miRNAs represent potential biomarkers in SLE as their expression reflects underlying pathogenic processes and correlates with disease activity. Upregulated miR-21 affects PDCD4 expression and regulates aberrant T cell responses in human SLE.
Periradicular granulomas and cysts represent two different stages in the development of chronic periradicular pathosis as a normal result of the process of immune reactions that cannot be inhibited.
Objective. The cells of the immune system originate from the bone marrow, where many of them also mature. This study was undertaken to examine gene expression in the bone marrow of patients with systemic lupus erythematosus (SLE), in order to better understand the aberrant immune response in this disease.Methods. Bone marrow mononuclear cells (BMMCs) from 20 SLE patients (11 with active disease and 9 with inactive disease) and peripheral blood mononuclear cells (PBMCs) from 27 patients (16 with active disease and 11 with inactive disease) were studied; BMMCs and PBMCs from 7 healthy individuals and 3 osteoarthritis patients were studied as controls. Samples were analyzed on genome-scale DNA microarrays, with 21,329 genes represented.Results. We identified 102 genes involved in various biologic processes that were differentially expressed between patient and control BMMCs; 53 of them are genes that are involved in major networks, including cell death, growth, signaling, and proliferation. Comparative analysis revealed 88 genes that were differentially expressed between bone marrow and blood, the majority of which are involved in cell growth and differentiation, cellular movement and morphology, immune response, and other hematopoietic cell functions. Unsupervised clustering of highly expressed genes revealed 2 major SLE patient clusters (active disease and inactive disease) based on gene expression in bone marrow, but not in peripheral blood. The up-regulated genes in the bone marrow of patients with active disease included genes involved in cell death and granulopoiesis.Conclusion. Microarray analysis of the bone marrow differentiated active from inactive SLE and provided further evidence of the role of apoptosis and granulocytes in the pathogenesis of the disease.
BackgroundGene profiling studies provide important information for key molecules relevant to a disease but are less informative of protein-protein interactions, post-translational modifications and regulation by targeted subcellular localization. Integration of genomic data and construction of functional gene networks may provide additional insights into complex diseases such as systemic lupus erythematosus (SLE).Methodology/Principal FindingsWe analyzed gene expression microarray data of bone marrow mononuclear cells (BMMCs) from 20 SLE patients (11 with active disease) and 10 controls. Gene networks were constructed using the bioinformatic tool Ingenuity Gene Network Analysis. In SLE patients, comparative analysis of BMMCs genes revealed a network with 19 central nodes as major gene regulators including ERK, JNK, and p38 MAP kinases, insulin, Ca2+ and STAT3. Comparison between active versus inactive SLE identified 30 central nodes associated with immune response, protein synthesis, and post-transcriptional modification. A high degree of identity between networks in active SLE and non-Hodgkin's lymphoma (NHL) patients was found, with overlapping central nodes including kinases (MAPK, ERK, JNK, PKC), transcription factors (NF-kappaB, STAT3), and insulin. In validation studies, western blot analysis in splenic B cells from 5-month-old NZB/NZW F1 lupus mice showed activation of STAT3, ITGB2, HSPB1, ERK, JNK, p38, and p32 kinases, and downregulation of FOXO3 and VDR compared to normal C57Bl/6 mice.Conclusions/SignificanceGene network analysis of lupus BMMCs identified central gene regulators implicated in disease pathogenesis which could represent targets of novel therapies in human SLE. The high similarity between active SLE and NHL networks provides a molecular basis for the reported association of the former with lymphoid malignancies.
