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  • Radbruch, Andreas  (8)
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  • 1
    In: European Journal of Immunology, June 2014, Vol.44(6), pp.1615-1621
    Description: B‐cell‐derived interleukin‐10 (IL‐10) is known to act in a paracrine fashion to suppress inflammation. Here, we show that IL‐10 also acts in an autocrine manner to regulate the differentiation of activated human B cells. We report that IL‐10 expression is not restricted to a dedicated B‐cell subset, but is induced transiently in peripheral human naïve, memory, and CD5 B cells alike upon activation. Global transcriptome comparison of activated human B cells, secreting IL‐10 or not, identified 138 differentially regulated genes, most of which were associated with differentiation into antibody‐secreting cells and reflecting autocrine IL‐10 signaling. We monitored the differentiation of IL‐10‐secreting B cells and determined the effect of IL‐10‐blocking antibodies against its autocrine and paracrine signaling. IL‐10 signaling promoted the differentiation of activated IL‐10‐secreting B cells into IgM‐ or IgG‐secreting cells, but was dispensable for IgA secretion. Our data imply that B‐cell‐derived IL‐10 not only suppresses immune reactions via paracrine mechanisms, but can also contribute to the differentiation of IL‐10‐secreting B cells into IgM‐ and IgG‐secreting plasmablasts through both autocrine and paracrine signaling.
    Keywords: Antibody‐Secreting Cell ; Human B Cells ; Il‐10 ; Transcriptome
    ISSN: 0014-2980
    E-ISSN: 1521-4141
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  • 2
    In: European Journal of Immunology, June 2014, Vol.44(6), pp.1866-1869
    Keywords: 4 Cells ; Cellular Activation ; Gene Expression ; Microarray ; Transcription
    ISSN: 0014-2980
    E-ISSN: 1521-4141
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  • 3
    Language: English
    In: Journal of Molecular Medicine, 2010, Vol.88(10), pp.1065-1079
    Description: Several genome-wide transcriptome studies have shown that chronic inflammatory responses generally taking place in the inflamed tissue are also reflected at the level of peripheral blood leukocytes. Blood monocytes are highly sensitized cell type continuously activated under inflammatory conditions. For a better understanding of the transcriptional imprinting influenced by a multitude of pro- and anti-inflammatory mediators, we established a whole blood in vitro system to explore cell- and stimulus-specific gene expression signatures in peripheral monocytes. In an explorative study, whole blood from healthy donors was stimulated with tumour necrosis factor-alpha (TNF-α) or lipopolysaccharide (LPS) for 1.5 h. Subsequently, monocytes were isolated with a purity of 〉99% by high-speed fluorescence activated cell sorting. Transcriptional changes were explored by whole genome Affymetrix arrays using highly validated filtering algorithm to identify differentially expressed genes. In vitro stimulation of whole blood samples with TNF-α and LPS resulted in 4,529 and 5,036 differentially expressed genes, respectively. Although both stimuli induced similar inflammatory profiles in monocytes, TNF-α- or LPS-specific gene signatures were characterized. Functional classification identified significant numbers of differentially expressed cytokines, cytokine receptors and apoptosis-associated genes. To our knowledge, this is the first study presenting cell- and stimulus-specific gene expression signatures that can be used to decipher complex disease specific profiles of acute and chronic inflammation. Once a library of signatures from the most important inflammatory mediators is defined, it can be helpful to identify those signatures, which are predominantly driving the disease pathogenesis and which are of potential interest for a therapeutical intervention.
    Keywords: Monocytes ; Inflammation ; Transcriptomics ; TNF-α ; LPS
    ISSN: 0946-2716
    E-ISSN: 1432-1440
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  • 4
    Language: English
    In: Arthritis Research & Therapy, 01 August 2018, Vol.20(1), pp.1-10
    Description: Abstract Background Therapeutic targeting of tumour necrosis factor (TNF)-α is highly effective in ankylosing spondylitis (AS) patients. However, since one-third of anti-TNF-treated AS patients do not show an adequate clinical response there is an urgent need for new biomarkers that would aid...
    Keywords: Ankylosing Spondylitis ; Etanercept ; Cd8+ Nk Cells ; Tnf-Alpha Blocker ; Predictive Biomarker ; Medicine
    ISSN: 14786354
    E-ISSN: 1478-6362
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  • 5
    Language: English
    In: Journal of Molecular Medicine, 2012, Vol.90(11), pp.1295-1309
    Description: Many cytokines are involved in the pathogenesis of autoimmune diseases and are recognized as relevant therapeutic targets to attenuate inflammation, such as tumor necrosis factor (TNF)-α in rheumatoid arthritis (RA) and interferon (IFN)-α/γ in systemic lupus erythematosus (SLE). To relate the transcriptional imprinting of cytokines in a cell type- and disease-specific manner, we generated gene expression profiles from peripheral monocytes of SLE and RA patients and compared them to in vitro - generated signatures induced by TNF-α, IFN-α2a, and IFN-γ. Monocytes from SLE and RA patients revealed disease-specific gene expression profiles. In vitro-generated signatures induced by IFN-α2a and IFN-γ showed similar profiles that only partially overlapped with those induced by TNF-α. Comparisons between disease-specific and in vitro-generated signatures identified cytokine-regulated genes in SLE and RA with qualitative and quantitative differences. The IFN responses in SLE and RA were found to be regulated in a STAT1-dependent and STAT1-independent manner, respectively. Similarly, genes recognized as TNF-α regulated were clearly distinguishable between RA and SLE patients. While the activity of SLE monocytes was mainly driven by IFN, the activity from RA monocytes showed a dominance of TNF-α that was characterized by STAT1 down-regulation. The responses to specific cytokines were revealed to be disease-dependent and reflected the interplay of cytokines within various inflammatory milieus. This study has demonstrated that monocytes from RA and SLE patients exhibit disease-specific gene expression profiles, which can be molecularly dissected when compared with in vitro-generated cytokine signatures. The results suggest that an assessment of cytokine-response status in monocytes may be helpful for improvement of diagnosis and selection of the best cytokine target for therapeutic intervention.
