necrosis factor a-induced protein 3 (TNFAIP3), TNFAIP3 interacting protein 1 (TNIP1) were genotyped in 898 Chinese patients with SLE and 988 healthy controls by Sequenom MassArray technology. Single-marker genetic association analysis was performed, and additive and multiplicative interactions were analyzed. Associations of TNFAIP3 rs2230926 (p=1.43×10−3) and TNIP1 rs10036748 (p=4.33×10−3) with SLE were replicated in our study. Two other SNPs, NFKB1 rs28362491 and IκBL rs2071592, showed nominal evidence for association (p=4.70×10−2 and p=5.90×10−3, respectively) but these were not significant after applying Bonferroni correction. Additive interaction analysis revealed significant interaction between NFKB1 rs28362491 and TNFAIP3 rs2230926 (RERI=0.98, 95%CI=0.02–1.93; AP=43.2%, 95%CI=0.12–0.74). Significant multiplicative interaction was observed between NFKB1 rs28362491 and TNIP1 rs3792783 (p=0.03). Our results provide evidence for gene–gene interactions, which further support the important role of NF-κB signaling pathway in the genetic basis of SLE and the notion of genetic interactions accounting for missing heritability.

Subcutaneous and gonadal adipose tissue transcriptome differences in lean and obese female dogs

Canine obesity leads to shortened life span and increased disease incidence. Adipose tissue depots are known to have unique metabolic and gene expression profiles in rodents and humans, but few comparisons of depot gene expression have been performed in the dog. Using microarray technology, our objective was to identify differentially expressed genes and enriched functional pathways between subcutaneous and gonadal adipose of lean and obese dogs to better understand the pathogenesis of obesity in the dog. Because no depot × body weight status interactions were identified in the microarray data, depot differences were the primary focus. A total of 946 and 703 transcripts were differentially expressed (FDR P<0.05) between gonadal and subcutaneous adipose tissue in obese and lean dogs respectively. Of the adipose depot-specific differences in gene expression, 162 were present in both lean and obese dogs, with the majority (85%) expressed in the same direction. Both lean and obese dog gene lists had enrichment of the complement and coagulation cascade and systemic lupus erythematosus pathways. Obese dogs had enrichment of lysosome, extracellular matrix-receptor interaction, renin-angiotensin system and hematopoietic cell lineage pathways. Lean dogs had enrichment of glutathione metabolism and synthesis and degradation of ketone bodies. We have identified a core set of genes differentially expressed between subcutaneous and gonadal adipose tissue in dogs regardless of body weight. These genes contribute to depot-specific differences in immune function, extracellular matrix remodeling and lysosomal function and may contribute to the physiological differences noted between depots.

Circulating MicroRNA Expression Profiles Associated With Systemic Lupus Erythematosus

To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE). Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcription-polymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients. Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P < 2 × 10(-9) ). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis. Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor β signaling pathways. Other targets include regulation of apoptosis, cytokine-cytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.

Therapeutic potential of SIGIRR in systemic lupus erythematosus

Single immunoglobulin IL-1-related receptor (SIGIRR), which is also known as Toll/interleukin-1 receptor 8, is a member of the interleukin-1 receptor (IL-1R) family. Different from other typical IL-1R superfamily members, SIGIRR seems to exert negatively modulates in immune responses. Several previous studies demonstrated that SIGIRR influences chronic inflammatory or autoimmune diseases, such as intestinal inflammation, rheumatoid arthritis and psoriatic arthritis. Recent work has explored the role of SIGIRR in systemic lupus erythematosus (SLE), for example, the role of SIGIRR protects the mice from hydrocarbon oil-induced lupus has been reported. These results indicate that SIGIRR may represent a novel target for the treatment of SLE. In this review, we will discuss the SIGIRR and the therapeutic potential of modulating the pathway in SLE.

Alpha-defensin DEFA1A3 gene copy number variation in Asians and its genetic association study in Chinese systemic lupus erythematosus patients

Neutrophil extracellular traps (NETs) were closely associated with activation of type I interferon (IFN) pathway in systemic lupus erythematosus (SLE). We aimed to study the genetic basis of NETs-DEFA1A3 copy number variations (CNV) in SLE and HapMap CHB+JPT populations by quantitative real-time PCR and whole genome sequences data. DEFA1A3 CNs did not differ significantly between SLE patients and controls. DEFA1A3 CNs ranged from 3 to 11 in CHB and 4 to 16 in JPT. The median of DEFA1A3 CNV of CHB (6 copies) was significantly lower than that of JPT (9 copies). Associations of genotype of tag SNP rs2738113 with DEFA1A3 CNs and mRNA expression of IFNα were observed in CHB and JPT populations. Our data provided a genetic reference of DEFA1A3 CNV for further studies and suggested that the genetic pathogenesis of NETs, as well as DEFA1A3 in SLE should be further evaluated, specially in different populations.

