Role In Pathogenesis Of Systemic Lupus Erythematosus Research Articles

Serum tenascin-c in systemic lupus erythematosus and association with clinical expression of the disease

Background: Tenascin-C (TN-C) is a pro-inflammatory glycoprotein with various biological functions. TN-C plays a major role in cell adhesion, migration, proliferation, and cellular signaling through the induction of pro-inflammatory cytokines. Aim of the Work: This study was designed to investigate the relationship between serum TN-C levels and disease activity in patients with systemic lupus erthromatosus. Subjects and Methods: This is a case–control observational study that was carried out on 68 participants and divided into two groups. Group A included 34 systemic lupus erythematosus (SLE) patients and Group B included (34) apparently healthy volunteers. They were age and sex matched with the patients. Clinical examination as well as routine laboratory investigations confirmed their healthy status. All patients were subjected to full history taking, through clinical examination, laboratory investigations as C-reactive protein, erythrocyte sedimentation rate, C3, C4, ANA, and anti-dsDNA. Serum TN-C estimation of serum TN-C was done for SLE patients and the control group using double-antibody sandwich enzyme-linked immunosorbent assay. Disease activity of SLE patients was assessed according to SLE disease activity index 2000 score. Results: Serum level of TN-C was higher in SLE patients than healthy control but with no statistically significant difference (P > 0.05). There was highly statistically significant difference (P Conclusion: Serum TN-C level is elevated in SLE patients and correlates with disease activity which indicates its possible role in SLE pathogenesis. Thus, TN-C may provide a novel research target for the pathogenesis and therapy of SLE.

MiR-155 expression is a potential biomarker of systemic lupus erythematosus diagnosis and disease activity prediction

BackgroundEarly diagnosis of Systemic Lupus Erythematosus (SLE) and its activity has a curtail role in the proper management of the disease with positive effect on its prognosis. MicroRNAs (miRNAs) evidently take apart in the pathogenesis of autoimmune diseases. Many miRNAs play a role in SLE pathogenesis and miR-155 is one of them. ObjectiveTo examine miR-155 expression in patients with SLE and evaluate its role in the disease development and activity. Subjects and methodsThe current study evaluated miR-155 expression in 60 SLE patients and 40 apparently healthy controls (HCs) using real-time polymerase chain reaction. Diagnosis was according to Systemic Lupus International Collaborating Clinics (SLICC) criteria. Disease activity was evaluated by systemic lupus erythematosus disease activity index (SLEDAI-2 K) score. ResultsmiR-155 level was significantly higher in SLE patients than controls with significant positive correlation with SLEDAI score and positive relation to renal involvement, proteinuria, pulmonary complications, fever and dsDNA antibodies. Multivariate regression analysis revealed that miR-155 is a significant risk factor for SLE. ConclusionOverexpression of miR-155 occurs in SLE and it can be used as a predictor biomarker for disease's development and activity. It also may be a risk for renal involvement in the disease course.

