B cell signature during inactive systemic lupus
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Jean-Nicolas SCHICKEL
PROVIDER: E-GEOD-30153 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:NZB/WF1 female mice spontaneously develop autoimmune lupus nephritis. Expression profiling of kidney tissue from (a) 12 week NZB/W F1 female mice defined as asymptomatic for lupus nephritis, (b) 36 and 42 week NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 and 42 week NZB/W F1 female mice that are diseased/symptomatic for lupus nephritis and treated with Sirolimus was carried out. The goal of the study was to identify genes associated with lupus nephritis and modulated by Sirolimus, an inhibitor of mTOR. In addition, lupus nephritis genes resistant to Sirolimus therapy were also identfied This series of samples comprises of kidney tissue from (a) 12 week old NZB/W F1 female mice defined as asymptomatic for lupus nephritis (N=4), (b) 36 (N=3) and 42 week (N=3) old NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 (N=3)and 42 (N=3) week old NZB/W F1 female mice that are asymptomatic for lupus nephritis on treatment with Sirolimus
2008-11-20 | E-GEOD-12024 | biostudies-arrayexpress
Project description:T cells from many patients with systemic lupus erythematosus are hypoproliferative in response to TCR ligation. This defect is mediated, at least in part, through down regulation of the TCR zeta chain. Investigation of this phenomenon in lupus-prone mice revealed that the hypoproliferative T cell phenotype apparent in BXSB males is mediated in part by the Yaa locus. The BXSB model of lupus is a recombinant inbred strain that was originally derived from a cross between a male SB/LE mouse and a female C57BL/6 mouse. BXSB is unique among lupus-prone mouse strains, in that males carry an autoimmune accelerating factor on the Y chromosome, termed Yaa, which accelerates disease onset in male BXSB mice so that fatal glomerulonephritis occurs around 6 months of age. It was recently reported that the Yaa locus is a translocation of a short stretch of genes including that encoding Toll-like receptor 7 (Tlr-7) from the X to the Y chromosome, leading to a two-fold over expression of a subset of these genes, including Tlr-7, and hypersensitivity of Yaa+ cells to TLR-7 agonists. To more fully understand the functional significance of the Yaa gene and how it plays a part in the modulation of CD4+ T cell responses, we performed microarray analysis using Affymetrix 430 2.0 arrays on spleens from B6 male B6.Yaa male samples. The analysis revealed an enhanced signature of innate immunity, including increased expression not only of Tlr7 and Tlr8, in line with reports that the Yaa locus leads to a duplication of the murine Tlr7 and Tlr8 genes , but also of Tlr2, Tlr5, Cd14, Lbp, C2, C3 and genes for several heat-shock proteins. T cells from B6.Yaa mice also displayed decreased TCR? expression. Interestingly, cell surface levels of the inhibitory molecule B7-H1 were increased on B6.Yaa B cells and monocytes/macrophages. In line with increased TLR-7 expression reported in B6.Yaa mice, the TLR-7 agonist imiquimod increased B7-H1 expression on normal B cells. Restoration of proliferation in co-cultures of B6 T cells and B6.Yaa APC with B7-H1 blocking Ab demonstrated a mechanistic contribution of B7-H1 up-regulation to Yaa-mediated APC-dependent T cell hypoproliferation. In addition, T cell hypoproliferation was induced in normal B6 T cells in vitro by the application of imiquimod. However, this defect was not mediated by B7-H1 or secreted factors but was independent of APC and mediated through direct imiquimod stimulation of T cells themselves. We postulate that excessive TLR-7 stimulation in Yaa+ mice mediates T cell hypoproliferation in part through up-regulation of B7-H1 and possibly also through direct T cell-mediated effects. Keywords: differential gene expression, RNA, spleen, C57Bl/6J, B6.SB-Yaa/J, male, wild type, Yaa Control mice: four C57Bl/6J male spleens Experimental mice: three B6.SB-Yaa/J male spleens and one pool of two B6.Yaa male spleens for the third Yaa sample (GSM236622) All mice were obtained from the Jackson Laboratories between March and December 2005. Spleen cell suspensions were prepared by teasing spleen tissue through 70 micron nylon screens and lysing red cells with ammonium chloride. All mice were 8 weeks of age at the time of the experiment. RNA was separately extracted, labeled, and hybridized from each animal.