Clinical associations of serum interleukin-17 in systemic lupus erythematosus

IntroductionSerum interleukin (IL)-17 concentrations have been reported to be increased in systemic lupus erythematosus (SLE), but associations with clinical characteristics are not well understood. We characterized clinical associations of serum IL-17 in SLE.MethodsWe quantified IL-17 in serum samples from 98 SLE patients studied cross-sectionally, and in 246 samples from 75 of these patients followed longitudinally over two years. Disease activity was recorded using the SLE Disease Activity Index (SLEDAI)-2k. Serum IL-6, migration inhibitory factor (MIF), and B cell activating factor of the tumour necrosis factor family (BAFF) were also measured in these samples.ResultsSerum IL-17 levels were significantly higher in SLE patients compared to healthy donors (P <0.0001). No correlation was observed between serum IL-17 and SLEDAI-2k, at baseline or during longitudinal follow-up. However, we observed that SLEDAI-2k was positively correlated with IL-17/IL-6 ratio. Serum IL-17 was significantly increased in SLE patients with central nervous system (CNS) disease (P = 0.0298). A strong correlation was observed between serum IL-17 and IL-6 (r = 0.62, P <0.0001), and this relationship was observed regardless of disease activity and persisted when integrating cytokine levels over the period observed (r = 0.66, P <0.0001). A strong correlation of serum IL-17 was also observed with serum BAFF (r = 0.64, P <0.0001), and MIF (r = 0.36, P = 0.0016).ConclusionsSerum IL-17 concentration correlates poorly with SLE disease activity but is significantly elevated in patients with CNS disease. IL-17/IL-6 ratio may be more useful than IL-17 or IL-6 alone to characterize Th17-driven disease, such as SLE. The association of other cytokines with serum IL-17 suggests that IL-17 may drive activation of diverse immune pathways in SLE.

Targeting the BLyS-APRIL signaling pathway in SLE

The B lymphocyte stimulator (BLyS)-A PRoliferation-Inducing Ligand (APRIL) signaling pathway has an important role in the selection, maturation and survival of B cells and plays a significant role in the pathogenesis of systemic lupus erythematosus (SLE). The inhibition of BLyS, a survival factor for transitional and mature B cells, has recently proven to be successful in large phase III clinical trials that led to the approval of an anti-BLyS monoclonal antibody (belimumab) for the treatment of SLE. Yet, there is currently a need to both understand better the mechanisms of action of belimumab in SLE and better define the subsets of patients that are more likely to respond to the drug.

Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

MicroRNAs (miRNAs) function to fine-tune the control of immune cell signaling. It is well established that there are abnormalities in the interleukin-2 (IL-2)-related signaling pathways in systemic lupus erythematosus (SLE). The miR-31 microRNA has been found to be markedly underexpressed in patients with SLE, and thus the present study was undertaken to investigate the role of miR-31 in IL-2 defects in lupus T cells. Expression levels of miR-31 were quantitated using TaqMan miRNA assays. Transfection and stimulation of cultured cells followed by TaqMan quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and reporter gene assays were conducted to determine the biologic function of miR-31. NF-AT nuclear translocation and expression were quantitatively measured using an ImageStream cytometer. Bioinformatics analysis, small interfering RNA (siRNA) knockdown, and Western blotting were performed to validate miR-31 targets and effects. The expression of miR-31 was significantly decreased in lupus T cells, and this was positively correlated with the expression of IL-2. Overexpression of miR-31 in T cells increased the production of IL-2 by altering NF-AT nuclear expression and IL2 promoter activity, while knockdown of endogenous miR-31 reduced IL-2 production. RhoA expression was directly repressed by miR-31 in T cells. Of note, siRNA-mediated knockdown of RhoA enhanced IL2 promoter activity and, consequently, up-regulated IL-2 production. RhoA expression was consistently up-regulated and negatively correlated with the levels of miR-31 in lupus T cells. Manipulation of miR-31 expression in lupus T cells restored the expression of IL-2 at both the messenger RNA and protein levels. MicroRNA-31 is a novel enhancer of IL-2 production during T cell activation. Dysregulation of miR-31 and its target, RhoA, could be a novel molecular mechanism underlying the IL-2 deficiency in patients with SLE.