AB0051 SERUM AMYLOID A AND PENTRAXIN 3: INNATE IMMUNE RESPONSE AND DISEASE ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Systemic Lupus Erythematosus (SLE) is an autoimmune disease that involves several molecular patterns with a wide spectrum of clinical manifestations and symptoms. Inflammation and related pathway play a role in SLE pathogenesis. The pentraxin superfamily including long and short pentraxin, C Reactive Protein CRP, Serum amyloid A (SAA), Pentraxin 3 (PTX3) are key components of innate immune system and induce a variety of inflammation associated pathway. However Literature provides several evidences that CRP serum levels not correlated with clinical and immunological manifestations. This situation affected clinical practice and the patient follow up. PTX3 have been identified as a component of inflammatory status in several autoimmune conditions. SAA is an acute phase protein secreted in large quantity during inflammation.Objectives:We want to evaluated SAA, PTX3 and CRP concentrations, their correlation between SLE Disease Activity Index (SLEDAI), that including complement fractions C3, C4.Methods:We enrolled fifty patients that fulfilled the SLE American College of Rheumatology criteria and fifty healthy subjects. The SLE disease activity was classified with the SLEDAI (0 to 12). Patients were divided into two groups according to SLEDAI score: inactive group (Group 1, 25 patients, 50%: SLEDAI < 4) and active group (Group 2, 25 patients, 50%: SLEDAI 5 to 12). PTX3 concentration was measured by a sandwich ELISA kit (Hycult) with 2.8 ng/mL cut-off point. SAA concentration was detected by nephelometry performed on a BN ProSpec System (Siemens, Germany), with assay kit based on polyclonal antibodies (Siemens Healthcare Diagnostics Products, Germany, 6.5 mg/L cut-off point). High sensitive CRP concentrations were determined using the ci8200 platform (Abbott Laboratories Chicago, Illinois).Results:Plasma PTX3 and serum SAA levels was significantly higher in SLE patients than in the healthy subjects (PTX311.5 ± 7.3 ng/mL vs 2.3 ± 1.1; p < 0.001; SAA: 87 ±77 mg/L vs 2.6±2.5; p < 0.001). These differences were not evident in CRP levels (8.5 ± 7.8 mg/L vs 6.2± 2.5). Considering two groups, there were statistical differences in PTX3 level (Group 2: 14.9 ± 12 ng/mL vs Group 1: 2.16 ±0.5 ng/mL, p<0,05) and SAA concentration (Group 2: 114 ± 89 ng/mL vs Group 1: 3.6 ±1.7 ng/mL, p<0,05) but not in CRP concentration (Group 2: 11.5 ± 8.4 mg/L vs Group 1: 9.5 ±3.5). There was a significantly negative correlation between C3, C4 fractions, PTX3 and SSA levels (respectively r = −0.74, p=<0.05, and r = −0.79, p<0.05). No statistical correlation were appeared between C3, C4 fractions and CRP serum levels (r= −0,12., p= 0.82, and r= −0.18, p= 0,21). We noted a positive significant correlation between SLEDAI, PTX3 and SAA concentration (r = 0.79, p < 0.05, 0.83, p < 0.05, respectively) an increase in PTX3 and SAA levels followed the lupus flare and symptoms. No significant correlation appeared between SLEDAI and CRP (r= 0.15, p=0.89)Conclusion:PTX3 and SAA concentration was significantly higher in SLE patients than the healthy control subjects and their levels reflected disease activity. We showed a direct correlation between PTX3 and SAA. In SLE patients PTX3 and SAA concentrations were correlated with SLEDAI. We suggest an integrate viewpoint in witch SAA and PTX3 may play a role as a biomarker of disease activity, with synergic work during SLE events. Evidences suggested that PTX3 and SAA could trigger the same molecular pathway, by TLR4, via NF-kB.

Measurement Serum Level of Interleukin-34 in Patients with SLE and Healthy Control

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by abnormal function of T-cells and B-cells involving production of autoantibodies and different type of interleukins including complement activation and multiple tissue damage accompanied with different clinical manifestation, all of this happened along with break tolerance. Many researches revealed a key role of interleukins and other biological molecules in SLE patients. Interleukin 34 responsible for increasing differentiation and surviving of autoimmune cells in SLE. Objective: This study was aimed to estimate the concentration of IL-34 SLEpatients in compare with healthy people. Materials and Method: This is a case-control study accomplished in the Advisory Clinic for Rheumatic Diseases Center in Al-Najaf city, for the period from December 2018 to August 2019. A total of 60 individuals were included in this study, 30 were diagnosed with SLEby specialist rheumatogy physician, and 30 were healthy controls. Blood sample were collected by venipuncture from 30 patients and 30 healthy controls under sterilized technique and putting in gel tube which then used in sandwich ELISA technique to detect serum level of IL-34. All data that include age, gender, residence and history of autoimmune diseases were collected from all participants. The data were analyzed by using the statistical package social system (SPSS). Results: This study show that level of IL-34were significantly higher in SLE patients (49.58±64.03) than in control (0.4±1.25). It is also found that the prevalence of SLE was higher in female in comparewith male26 (86.7%) to 4 (13.3%) respectively. It also found that SLEwas more frequent in age interval from (31-50) years old. Conclusion: Elevation of Il-34 concentration may play important role in pathogenesis of SLE, SLE most commonly affectfemales age groups (31-50 years old).