2009-12-15 | E-GEOD-9287 | biostudies-arrayexpress
Project description:Our group has proposed that low-density granulocytes (LDGs) play an important role in lupus pathogenesis, as they can damage endothelial cells and synthesize increased levels of proinflammatory cytokines and type I interferons. LDGs have a heightened capacity to synthesize neutrophil extracellular traps (NETs). NETs from LDGs display increased levels of bactericidal and immunostimulatory proteins, such as the cathelicidin LL37 and externalize double-stranded DNA (dsDNA). Lupus netting LDGs have increased capacity to kill endothelial cells and expose IL-17. Through NETosis, lupus neutrophils stimulate plasmacytoid DCs to synthesize IFN-?. Our results further expand the potential pathogenic role of aberrant lupus neutrophils through a NET-mediated effect. We used microarrays to analyze the gene expression of neutrophils in healthy and lupus patients, and of low-density granulocytes in lupus patients. Human neutrophils and LDGs were isolated from PBMCs. RNA from healthy neutrophils, lupus neutrophils and lupus LDGs was extracted and processed for hybridization on Affymetrix microarrays.
2011-06-22 | E-GEOD-26975 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE32583: Expression data from lupus NZB/W, NZM2410, NZW/BXSB mouse kidneys prenephritic and nephritic. GSE32591: Expression data from human with lupus nephritis (LN) Refer to individual Series
2012-08-01 | E-GEOD-32592 | biostudies-arrayexpress
Project description:In lupus autoimmunity, pathogenic IgG autoantibodies that fix complement and bind FcGammaR on inflammatory cells, are produced with help from T helper (Th1 and Th17) cells specific for peptides from nucleosomes of apoptotic cells; and these Th cells also infiltrate vital organs (1-9). Macrophages (e.g. tingible body MΦ), and DCs are normally tolerant to apoptotic cell antigens (10), but they are activated to present such autoantigens after binding to IgG immune complexes (IC) containing apoptotic cell derived DNA/RNA, which then dually stimulate their TLR and FcGammaR (11-16). Hence, to generate the activating IC, IgG-switched autoantibodies have to be made first by T cell help. Moreover, B cells become efficient antigen presenting cells (APC) to Th cells pre-primed by other APC (17), or if the B cells have developed high affinity somatically mutated receptors by T cell help (18). Thus, conventional APCs participate as disease progresses, but it is unknown who initially primes autoimmune Th cells. We fractionated spleen cells of lupus prone SNF1 mice in search of such APC. To produce lupus-prone SNF1 mice, NZB and SWR mice were purchased from The Jackson Laboratory, ME to breed the lupus-prone SNF1 hybrids (19). Female SNF1 mice, like BWF1, have high serum levels of IgG class anti-DNA and other anti-nuclear autoantibodies by 2 mo, and spontaneously begin to develop severe lupus nephritis by 5 mo age (20). We depleted spleen cells of lupus-prone SNF1 mice of cells with mature lineage markers, including conventional APC, and then isolated pure CD117+ (c-Kit+ or K+) cells from the lineage– (Lin– or L–) cells. These Lin–c-Kit+pure cells, which had morphology of hematopoietic progenitor cells, were the main type of APC inducing nuclear autoantigen-specific T helper cell (Th17) response upon feeding them with nucleosomes. These Lin–c-Kit+pure cell isolate is called "LinminuscKitplus pure" in the Sample titles shown below. CD117 (c-Kit) is also a marker for macrophage/dendritic cell precursors (MDP), which also express CX3CR1 (21-23). Therefore, from T and B-cell depleted spleen cells, we sorted out CD117+CX3CR1–, CD117+CX3CR1+, CD117–CX3CR1+, and CD117–CX3CR1– cell subsets, and then tested their abilities to induce Th responses to nucleosomes. The CD117+CX3CR1– cells were Lin– (Lin–c-Kit+CX3CR1– or L–K+Cx–; named as "LinminuscKitplusCX3CR1minus" in the sample titles below) were very similar to L–K+pure cells (LinminuscKitplus pure), which are also CX3CR1–, although isolated in a different way. Therefore, we compared gene expression profiles of nucleosome-pulsed APC that were isolated in those two ways, namely purified Lin–c-Kit+ pure (LinminuscKitplus pure) cells or the Lin–c-Kit+CX3CR1– (LinminuscKitplusCX3CR1minus) cell subset, with other types of APCs, namely the Lin–c-Kit+CX3CR1+ subset (named as "LinminuscKitminusCX3CR1plus" in sample titles below), or CD11c+CD11blowc-Kit– cells (Dendritic cells in the sample titles below). REFERENCES 1. Adams, S., P. Leblanc, and S. K. Datta. 