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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of cell biology, 03 September 2012, Vol.198(5), pp.773-83
    Description: Neutrophil extracellular traps (NETs) are made of processed chromatin bound to granular and selected cytoplasmic proteins. NETs are released by white blood cells called neutrophils, maybe as a last resort, to control microbial infections. This release of chromatin is the result of a unique form of cell death, dubbed "NETosis." Here we review our understanding of how NETs are made, their function in infections and as danger signals, and their emerging importance in autoimmunity and coagulation.
    Keywords: Chromatin -- Immunology ; Neutrophil Activation -- Immunology ; Neutrophils -- Immunology
    ISSN: 00219525
    E-ISSN: 1540-8140
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  • 2
    In: Neurology, 2011, Vol.76(8_Supplement_3 Suppl 3, Modulation of S1P Signaling), pp.S3-S8
    Description: Sphingosine 1-phosphate (S1P) and 5 specific high-affinity S1P receptor (S1PR) subtypes, S1P1–5, have important regulatory functions in normal physiology and disease processes, particularly involving the immune, central nervous, and cardiovascular systems. Within the immune system, downmodulation of S1P1 prevents the egress of B and T cells from lymph nodes (LN) into the lymphatic circulation. This is especially relevant in certain autoimmune diseases, including multiple sclerosis (MS), in which demyelination and brain atrophy occur due to the presence of autoreactive lymphocytes within the CNS. Accordingly, S1P1-directed pharmacologic interventions that aim to retain these autoreactive lymphocytes in the LN and thus prevent their recirculation and subsequent infiltration into the CNS have been investigated as a means of preventing disease progression in patients with MS. Fingolimod (FTY720), a structural analog of sphingosine, is phosphorylated in vivo into fingolimod phosphate by sphingosine kinase-2. Fingolimod phosphate, which binds to S1PRs, has been shown to modulate the activity of S1P1 in patients with MS and to reduce immune cell infiltration into the CNS, consistent with its previously established effects in animal models of the disease. Preclinical studies also suggest that fingolimod has beneficial effects within the CNS that are independent of its immune cell trafficking activity. This review highlights the normal physiologic processes modulated by S1P and S1PRs, and the therapeutic effects of S1PR modulation in the immune, central nervous, and cardiovascular systems. GLOSSARY:
    Keywords: Central Nervous System ; Cardiovascular System ; Multiple Sclerosis ; Lymphocytes B ; Immune System ; Autoimmune Diseases ; Brain ; Animal Models ; Sphingosine 1-Phosphate ; Demyelination ; Fty720 ; Lymph Nodes ; Reviews ; Lymphocytes T ; Atrophy ; Neurology & Neuropathology;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 3
    In: Neurology, 2011, Vol.76(8_Supplement_3 Suppl 3, Modulation of S1P Signaling), pp.S15-S19
    Description: Viral infections may have an important role in the precipitation or relapse of multiple sclerosis (MS) and its treatment. This review describes the normal immune response to viral infection, the possible associations between viral infections and MS therapy, and the impact of sphingosine 1-phosphate (S1P) receptor (S1PR) modulation with fingolimod (FTY720) on the immune responses to viral infection. The physiologic immune response to viral infection involves lymphocyte activation and control of the circulation of subsets of lymphocytes with different functions between the lymph nodes, vascular system, and tissues, under the control of the S1P/S1PR signaling mechanism. In MS, it has been postulated that viral infections may play a role in triggering MS relapses, with virus-specific T cells being responsible for the demyelinating lesions within the CNS. Fingolimod—an S1PR modulator approved for the treatment of relapsing MS in some countries—is thought to act by downmodulating lymphatic S1P subtype 1 receptors. This retains naïve T cells and central memory T cells, but not effector memory T cells, within the lymph nodes and prevents their circulation to the CNS. Evidence from infection models supports that the selective effects of fingolimod on T cell subsets allows key immune responses to be preserved during therapy. However, in patients, long-term observation is important as both the risk of cancer and infection is potentially increased by the use of any immunomodulatory agent. GLOSSARY:
    Keywords: Central Nervous System ; Multiple Sclerosis ; Memory Cells ; Immunological Memory ; Sphingosine 1-Phosphate ; Demyelination ; Infection ; Fty720 ; Immunomodulation ; Cancer ; Lymph Nodes ; Effector Cells ; Cell Activation ; Neuromodulation ; Reviews ; Lymphocytes T ; Immune Response ; Vascular System ; Neurology & Neuropathology ; Autoimmunity;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 4
    Language: English
    In: Science (New York, N.Y.), 05 March 2004, Vol.303(5663), pp.1532-5
    Description: Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.