Clinical utility of progranulin in patients with systemic lupus erythematosus

Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. SLE has different presentations that are not specific to the disease itself. Diagnosis and assessment of disease activity are considered a challenge to patients and physician, as both need experienced clinician to evaluate symptoms and laboratory findings. So, it is very important to search for an accurate diagnostic marker for SLE activity. In the past few years, increasing evidence has shown that progranulin (PGRN) may play a role in regulation of adaptive and innate immunity, so it might be a marker for disease activity. Aim To investigate the clinical significance of PGRN in patients with SLE regarding its role in pathogenesis and its correlation to clinical manifestations and disease activity. Patients and methods This is a case–control study conducted on 96 participants. Group I included 56 patients with SLE subdivided according to SLE Disease Activity Index (SLEDAI) score into patients with active and inactive SLE. Group II included 40 apparently healthy volunteers as a control group. All patients were subjected to a thorough history; complete clinical examination; assessment of disease activity by using SLEDAI; and laboratory investigations, including complete blood count, liver function, kidney function, complete urine analysis, anti-nuclear antibody, anti-double-stranded DNA antibody, complement 3, complement 4, and serum PGRN. Results There was a highly statistically significant increase in serum PGRN level in patients with SLE compared with healthy control group. Moreover, a positive correlation was found between PGRN levels and SLEDAI score. Conclusion Patients with SLE with higher SLEDAI score have higher serum PGRN level. So, serum PGRN level might play a role in SLE pathogenesis and as diagnostic marker for SLE activity.

A Bayesian gene network reveals insight into the JAK-STAT pathway in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic, remitting, and relapsing, inflammatory disease involving multiple organs, which exhibits abnormalities of both the innate and adaptive immune responses. A limited number of transcriptomic studies have characterized the gene pathways involved in SLE in an attempt to identify the key pathogenic drivers of the disease. In order to further advance our understanding of the pathogenesis of SLE, we used a novel Bayesian network algorithm to hybridize knowledge- and data-driven methods, and then applied the algorithm to build an SLE gene network using transcriptomic data from 1,760 SLE patients’ RNA from the two tabalumab Phase III trials (ILLUMINATE-I & -II), the largest SLE RNA dataset to date. Further, based on the gene network, we carried out hub- and key driver-gene analyses for gene prioritization. Our analyses identified that the JAK-STAT pathway genes, including JAK2, STAT1, and STAT2, played essential roles in SLE pathogenesis, and reaffirmed the recent discovery of pathogenic relevance of JAK-STAT signaling in SLE. Additionally, we showed that other genes, such as IRF1, IRF7, PDIA4, FAM72C, TNFSF10, DHX58, SIGLEC1, and PML, may be also important in SLE and serve as potential therapeutic targets for SLE. In summary, using a hybridized network construction approach, we systematically investigated gene-gene interactions based on their transcriptomic profiles, prioritized genes based on their importance in the network structure, and revealed new insights into SLE activity.

Expression of several long noncoding RNAs in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

PurposeAccumulating evidence has linked long noncoding RNAs (lncRNAs) to autoimmune and inflammatory disorders. This study aimed to detect the expression levels of five lncRNAs (lnc0640, lnc3643, lnc5150, lnc7514 and lncagf) in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE), as well as their correlation with clinical and laboratory features. Materials/methodsWe recruited 76 patients with SLE and 71 normal controls into the present study, and obtained PBMCs from the blood samples of all study subjects. Expression levels of lncRNAs were determined by quantitative real-time reverse transcription polymerase chain reaction and their associations with clinical and laboratory characteristics were analyzed. ResultsLnc5150 expression levels were statistically significantly decreased (Z=−6.016, P < 0.001) compared with normal controls. Lnc3643 levels were also statistically significantly decreased in SLE patients with proteinuria compared with those without (Z=−2.934, P = 0.003), and the lnc7514 levels were statistically significantly lower in anti-dsDNA(+) patients compared with anti-dsDNA(-) patients. The expression levels of lnc3643 were correlated with C-reactive protein and erythrocyte sedimentation rate (ESR), lnc7514 was correlated with disease activity and ESR (all P < 0.01). ConclusionsThe aberrant lncRNA expression levels and their associations with laboratory features in SLE suggest their important role in SLE pathogenesis.