Gene Expression Profiling of Dendritic Cells in Different Physiological Stages under Cordyceps sinensis Treatment

Cordyceps sinensis (CS) has been commonly used as herbal medicine and a health supplement in China for over two thousand years. Although previous studies have demonstrated that CS has benefits in immunoregulation and anti-inflammation, the precise mechanism by which CS affects immunomodulation is still unclear. In this study, we exploited duplicate sets of loop-design microarray experiments to examine two different batches of CS and analyze the effects of CS on dendritic cells (DCs), in different physiology stages: naïve stage and inflammatory stage. Immature DCs were treated with CS, lipopolysaccharide (LPS), or LPS plus CS (LPS/CS) for two days, and the gene expression profiles were examined using cDNA microarrays. The results of two loop-design microarray experiments showed good intersection rates. The expression level of common genes found in both loop-design microarray experiments was consistent, and the correlation coefficients (Rs), were higher than 0.96. Through intersection analysis of microarray results, we identified 295 intersecting significantly differentially expressed (SDE) genes of the three different treatments (CS, LPS, and LPS/CS), which participated mainly in the adjustment of immune response and the regulation of cell proliferation and death. Genes regulated uniquely by CS treatment were significantly involved in the regulation of focal adhesion pathway, ECM-receptor interaction pathway, and hematopoietic cell lineage pathway. Unique LPS regulated genes were significantly involved in the regulation of Toll-like receptor signaling pathway, systemic lupus erythematosus pathway, and complement and coagulation cascades pathway. Unique LPS/CS regulated genes were significantly involved in the regulation of oxidative phosphorylation pathway. These results could provide useful information in further study of the pharmacological mechanisms of CS. This study also demonstrates that with a rigorous experimental design, the biological effects of a complex compound can be reliably studied by a complex system like cDNA microarray.

Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus

Autophagy is a lysosome-mediated catabolic process that allows cells to degrade unwanted cytoplasmic constituents and to recycle nutrients. Autophagy is also involved in innate and adaptive immune responses, playing a key role in interactions against microbes, in antigen processing for major histocompatibility complex (MHC) presentation, and in lymphocyte development, survival, and proliferation. Over recent years, perturbations in autophagy have been implicated in a number of diseases, including autoimmunity. Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by autoimmune responses against self-antigens generated by dying cells. Genome-wide association studies have linked several single-nucleotide polymorphisms (SNPs) in the autophagy-related gene Atg5 to SLE susceptibility. Loss of Atg5-dependent effects, including clearance of dying cells and cell antigen presentation, might contribute to the autoimmunity and inflammation associated with SLE. Moreover, activation of the mammalian target of rapamycin (mTOR), a key player in the autophagy regulation, has recently been demonstrated in SLE, confirming an altered autophagy pathway in this disease. In the present review, we summarize the autophagy mechanisms, their molecular regulation, and their relevance in immunity and autoimmunity. The potential of targeting autophagy pathway in SLE, by developing innovative therapeutic approaches, has finally been discussed.

Inflammation associated anemia and ferritin as disease markers in SLE

IntroductionIn a recent screening to detect biomarkers in systemic lupus erythematosus (SLE), expression of the iron storage protein, ferritin, was increased. Given that proteins that regulate the storage, transfer and release of iron play an important role in inflammation, this study aims to determine the serum and urine levels of ferritin and of the iron transfer protein, transferrin, in lupus patients and to correlate these levels with disease activity, inflammatory cytokine levels and markers of anemia.MethodsA protein array was utilized to measure ferritin expression in the urine and serum of SLE patients and healthy controls. To confirm these results as well as the role of the iron transfer pathway in SLE, ELISAs were performed to measure ferritin and transferrin levels in inactive or active SLE patients and healthy controls. The relationship between ferritin/transferrin levels and inflammatory markers and anemia was next analyzed.ResultsProtein array results showed elevated ferritin levels in the serum and urine of lupus patients as compared to controls, which were further validated by ELISA. Increased ferritin levels correlated with measures of disease activity and anemia as well as inflammatory cytokine titers. Though active SLE patients had elevated urine transferrin, serum transferrin was reduced.ConclusionUrine ferritin and transferrin levels are elevated significantly in SLE patients and correlate with disease activity, bolstering previous reports. Most importantly, these changes correlated with the inflammatory state of the patients and anemia of chronic disease. Taken together, altered iron handling, inflammation and anemia of chronic disease constitute an ominous triad in SLE.