    Keywords: Immunity, Innate ; Neutrophil Activation ; Neutrophils -- Immunology ; Salmonella Typhimurium -- Physiology ; Shigella Flexneri -- Physiology ; Staphylococcus Aureus -- Physiology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 2010, Vol.107(21), pp.9813-9818
    Description: Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients develop autoantibodies to DNA, histones, and often to neutrophil proteins. These form immune complexes that are pathogenic and may cause lupus nephritis. In SLE patients, infections can initiate flares and are a major cause of mortality. Neutrophils respond to infections and release extracellular traps (NETs), which are antimicrobial and are made of DNA, histones, and neutrophil proteins. The timely removal of NETs may be crucial for tissue homeostasis to avoid presentation of self-antigens. We tested the hypothesis that SLE patients cannot clear NETs, contributing to the pathogenesis of lupus nephritis. Here we show that serum endonuclease DNase1 is essential for disassembly of NETs. Interestingly, a subset of SLE patients' sera degraded NETs poorly. Two mechanisms caused this impaired NET degradation: (i) the presence of DNase1 inhibitors or (ii) anti-NET antibodies prevented DNase1 access to NETs. Impairment of DNase1 function and failure to dismantle NETs correlated with kidney involvement. Hence, identification of SLE patients who cannot dismantle NETs might be a useful indicator of renal involvement. Moreover, NETs might represent a therapeutic target in SLE. ; Includes references ; p. 9813-9818.
    Keywords: Extracellular Matrix -- Health Aspects ; Nephritis -- Health Aspects ; Systemic Lupus Erythematosus -- Health Aspects;
    ISSN: 0027-8424
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  • 6
    In: Molecular Microbiology, March 2012, Vol.83(6), pp.1229-1243
    Description: The importance of pathogen‐induced host cell remodelling has been well established for red blood cell infection by the human malaria parasite . Exported parasite‐encoded proteins, which often possess a signature motif, termed export element (PEXEL) or host‐targeting (HT) signal, are critical for the extensive red blood cell modifications. To what extent remodelling of erythrocyte membranes also occurs in non‐primate hosts and whether it is in fact a hallmark of all mammalian parasites remains elusive. Here we characterize a novel PEXEL/HT‐containing protein, which we term IBIS1. Temporal expression and spatial localization determined by fluorescent tagging revealed the presence of IBIS1 at the parasite/host interface during both liver and blood stages of infection. Targeted deletion of the IBIS1 protein revealed a mild impairment of intra‐erythrocytic growth indicating a role for these structures in the rapid expansion of the parasite population in the blood . In red blood cells, the protein localizes to dynamic, punctate structures external to the parasite. Biochemical and microscopic data revealed that these intra‐erythrocytic ‐induced structures (IBIS) are membranous indicating that , like , creates an intracellular membranous network in infected red blood cells.