Identification of circular RNAs hsa_circ_0044235 and hsa_circ_0068367 as novel biomarkers for systemic lupus erythematosus

Circular RNAs (circRNAs) have emerged as novel biomarkers for disease diagnosis. However, the expression profiles and clinical significance of circRNAs in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) remain unclear. In the present study, the expression profile of circRNAs in PBMCs from patients with SLE and healthy controls (HCs) was detected by using microarray analysis and verified by reverse transcription-quantitative polymerase chain reaction. A total of 1,603 circRNAs were identified to be significantly aberrantly expressed in PBMCs from patients with SLE. Validation assays in 30 SLE patients and 20 HCs demonstrated that the levels of hsa_circ_0044235 and hsa_circ_0068367 were significantly decreased in the patients with SLE. Receiver operating characteristic curve analysis suggested that hsa_circ_0044235 and hsa_circ_0068367 were significant for SLE diagnosis. Furthermore, the diagnostic potential of hsa_circ_0044235 and hsa_circ_0068367 for SLE was validated in an independent validation set with 45 patients with SLE, 38 HCs and 30 patients with rheumatoid arthritis. In addition, the level of hsa_circ_0044235 in the PBMCs from patients with SLE were identified to be significantly increased in new-onset SLE patients and in patients who were determined to be positive for anti-double-stranded DNA and anti-ribosomal protein P antibodies. Additionally, the level of a microRNA (miRNA) target of hsa_circ_0044235, hsa-miRNA-892a, was identified to be significantly increased in the PBMCs from patients with SLE. The present study suggested that the dysregulation of circRNAs may serve a role in SLE pathogenesis, and that the levels of hsa_circ_0044235 and hsa_circ_0068367 in PBMC have potential as biomarkers for SLE diagnosis.

Osteopontin and interleukin-17A genes polymorphisms in Egyptian systemic lupus erythematosus patients: A relation to disease activity and severity

Osteopontin (OPN) is involved in the regulation of the immune response and is accused in the pathogenesis of several autoimmune diseases including systemic lupus erythematosus (SLE). An obvious link between OPN and T cells, particularly T helper 17 cells is reported, where OPN produced by dendritic cells supports interleukin-17 (IL-17) expression, contributing to pathology of autoimmune disorders. The aim of the study was to investigate the association of genotypes and alleles frequencies of OPN 9250 (rs1126616) and IL-17A 197 (rs2275913) genes polymorphisms with their serum levels, susceptibility, disease activity and severity in Egyptian SLE patients. A total of 80 SLE patients and 80 healthy subjects were enrolled. The PCR-RFLP technique was used to detect OPN 9250 C/T and IL-17A 197 G/A genes polymorphisms. Serum OPN and IL- 17 levels were measured by the enzyme-linked immunosorbent assay. OPN TT genotype and T allele were significantly detected in SLE patients more than controls (P = 0.003, P < 0.001 respectively). IL-17A AA genotype showed non-significant higher frequency in SLE patients than in their controls (P = 0.07). While only the A allele of IL-17A polymorphism was significantly elevated in patients (P = 0.048). There was statistical significant association between OPN CT and TT genotypes and both renal and mucocutaneous manifestations. Also IL-17A AG and AA genotypes was significantly associated with renal, mucocutaneous in addition to the hematological manifestations. Serum OPN levels were significantly increased with TT genotype while serum IL-17 levels were significantly increased with AA genotype. Disease activity and severity scores were significantly elevated with both OPN TT and IL-17A AA genotypes. In conclusion, OPN 9250 C/T and IL-17A 197 G/A genes polymorphisms and their serum levels seemed to have a role in pathogenesis of SLE.