1991. Junctional region sequences of T-cell receptor b chain genes expressed by pathogenic anti-DNA autoantibody-inducing T helper cells from lupus mice: Possible selection by cationic autoantigens. Proc. Natl. Acad. Sci. USA. 88:11271-11275. 2. Mohan, C., S. Adams, V. Stanik, and S. K. Datta. 1993. Nucleosome: A major immunogen for the pathogenic autoantibody-inducing T cells of lupus. J. Exp. Med. 177:1367-1381. 3. Kaliyaperumal, A., C. Mohan, W. Wu, and S. K. Datta. 1996. Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J. Exp. Med. 183:2459-2469. 4. Lu, L., A. Kaliyaperumal, D. T. Boumpas, and S. K. Datta. 1999. Major peptide autoepitopes for nucleosome-specific T cells of human lupus. J. Clin. Invest. 104:345-355. 5. Balomenos, D., R. Rumold, and A. N. Theofilopoulos. 1998. Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J. Clin. Invest. 101:364-371. 6. Doreau, A., A. Belot, J. Bastid, B. Riche, M. C. Trescol-Biemont, B. Ranchin, N. Fabien, P. Cochat, C. Pouteil-Noble, P. Trolliet, I. Durieu, J. Tebib, B. Kassai, S. Ansieau, A. Puisieux, J. F. Eliaou, and N. Bonnefoy-Berard. 2009. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat. Immunol. 10:778-785. 7. Kang, H.-K., M. Liu, and S. K. Datta. 2007. Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells (cover page Figure). J Immunol 178:7849-7858. 8. Hsu, H. C., P. Yang, J. Wang, Q. Wu, R. Myers, J. Chen, J. Yi, T. Guentert, A. Tousson, A. L. Stanus, T. V. Le, R. G. Lorenz, H. Xu, J. K. Kolls, R. H. Carter, D. D. Chaplin, R. W. Williams, and J. D. Mountz. 2008. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 9:166-175. 9. Crispin, J. C., M. Oukka, G. Bayliss, R. A. Cohen, C. A. Van Beek, I. E. Stillman, V. C. Kyttaris, Y. T. Juang, and G. C. Tsokos. 2008. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J. Immunol. 181:8761-8766. 10. Steinman, R. M., D. Hawiger, and M. C. Nussenzweig. 2003. Tolerogenic dendritic cells. Annu Rev Immunol 21:685-711. 11. Leadbetter, E. A., I. R. Rifkin, A. M. Hohlbaum, B. C. Beaudette, M. J. Shlomchik, and A. Marshak-Rothstein. 2002. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:595-598. 12. Blanco, P., A. K. Palucka, M. Gill, V. Pascual, and J. Banchereau. 2001. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 294:1540-1543. 13. Means, T. K., E. Latz, F. Hayashi, M. R. Murali, D. T. Golenbock, and A. D. Luster. 2005. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115:407-417. 14. Bave, U., M. Magnusson, M. L. Eloranta, A. Perers, G. V. Alm, and L. Ronnblom. 2003. Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG. J Immunol 171:3296-3302. 15. Niewold, T. B., J. A. Kelly, M. H. Flesch, L. R. Espinoza, J. B. Harley, and M. K. Crow. 2008. Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum. 58:2481-2487. 16. Teichmann, L. L., M. L. Ols, M. Kashgarian, B. Reizis, D. H. Kaplan, and M. J. Shlomchik. 2010. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33:967-978. 17. Rock, K. L., B. Benacerraf, and A. K. Abbas. 1984. Antigen presentation by hapten-specific B lymphocytes. J. Exp. Med. 160:1102-1113. 18. Chaturvedi, A., D. Dorward, and S. K. Pierce. 2008. The B cell receptor governs the subcellular location of Toll-like receptor 9 leading to hyperresponses to DNA-containing antigens. Immunity 28:799-809. 19. Datta, S. K., and R. S. Schwartz. 1976. Genetics of expression of xenotropic virus and autoimmunity in NZB mice. Nature. 263:412-415. 20. Datta, S. K., N. Manny, C. Andrzejewski, J. Andre-Schwartz, and R. S. Schwartz. 1978. Genetic studies of autoimmunity and retrovirus expression in crosses of New Zealand Black mice. I. xenotropic virus. J. Exp. Med. 147:854-871. 21. Fogg, D. K., C. Sibon, C. Miled, S. Jung, P. Aucouturier, D. R. Littman, A. Cumano, and F. Geissmann. 2006. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311:83-87. 22. Onai, N., A. Obata-Onai, M. A. Schmid, T. Ohteki, D. Jarrossay, and M. G. Manz. 2007. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat. Immunol. 8:1207-1216. 23. Waskow, C., K. Liu, G. Darrasse-Jeze, P. Guermonprez, F. Ginhoux, M. Merad, T. Shengelia, K. Yao, and M. Nussenzweig. 2008. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat. Immunol. 9:676-683. 24. Du, P., W. A. Kibbe, and S. M. Lin. 2008. lumi: a pipeline for processing Illumina microarray. Bioinformatics 24:1547-1548. 25. Lin, S. M., P. Du, W. Huber, and W. A. Kibbe. 2008. Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res 36:e11. 26. Du, P., W. A. Kibbe, and S. M. Lin. 2007. nuID: a universal naming scheme of oligonucleotides for illumina, affymetrix, and other microarrays. Biol Direct 2:16. 27. Wettenhall, J. M., and G. K. Smyth. 