Background and objectives Polymorphisms to PD-1, a negative regulator of T cell function involved in peripheral tolerance, increase the susceptibility to SLE. The authors sought to defi ne the mechanisms involved by exploring its effects on miR-21 expression known to promote T cell hyperactivity in lupus. Materials and methods PD-1 expression levels were quantifi ed by real time PCR in purifi ed CD4 + T cells. Ambion miRVana Kit and primers were used for the detection of miR-21. T cells were stimulated with plate-bound anti-CD3/anti-CD28 mAb and PDL1.Ig was used for PD-1 crosslinking. Silencing of PD-1 was performed with a specifi c siRNA. Results Under basal conditions, freshly isolated T cells from active lupus patients had 2.3-fold higher miR-21 levels compared to healthy T cells. Combined anti-CD3/anti-CD28-stimulation induced higher miR-21 levels in SLE T cells than in controls (mean 4.0-fold vs 1.6-fold, respectively), suggesting aberrant regulation of miR-21 expression in SLE. PD-1 mRNA and miR21 levels correlated with disease activity. There was an inverse correlation between PD-1 mRNA and miR-21 levels in SLE patients (r 2 =−0.93) suggesting a co-regulation. This was documented by stimulating SLE T cells with anti-CD3/anti-CD28 in the presence or not of PDL1.Ig. PD-1 cross-linking
The expression of retinoid acid receptors α (RARα) and β (RARβ) and estrogen receptor α (ERα) was assessed by immunohistochemistry and Western blotting in normal ovaries, serous cystadenoma (n = 20), serous borderline (n = 14), and serous ovarian cancer (n = 47) and was correlated in cancer cases with stage, grade, progress-free survival (PFS), and survival. RARα was increasingly expressed in benign cystadenomas, borderline, and low-stage and advanced-stage neoplasms (p < 0.001). In stage III, G3 serous carcinoma, increased RARα expression was an independent prognostic factor associated with lower chemoresponse to first-line chemotherapy (taxol and carboplatin) and shorter PFS (p < 0.002).RARβ and ERα expression did not correlate with RARα tumor characteristics or PFS and survival.
Objective MicroRNAs (miRNAs) are potent negative regulators of gene expression involved in innate and adaptive immune responses. The authors examined whether miRNAs are implicated in immune deregulation and lymphocyte hyperactivity in human systemic lupus erythematosus (SLE). Methods TaqMan miRNA arrays were used to study the expression of 365 miRNAs. Expression of miRNAs and their gene targets were assayed by real-time PCR and western blot, respectively. miRNAs silencing by transfection with antagomiRs was performed to assess the effect of miRNAs on anti-CD3/anti-CD28-induced T cell proliferation and cytokine production. Results A total of 27 miRNAs were differentially expressed in peripheral blood mononuclear cells of patients with SLE and healthy individuals. miR-21, miR-25, miR-106b and miR-148b were highly correlated with SLE disease activity (r 2 >0.85), with miR-21 displaying the strongest correlation. SLE T lymphocytes had increased basal and activation-induced miR-21 expression, correlating with decreased expression of its gene target PDCD4 and enhanced proliferation upon anti-CD3/CD28 activation. This effect was reversed by silencing miR-21 which resulted in increased PDCD4 expression. Importantly, restoration of PDCD4 levels by silencing miR-21 suppressed the production of interleukin 10 and the expression of membrane CD40 ligand by activated SLE T lymphocytes. Conclusion miR-21 is a key regulator of the apoptosis-related protein PDCD4 and may be involved in multiple immune processes such as proliferation, costimulation and cytokine production. Deregulated miR-21 expression associated with decreased PDCD4 levels may contribute to aberrant T cell responses in human SLE.on 12 May 2018 by guest. Protected by copyright.
Background: Gene profiling studies provide important information for key molecules relevant to a disease but are less informative of protein-protein interactions, post-translational modifications and regulation by targeted subcellular localization. Integration of genomic data and construction of functional gene networks may provide additional insights into complex diseases such as systemic lupus erythematosus (SLE).Methodology/Principal Findings: We analyzed gene expression microarray data of bone marrow mononuclear cells (BMMCs) from 20 SLE patients (11 with active disease) and 10 controls. Gene networks were constructed using the bioinformatic tool Ingenuity Gene Network Analysis. In SLE patients, comparative analysis of BMMCs genes revealed a network with 19 central nodes as major gene regulators including ERK, JNK, and p38 MAP kinases, insulin, Ca 2+ and STAT3. Comparison between active versus inactive SLE identified 30 central nodes associated with immune response, protein synthesis, and post-transcriptional modification. A high degree of identity between networks in active SLE and non-Hodgkin's lymphoma (NHL) patients was found, with overlapping central nodes including kinases (MAPK, ERK, JNK, PKC), transcription factors (NF-kappaB, STAT3), and insulin. In validation studies, western blot analysis in splenic B cells from 5month-old NZB/NZW F1 lupus mice showed activation of STAT3, ITGB2, HSPB1, ERK, JNK, p38, and p32 kinases, and downregulation of FOXO3 and VDR compared to normal C57Bl/6 mice.Conclusions/Significance: Gene network analysis of lupus BMMCs identified central gene regulators implicated in disease pathogenesis which could represent targets of novel therapies in human SLE. The high similarity between active SLE and NHL networks provides a molecular basis for the reported association of the former with lymphoid malignancies.
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