Cell lineage-specific genome-wide DNA methylation analysis of patients with paediatric-onset systemic lupus erythematosus

ABSTRACT Patients with paediatric-onset systemic lupus erythematosus (SLE) often present with more severe clinical courses than adult-onset patients. Although genome-wide DNA methylation (DNAm) profiling has been performed in adult-onset SLE patients, parallel data on paediatric-onset SLE are not available. Therefore, we undertook a genome-wide DNAm study in paediatric-onset SLE patients across multiple blood cell lineages. The DNAm profiles of four purified immune cell lineages (CD4 + T cells, CD8 + T cells, B cells and neutrophils) and whole blood were compared in 16 Chinese patients with paediatric-onset SLE and 13 healthy controls using the Illumina HumanMethylationEPIC BeadChip. Comparison of DNAm in whole blood and within each independent cell lineage identified a consistent pattern of loss of DNAm at 21 CpG sites overlapping 15 genes, which represented a robust, disease-specific DNAm signature for paediatric-onset SLE in our cohort. In addition, cell lineage-specific changes, involving both loss and gain of DNAm, were observed in both novel genes and genes with well-described roles in SLE pathogenesis. This study also highlights the importance of studying DNAm changes in different immune cell lineages rather than only whole blood, since cell type-specific DNAm changes facilitated the elucidation of the cell type-specific molecular pathophysiology of SLE.

Regulation of microRNA in systemic lupus erythematosus: the role of miR-21 and miR-210.

miRNAs are small non-coding RNA molecules that participate through silencing in post-transcriptional regulation of gene expression. Recent studies have highlighted the importance of microRNAs (miRNAs) as regulators of both the innate and the adaptive immune response. There are emerging data regarding the role of miRNAs in patients with Systemic Lupus Erythematosus (SLE). One of the main stimuli for the induction of miR-21 is hypoxia. Moreover, the expression and function of miR-210 is directly related to the activity of “hypoxia inducible factor-1a” (HIF-1a). The aim of the study is to examine the regulation of miR-21 and mir-210 in patients with SLE based on the hypothesis that cellular hypoxia may have an important role in SLE pathogenesis. Plasma, PBMC and urine samples will be collected from patients with SLE and normal controls. miR expression will be studied with real-time PCR. Functional experiments will examine the effect of miR-21 and miR- 210 on HIFa and ERK1/2 και PI3K/AKT signalling pathways. The study will provide novel data regarding the expression and the role of miR-21 and miR-210 in patients with SLE. The results of the study will contribute to a better understanding of miR network regulation in SLE in order to ultimately identify molecules that can be used in clinical practice as diagnostic or prognostic markers, treatment response markers, or even as potential future therapeutic targets.

Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by high levels of pathogenic autoantibodies and tissue damage. Multiple studies showed that dendritic cell (DC) activation plays a critical role in SLE pathogenesis. Human alpha 1 antitrypsin (hAAT) is a serine proteinase inhibitor with potent anti-inflammatory and cytoprotective properties. In this study, we first examined the effects of hAAT on the functions of DCs from lupus-prone mice, and we showed that hAAT treatment efficiently inhibited CpG- (TLR9 agonist) induced activation of bone marrow-derived conventional and plasmacytoid DCs as well as the production of pro-inflammatory cytokines. The hAAT treatment also attenuated DC help for B cell proliferation and immunoglobulin M (IgM) production. We next tested the protective effect of hAAT protein and gene therapy using recombinant adeno-associated virus 8 (rAAV8-CB-hAAT) in a spontaneous lupus mouse model, and we showed that both treatments decreased autoantibody levels. Importantly, rAAV8-CB-hAAT did not induce an immune response to its transgene product (hAAT), but it showed more pronounced therapeutic effects in reducing urine protein levels and extending the lifespan of these mice. These results indicate that AAT has therapeutic potential in the treatment of SLE in humans.