Targeting lymphocyte signaling pathways as a therapeutic approach to systemic lupus erythematosus

Over the past year several key pathways in systemic lupus erythematosus (SLE) lymphocyte signaling have been identified. Pathways that can be exploited for therapy are discussed in this review. Inhibition of SLE T cell activation by blocking spleen tyrosine kinase (Syk) and SLE T cell migration by blocking CD44 or CXCR4 lead to amelioration of lupus in lupus-prone mice. Similar results can be achieved by boosting CD8+ Treg numbers. Small molecules that block the kinases CaMKIV (calcium and calmodulin dependent kinase IV) and Bruton Tyrosine kinase (Btk) and the phosphatase calcineurin were shown to be effective in treating murine lupus. Finally, gene methylation status determines the expression of several key genes in SLE and strategies to correct it have shown promising results in preclinical studies. Molecules that enhance T cell receptor (TCR) signaling or increase lymphocyte migration can be inhibited successfully with significant improvement of disease intensity in lupus-prone mice using small molecules. Manipulation of promoter methylation and histone acetylation represents a novel way to alter gene transcription in SLE.

Regulation of VLA-4 in lupus monocytes objectives

ObjectivesThe development of atherosclerosis and subsequent increased risk of cardiovascular disease (CVD) is known to be associated with inflammation. Studies have shown an increased risk of CVD in systemic lupus...

Association of a functional polymorphism in the 3′-untranslated region of SPI1 with systemic lupus erythematosus

SPI1, also referred to as PU.1, is an Ets family transcription factor that interacts with IRF2, IRF4, and IRF8. In view of the significance of the type I interferon pathway in systemic lupus erythematosus (SLE), this study was undertaken to investigate a possible association between SPI1 polymorphisms and SLE. A case-control association study was performed using 6 tag single-nucleotide polymorphisms (SNPs), as well as a SNP located upstream of SPI1 previously found to be associated with acute myelogenous leukemia, in 400 Japanese patients with SLE and 450 healthy controls. Resequencing of all exons and known regulatory regions was performed to identify functional polymorphisms. Association of genotype and SPI1 expression was examined using the GENEVAR database and reporter assays. A significant association was detected in 2 SNPs in intron 2 (rs10769258 and rs4752829) (P = 0.005 and P = 0.008, respectively, under the dominant model). The association was stronger in patients with nephropathy. Resequencing identified a potentially functional polymorphism in the 3'-untranslated region (3'-UTR), rs1057233, which was in strong linkage disequilibrium with the SNPs in intron 2. The number of risk alleles at rs1057233 was strongly correlated with SPI1 messenger RNA (mRNA) level in the database analysis (P = 0.0002), and was confirmed by a reporter assay. Interestingly, rs1057233 alters a target sequence for microRNA hsa-miR-569 (miR-569). Transfection experiments demonstrated that miR-569 inhibits expression of a reporter construct with the 3'-UTR sequence containing the nonrisk allele but not the risk allele. Our findings indicate that a SNP in the 3'-UTR of SPI1 is associated with elevated SPI1 mRNA level and with susceptibility to SLE.

Unique Gene Expression Patterns in Hematopoietic Stem Cells from Various Sources

Hematopoietic stem cells are involved in the production of blood cells. These cells are derived from various origins. In this study, we examined, using microarray software GeneSpring GX, whether HSCs derived from four different origins i.e., cord blood, liver, bone marrow and peripheral blood, exhibit unique gene expression pattern. A total of 23 individual normal hematopoietic cell expression profiles were identified in NCBI's GEO database -10 normal CD34+ bone marrow sample, 4 normal CD34+ liver sample, 5 normal CD34+ cord blood sample and 4 normal CD34+ peripheral blood sample. These studies were performed using U133A array platform. The data analysis was done by GeneSpring GX Microarray software 7.3 version. Our results indicated that HSCs derived from various origins exhibited unique gene expression patterns. We also determined the specific biological function of HSCs using upregulated genes that are uniquely expressed in each origin. We observed the following results - cord blood HSCs play an important role in development of embryos; Liver HSCs play an important role in apoptosis, angiogenesis and neural transdifferentiation; Bone marrow HSCs play an important role in cell proliferation, cell migration and cell retention and peripheral blood HSCs play an important role in nucleosome assembly. These HSCs genes present in peripheral blood, when altered, get involved in Systemic Lupus Erythematosus Pathway.

How does interferon‐α insult the vasculature? Let me count the ways

How does interferon‐α insult the vasculature? Let me count the ways