    Keywords: Monocytes ; RA ; SLE ; Transcriptome ; IFN-α/γ ; TNF-α
    ISSN: 0946-2716
    E-ISSN: 1432-1440
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  • 6
    In: Journal of Cellular Physiology, June 2017, Vol.232(6), pp.1326-1336
    Description: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent, acute and self‐limiting attacks of fever. In the present study we presented for the first time results supporting a role of deregulated autophagy in the pathogenesis of FMF.
    Keywords: Genetic Research – Analysis ; DNA Microarrays – Analysis ; Algorithms – Analysis ; Periodic Disease – Genetic Aspects ; Periodic Disease – Analysis;
    ISSN: 0021-9541
    E-ISSN: 1097-4652
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  • 7
    Language: English
    In: Arthritis & Rheumatism, April 2008, Vol.58(4), pp.1136-1145
    Description: OBJECTIVEType I interferon (IFN) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) and is therefore considered a potential therapeutic target. This study was undertaken to establish a feasible biomarker for IFN effects with respect to disease activity and effectiveness of IFN-suppressive therapy in SLE patients. METHODSTranscriptomes of purified monocytes from 9 SLE patients and 7 healthy controls were analyzed by Affymetrix GeneChip technology. Levels of sialic acid-binding Ig-like lectin 1 (Siglec-1) (sialoadhesin, CD169) in inflammatory and resident monocytes were determined at the protein level in 38 healthy controls and 52 SLE patients, using multicolor flow cytometry. RESULTSTranscriptomes of peripheral monocytes from SLE patients revealed a dominant type I IFN signature. Siglec-1 was identified as one of the most prominent type I IFN-regulated candidate genes. At the protein level, the frequency of Siglec-1-expressing monocyte subsets was correlated with disease activity (as measured by the SLE Disease Activity Index) and was inversely correlated with levels of complement factors. Most interestingly, levels of anti-double-stranded DNA (anti-dsDNA) antibodies were highly correlated with the percentage of resident monocytes, but not inflammatory monocytes, expressing Siglec-1. High-dose glucocorticoid treatment resulted in a dramatic reduction of Siglec-1 expression in cells from patients with active SLE. CONCLUSIONOur findings indicate that Siglec-1 expression in resident blood monocytes is a potential biomarker for monitoring disease activity, displaying type I IFN responses, and estimating levels of anti-dsDNA antibodies. Moreover, our results suggest that resident and inflammatory monocytes contribute differently to the process of autoantibody formation in SLE.
    Keywords: Adult–Blood ; Aged–Blood ; Biomarkers–Metabolism ; Case-Control Studies–Immunology ; Female–Metabolism ; Gene Expression Profiling–Metabolism ; Humans–Metabolism ; Lupus Erythematosus, Systemic–Metabolism ; Male–Metabolism ; Membrane Glycoproteins–Metabolism ; Middle Aged–Metabolism ; Monocytes–Metabolism ; Receptors, Immunologic–Metabolism ; Severity of Illness Index–Metabolism ; Sialic Acid Binding Ig-Like Lectin 1–Metabolism ; Abridged ; Biomarkers ; Membrane Glycoproteins ; Receptors, Immunologic ; Siglec1 Protein, Human ; Sialic Acid Binding Ig-Like Lectin 1;
    ISSN: 0004-3591
    E-ISSN: 1529-0131
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  • 8
    Language: English
    In: Cytometry Part A, April 2008, Vol.73(4), pp.333-340
    Description: Gene expression studies of peripheral blood cells in inflammatory diseases revealed a large array of new antigens as potential biomarkers useful for diagnosis, prognosis, and therapy stratification. Generally, their validation on the protein level remains mainly restricted to a more hypothesis‐driven manner. State‐of‐the‐art multicolor flow cytometry make it attractive to validate candidate genes at the protein and single cell level combined with a detailed immunophenotyping of blood cell subsets. We developed multicolor staining panels including up to 50 different monoclonal antibodies that allowed the assessment of several hundreds of phenotypical parameters in a few milliliters of peripheral blood. Up to 10 different surface antigens were measured simultaneously by the combination of seven different fluorescence colors. In a pilot study blood samples of ankylosing spondylitis (AS) patients were compared with normal donors (ND). A special focus was set on the establishment of suitable bioinformatic strategy for storing and analyzing hundreds of phenotypical parameters obtained from a single blood sample. We could establish a set of multicolor stainings that allowed monitoring of all major leukocyte populations and their corresponding subtypes in peripheral blood. In addition, antigens involved in complement and antibody binding, cell migration, and activation were acquired. The feasibility of our cytometric profiling approach was demonstrated by a successful classification of AS samples with a reduced subset of 80 statistically significant parameters, which are partially involved in antigen presentation and cell migration. Furthermore, these parameters allowed an error‐free prediction of independent AS and ND samples originally not included for parameter selection. This study demonstrates a new level of multiparametric analysis in the post‐transcriptomic era. The integration of an appropriate bioinformatic solution as presented here by the combination of a custom‐made Access database along with cluster‐ and prediction‐analysis tools predestine our approach to promote the human cytome project. © 2008 International Society for Analytical Cytology
    Keywords: Cytomics ; Cluster Analysis ; Prediction Analysis ; Multicolor Flow Cytometry ; Ankylosing Spondylitis
    ISSN: 1552-4922
    E-ISSN: 1552-4930
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