Regulatory T Cells and Their Association with Serum Markers and Symptoms in Systemic Lupus Erythematosus and Rheumatoid Arthritis

ABSTRACTPurpose: Impairment in number and functions of regulatory T cells (Treg) has been found to be associated with many autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study was conducted to identify and compare Treg by flow cytometry using two different staining approaches.Methods: Treg were identified by using CD4+CD25+high and CD4+CD25+CD127dim staining approaches in SLE and RA patients and healthy controls. Association of both identified Treg levels with various serum markers and clinical presentation was also examined.Results: Blood CD4+CD25+CD127dim cells levels were 11.4+3.57 %, 9.76+2.37 % and 6.95+1.16 %; while CD4+CD25+high cells were 1.46+1.09 %, 0.95+0.59 % and 1.87+1.14 % in SLE patients, RA patients and healthy controls respectively. Number of CD4+CD25+CD127dim cells was higher than CD4+CD25+high cells in blood samples of all three study groups. Levels of CD4+CD25+CD127dim cells were significantly higher in SLE and RA patients, compared to healthy controls, but this difference was not observed for CD4+CD25+high Treg. CD4+CD25+high levels showed significant correlation with serum C4, IFN-γ and IL-10 levels in healthy subjects and with C4 levels and fever in SLE patients. CD4+CD25+CD127dim levels showed significant association with alopecia and oral ulcers in SLE patients only, but no correlation with measured serum markers.Conclusion: Results suggest that both staining approaches detect Treg differently and also that Treg play different role in pathogenesis of SLE and RA.

Procyanidin B2 prevents lupus nephritis development in mice by inhibiting NLRP3 inflammasome activation.

Lupus nephritis (LN) is a multifactorial event that contributes to the long-term mortality of systemic lupus erythematosus (SLE). Activation of NLRP3 inflammasome has been known to play a role in SLE pathogenesis. We evaluated the renal protection effects of procyanidin B2 (PCB2) and the involvement of NLRP3 in a mouse model involving MRL/lpr and MRL/MpJ mice. Kidney injury was evaluated by measuring the renal clinical and pathological features, renal immune complex deposition, and serum anti-double-stranded (anti-dsDNA) Abs. ELISA and Western blotting were used to detect NLRP3 inflammasome activation and IL-1β/IL-18 production. NLRP3 gene silencing was introduced into MRL/lpr mice by short hairpin RNA, and the renal damage was compared with the treatment of PCB2. PCB2 remarkably reduced renal damage in MRL/lpr mice, reflected by the reduced proteinuria, and serum levels of blood urea nitrogen and creatinine, as well as pathological features with less renal injury. PCB2 significantly reduced renal immune complex deposition and serum anti-dsDNA levels, notably inhibited the NLRP3 inflammasome activation, and reduced the renal and serum levels of IL-1β and IL-18 in MRL/lpr mice compared with those of NLRP3 gene-silenced MRL-lpr mice. PCB2 significantly suppressed LN in MRL-lpr mice by inhibiting the activation of NLRP3 inflammasome and subsequent IL-1β and IL-18 production. This finding explores a novel mechanism by which procyanidin exerts inflammatory suppression effects and its clinical benefits in LN prevention.

Differential expressions of plasma proteins in systemic lupus erythematosus patients identified by proteomic analysis.

Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease with a wide range of clinical manifestations that affects multiple organs and tissues. Therefore the differential expression of proteins in the serum/plasma have potential clinical applications when treating SLE. We have compared the plasma/serum protein expression patterns of nineteen active SLE patients with those of twelve age-matched and gender-matched healthy controls by proteomic analysis. To investigate the differentially expressed proteins among SLE and controls, a 2-dimensional gel electrophoresis coupled with high-resolution liquid chromatography tandem mass spectrometry was performed. To further understand the molecular and biological functions of the identified proteins, PANTHER and Gene Ontology (GO) analyses were employed. A total of 14 significantly expressed (p<0.05, p<0.01) proteins were identified, and of these nine were up-regulated and five down-regulated in the SLE patients. The functional enrichment analysis assigned the majority of the identified proteins including alpha 2 macroglobulin, complement C4, complement factor H, fibrinogen beta chain, and alpha-1-antitrypsin were part of the complement/coagulation cascade, which is an important pathway that plays a crucial role in SLE pathogenesis. In addition to these proteins the differential expressions of ceruloplasmin, transthyretin, and haptoglobin play a potential role in the renal system abnormalities of SLE. Therefore, the identified differentially expressed proteins are relevant to SLE patient's cohort. Most importantly the up-regulated proteins might be the potential candidates for renal system involvement in SLE disease pathogenesis. In order to confirm the diagnostic/therapeutic potential of the identified proteins, future validation studies are required.

