Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus
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ABSTRACT:
PROVIDER: PRJNA798906 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17676746_1.fastq.gz | Fastqsanger.gz | |||
| SRR17676746_2.fastq.gz | Fastqsanger.gz | |||
| SRR17676747_1.fastq.gz | Fastqsanger.gz | |||
| SRR17676747_2.fastq.gz | Fastqsanger.gz | |||
| SRR17676748_1.fastq.gz | Fastqsanger.gz |
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Project description:The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.
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Project description:Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis–associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis-associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications — TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen.
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Project description:Interferon lambdas share important functional similarities with type I interferons, but their role in inflammation and autoimmune disease remains controversial and is not well studied. Here, we present the first evidence that interferon lambda is pathogenic and has nonredundant functions in TLR7-associated lupus inflammation. Most notably, we found that interferon lambda promotes systemic immune dysregulation through localized effects in the skin and kidneys. These data identify a novel role for interferon lambda in lupus immunobiology and tissue-specific pathology.
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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: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:Systemic lupus erythematosus carries increased risk of pregnancy complications. To understand the underlying molecular mechanisms, we characterized the blood transcriptome of lupus patients and healthy controls during pregnancy and postpartum and performed multicolor flow-cytometry in a subset. We also followed healthy women undergoing assisted reproductive technology, allowing for analysis around embryo implantation. A striking and sustained down modulation of two lupus-related signatures, interferon and plasma cells, takes place during healthy pregnancy. These changes appear immediately post embryo implantation and are mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early upregulation of neutrophil signatures and expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as ICOS+ CD4+ T cell counts. Thus, healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and failure to do so is associated with adverse outcomes.
2019-03-22 | GSE108497 | GEO