    Keywords: Malaria ; Proteins ; Plasmodium Falciparum;
    ISSN: 0950-382X
    E-ISSN: 1365-2958
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  • 7
    Language: English
    In: American Heart Journal, November 2014, Vol.168(5), pp.632-644
    Description: Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator, was the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis; it reduces autoreactive lymphocytes’ egress from lymphoid tissues by down-regulating S1PRs. Sphingosine-1-phosphate signaling is implicated in a range of physiologic functions, and S1PRs are expressed differentially in various tissues, including the cardiovascular system. Modulation of S1PRs on cardiac cells provides an explanation for the transient effects of fingolimod on heart rate and atrioventricular conduction at initiation of fingolimod therapy, and for the mild but more persistent effects on blood pressure observed in some patients on long-term treatment. This review describes the nontherapeutic actions of fingolimod in the context of sphingosine-1-phosphate signaling in the cardiovascular system, as well as providing a summary of the associated clinical implications useful to physicians considering initiation of fingolimod therapy in patients. A transient reduction in heart rate (mean decrease of 8 beats per minute) and, less commonly, a temporary delay in atrioventricular conduction observed in some patients when initiating fingolimod therapy are both due to activation of S1PR subtype 1 on cardiac myocytes. These effects are a reflection of fingolimod first acting as a full S1PR agonist and thereafter functioning as an S1PR antagonist after down-regulation of S1PR subtype 1 at the cell surface. For most individuals, first-dose effects of fingolimod are asymptomatic, but all patients need to be monitored for at least 6 hours after the first dose, in accordance with the label recommendations.
    Keywords: Medicine
    ISSN: 0002-8703
    E-ISSN: 1097-6744
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  • 8
    Language: English
    In: Journal of innate immunity, 2018, Vol.10(5-6), pp.414-421
    Description: Nearly 15 years after the first description of neutrophil extracellular traps (NETs), our knowledge concerning this structure has expanded considerably. Initially, NETs were considered solely an elaborate function of the innate immune system to combat invading microorganisms. Successively it became clear that NETs have farther-reaching capabilities. They are involved in a series of pathophysiological mechanisms ranging from inflammation to thrombosis where they fulfill essential functions when produced at the right site and the right time but can have a serious impact when generation or clearance of NETs is inadequately controlled. This review provides a concise overview on the far-reaching functions of NETs in health and disease.
    Keywords: Autoimmunity ; Bacterial Infection ; Cancer ; Coagulation ; Extracellular Traps ; Inflammation
    ISSN: 1662811X
    E-ISSN: 1662-8128
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  • 9
  • 10
    Language: English
    In: PLoS ONE, 01 January 2011, Vol.6(11), p.e27156
    Description: Large-scale molecular profiling technologies have assisted the identification of disease biomarkers and facilitated the basic understanding of cellular processes. However, samples collected from human subjects in clinical trials possess a level of complexity, arising from multiple cell types, that can obfuscate the analysis of data derived from them. Failure to identify, quantify, and incorporate sources of heterogeneity into an analysis can have widespread and detrimental effects on subsequent statistical studies.We describe an approach that builds upon a linear latent variable model, in which expression levels from mixed cell populations are modeled as the weighted average of expression from different cell types. We solve these equations using quadratic programming, which efficiently identifies the globally optimal solution while preserving non-negativity of the fraction of the cells. We applied our method to various existing platforms to estimate proportions of different pure cell or tissue types and gene expression profilings of distinct phenotypes, with a focus on complex samples collected in clinical trials. We tested our methods on several well controlled benchmark data sets with known mixing fractions of pure cell or tissue types and mRNA expression profiling data from samples collected in a clinical trial. Accurate agreement between predicted and actual mixing fractions was observed. In addition, our method was able to predict mixing fractions for more than ten species of circulating cells and to provide accurate estimates for relatively rare cell types (〈10% total population). Furthermore, accurate changes in leukocyte trafficking associated with Fingolomid (FTY720) treatment were identified that were consistent with previous results generated by both cell counts and flow cytometry. These data suggest that our method can solve one of the open questions regarding the analysis of complex transcriptional data: namely, how to identify the optimal mixing fractions in a given experiment.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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