A Novel Human Systemic Lupus Erythematosus Model in Humanised Mice

Mouse models have contributed to the bulk of knowledge on Systemic Lupus Erythematosus (SLE). Nevertheless, substantial differences exist between human and mouse immune system. We aimed to establish and characterise a SLE model mediated by human immune system. Injection of pristane into immunodeficient mice reconstituted with human immune system (humanised mice) recapitulated key SLE features, including: production of human anti-nuclear autoantibodies, lupus nephritis, and pulmonary serositis. There was a reduction in the number of human lymphocytes in peripheral blood, resembling lymphopenia in SLE patients. Concurrently, B cells and T cells were systemically hyperactivated, with a relative expansion of CD27+ and CD27−IgD− memory B cells, increased number of plasmablasts/plasma cells, and accumulation of effector memory T cells. There was also an increased production of human pro-inflammatory cytokines, including: IFN-γ, IL-8, IL-18, MCP-1, and IL-6, suggesting their role in SLE pathogenesis. Increased expression of type I IFN signature genes was also found in human hepatocytes. Altogether, we showed an SLE model that was mediated by human immune system, and which recapitulated key clinical and immunological SLE features. The advancements of humanised mice SLE model would provide an in vivo platform to facilitate translational studies and pre-clinical evaluations of human-specific mechanisms and immunotherapies.

New Insights on Platelets and Platelet-Derived Microparticles in Systemic Lupus Erythematosus.

Current knowledge on the role of platelets and platelet-derived microparticles (PMPs) on the immune system has been fast-growing. Systemic lupus erythematosus (SLE) is a systemic auto-immune disorder characterized by a loss of tolerance toward nuclear auto-antigens. Although recent studies allowed a better understanding of SLE pathogenesis, there is an urgent need for the development of new treatments and the identification of new biomarkers to assess the disease activity. We describe here the state-of-the-art knowledge linking platelets and PMPs to SLE. Platelet system activation is a key event in the pathogenesis of SLE. Circulating immune complexes, anti-phospholipid antibodies, and infectious agents such as virus are the main activators of platelets in SLE. Platelet activation can be monitored through different ways such as P-selectin expression, mean platelet volume, or circulating PMP levels, suggesting their potential use as biomarkers. Upon activation, platelets promote type I interferon production, NETosis, dendritic cell activation, and T and B lymphocyte activation, all essential events contributing to the development of SLE. Of interest, platelets also play a fundamental role in SLE organ disease such as the development of cardiovascular, thrombotic, and renal diseases. Finally, we review current knowledge on drugs targeting platelet activation and their potential impact on SLE pathogenesis. Platelets play a major role in SLE pathogenesis and organ disease and represent a great potential for novel biomarkers and drug development.

Effect of Secretome Mesenchymal Stem Cells On Expression Interleukin 10 And Interleukin 17 in Mice Lupus Model