2004. limmaGUI: a graphical user interface for linear modeling of microarray data. Bioinformatics 20:3705-3706. Gene profiling microarray and data analysis. Spleen cells from 3 batches of three 5 mo SNF1 female mice each time were used to obtain three independent isolations of each type of APC population. Total RNA was purified from each APC after incubation with nucleosomes (20µg/ml) for 6h. RNA expression analysis of each type of APC isolate in triplicate was performed at our Genomics Core Facility using Illumina Mouse WG-6 v2.0 Expression Beadchips, which provides coverage of around 45,281 genes and expressed sequence tags. Raw signal intensities of each probe were obtained using data analysis software (Beadstudio; Illumina) and imported to the Lumi package of Bioconductor for data analysis. Before transformation and normalization (24-26), A/P call detection was performed based on detection p value. 20,890 out of 45,281 probes with less than 0.01 were considered as valid signals. For each pairs of four comparisons: Lin–c-Kit+CX3CR1– versus Lin–c-Kit+ CX3CR1+; Lin–c-Kit+pure vs. Lin–c-Kit+CX3CR1+; Lin–c-Kit+CX3CR1– vs. DC; and Lin–c-Kit+pure vs. DC; differentially expressed genes were identified using an Analysis of Variance (ANOVA) model with empirical Bayesian variance estimation (27). Thus, 1,619 genes were identified as being differentially expressed (up or down) on the basis of a statistically significant (raw P-value < 0.01 and false discovery rate adjusted P-value < 0.05), and 1.5-fold change (up or down) in expression level in at least one of the comparisons, and out of these 230 genes were significantly UP-regulated by the above criteria in all 4 pair comparisons.
2012-06-20 | E-GEOD-36284 | biostudies-arrayexpress
Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (pâ¤0.05,SI>orâ¤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with pâ¤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN. We analyzed blood from 11 female subjects (5 lupus, 3 lupus nephritis and 3 healthy control) using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Alt Analyze and Genespring software. No techinical replicates were performed. One of the outiler sample (HC2) was excluded from further analysis.
2016-01-06 | E-GEOD-62764 | biostudies-arrayexpress
Project description:To identify any differentially expressed miRNAs in the CD4+ T cells of lupus. MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states, including human lupus. By using high-throughput microRNA profiling analysis, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both lupus patients and lupus-prone MRL/lpr mice,which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. We isolated the splenic CD4+ T cells and B cells from MRL/lpr mice at 5 and 16 weeks of age.Cells were collected and total RNA was extracted for the TaqMan® Low Density Assay v2.0 Normalization was performed with snoRNA202, reference snRNAs for mouse.Comparative real-time PCR was performed in triplicate, including no-template.controls. Relative expression was calculated with the comparative cycle threshold method.
2010-07-06 | E-GEOD-21220 | biostudies-arrayexpress
Project description:Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies. We used microarrays to analyze the renal transcriptome of three different lupus mouse models, at early stage of lupus and during lupus nephritis. RNA from whole kidneys was extracted and processed for hybridization on Affymetrix microarrays.
2012-08-01 | E-GEOD-32583 | biostudies-arrayexpress
Project description:The goal of this study was to determine what genes are up- and down-regulated in response to lupus immune complexes in total peripheral blood mononuclear cells (PBMCs). Our results have shown that novel genes are induced by immune complexes that are likely important for lupus pathogenesis plus that C1q regulates these pathways and induces multiple new pathways not previously identified. Total RNA was isolated from PBMCs from 2 donors after 5 hours with the following condiitons: 1) Unstimulated, 2) Lupus immune complex alone, 3) Lupus immune complex + C1q, 4) C1q alone
2011-12-07 | E-GEOD-32279 | biostudies-arrayexpress
Project description:This is the first high-throughput analysis of DNA methylation in autoimmune diseases. We have used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease. Total DNA isolated by standard procedures from 59 White Blood Cell (WBC) samples corresponding to monozygotic twins discordant for three different autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and dermatomyositis (DM) and two additional controls for each MZ twin pair.
2009-11-16 | E-GEOD-19033 | biostudies-arrayexpress