Background: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disease with extensive clinical features. The role of Interleukin 10 (IL-10) is to promote autoantibody production and autoreactive B cell proliferation. Interleukin 17 (IL-17) associated with pathogenesis of SLE and positively correlated with disease activity. Intraperitoneal pristane can induce lupus in mice. Mesenchymal stem cells secretome work in paracrine effects asantiinflammatory and immunomodulation agent by suppressing autoreactive T and B cell, which play an important role in pathogenesis of SLE. The aim of this study is to evaluate effect of mesenchymal stem cells secretome on the expression of IL-10 and IL-17 in murine lupus models induced by pristane.Methods: A randomized experimental study, post-test only control group design, samples using 21 female Mus Musculus mice strain Balb/C, divided into 3 groups: control group with intraperitoneal injection of 0.5 mL of 0.9% NaCl, treatment group with intraperitoneal injection of 0.5 mL pristane, therapy group with intraperitoneal injection of 0.5 mL pristane and 0.45 mL of secretome. Statistical analysis using ANOVA test. A p-value &lt; 0.05 was considered statistically significant.Results: The results showed significant relationship between control and pristane groups both at the levels of IL-17 (control 6.9±1.95,pristane 9.9±2.27, pristane+secretome 6.1±1.95 p=0.016), and there are significant differences in the expression of IL-10 in the control group vs pristane group (-4,42±1,43 per 100 lymphocyte; p=0,006), pristane group vs pristane+secretome group (4,00±1,43 per 100 lymphocyte; p=0,012).Conclusion: Mesenchymal stem cells secretome decreased the expression of IL-10 and IL-17 levels in murine lupus models induced by pristane.Bangladesh Journal of Medical Science Vol.16(3) 2017 p.418-422

Evaluation of TLR9 expression on PBMCs and CpG ODN-TLR9 ligation on IFN-α production in SLE patients

Context: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoreactive antibodies. Recent findings revealed the importance of innate immune responses, especially Toll-like receptors (TLRs) in the pathogenesis of SLE.Objective: In this study, the level of TLR9 expression on peripheral blood mononuclear cells (PBMCs) was analyzed. The levels of produced IFN-α were also measured in supernatant of PBMCs from SLE patients and healthy controls after stimulation with CpG ODN2216 which is a plasmocytoid dendritic cell (pDC)-specific TLR9 ligand.Materials and methods: TLR9 expression was analyzed by real-time polymerase chain reaction (PCR) and flow cytometry in 35 SLE patients and 38 healthy controls and IFN-α concentration was measured in supernatants using enzyme-linked immunosorbent assay (ELISA).Results: The results showed that the TLR9 expression in the mRNA and the protein level was significantly higher in PBMCs from SLE patients. However, IFN-α concentration in patients and controls significantly increased in response to CpG stimulation but this increase was significantly higher in healthy controls compared with SLE patients. Our results do not show any association between taking hydroxychloroquine and reduction in IFN-α production in SLE patients.Discussion and conclusions: Regarding the findings of the study, there is the possibility that TLR9 has played a role in SLE pathogenesis, and consequently it implies that TLRs can be considered to be the therapeutic targets for systemic autoimmunity. We may conclude that PBMCs in patients are functionally impaired in response to TLR ligation via innate response stimulating pathogen-associated molecular patterns (PAMPs).

Gender differences of B cell signature related to estrogen-induced IFI44L/BAFF in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) possesses a gender-dependent incidence characterized by a male/female ratio 1:9. B-cell, a vital part of the immune system, plays an important role in pathogenesis of SLE. Thus, we hypothesize that gender differences of B cells may exist in SLE and relate to the onset and the progression of SLE. Here, we showed that the genes expression pattern is similar between healthy female and male. However, SLE female and SLE male showed more upregulated genes, in which the trendline of SLE male is higher than that of SLE female. The most differentially expressed genes between SLE male patients and female patients are only on two chromosomes. While the differentially expressed genes between healthy male and female are distributed on several chromosomes. There are more differentially expressed genes in SLE male vs healthy male than these in SLE female vs healthy female. OAS3, RGS13, STAG3, IFI44L, STS-1, FERIL14, ZBTB16, USP18, USP41, RSAD2, FKBP5, IL1R2, DNAPTP6 and ILI27, which top 14 significantly upregulated mRNAs in SLE patients compared with healthy donors, showed different expression pattern in gender-based analyses. Furthermore, we revealed that this difference may be related to estrogen-induced IFI44L/BAFF. Therefore, we conclude that the diagnosis and treatment of these immune-related diseases should consider the baseline gender-related differences.