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    ABSTRACT: In most metazoans, all tissues contain phagocytes "in residence," generally termed "macrophages" in vertebrates. In contrast to myeloid cells produced continuously by the bone marrow (BM), tissue-resident macrophages develop during embryogenesis together with their tissue of residence, and persist in adulthood, independently of hematopoietic stem cells and the transcription factor Myb. They therefore represent an independent lineage from blood monocytes, dendritic cells, and monocytes/macrophages that are recruited to tissues during inflammation. Tissue-resident macrophage functions are yet to be completely defined. They all share the ability to scavenge toxic compounds, lipids, microorganisms, and dead cells and contribute to tissue remodeling, via phagocytosis and the production of growth factors. In contrast, the production of inflammatory mediators seems to be more associated with BM-derived cells. Tissue-resident macrophages and BM-derived myeloid cells thus differ in developmental origin and functions; the term "macrophages" could be reserved for Myb-independent-resident macrophages to avoid confusion. A genetic and molecular dissection of resident macrophage functions will reveal their roles in tissue metabolism and the maintenance of homeostasis independently of the extravasation of inflammatory leukocytes, and in the control of the recruitment of BM-derived cells in overt inflammation.
    Cold Spring Harbor Symposia on Quantitative Biology 10/2013; DOI:10.1101/sqb.2013.78.020032
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    ABSTRACT: Infections disturb metabolic homeostasis in many contexts, but the underlying connections are not completely understood. To address this, we use paired genetic and computational screens in Drosophila to identify transcriptional regulators of immunity and pathology and their associated target genes and physiologies. We show that Mef2 is required in the fat body for anabolic function and the immune response. Using genetic and biochemical approaches, we find that MEF2 is phosphorylated at a conserved site in healthy flies and promotes expression of lipogenic and glycogenic enzymes. Upon infection, this phosphorylation is lost, and the activity of MEF2 changes-MEF2 now associates with the TATA binding protein to bind a distinct TATA box sequence and promote antimicrobial peptide expression. The loss of phosphorylated MEF2 contributes to loss of anabolic enzyme expression in Gram-negative bacterial infection. MEF2 is thus a critical transcriptional switch in the adult fat body between metabolism and immunity.
    Cell 09/2013; DOI:10.1016/j.cell.2013.09.007
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    ABSTRACT: The improved characterisation of risk factors for rheumatoid arthritis (RA) suggests they could be combined to identify individuals at increased disease risks in whom preventive strategies may be evaluated. We aimed to develop an RA prediction model capable of generating clinically relevant predictive data and to determine if it better predicted younger onset RA (YORA). Our novel modelling approach combined odds ratios for 15 four-digit/10 two-digit HLA-DRB1 alleles, 31 single nucleotide polymorphisms (SNPs) and ever-smoking status in males to determine risk using computer simulation and confidence interval based risk categorisation. Only males were evaluated in our models incorporating smoking as ever-smoking is a significant risk factor for RA in men but not women. We developed multiple models to evaluate each risk factor's impact on prediction. Each model's ability to discriminate anti-citrullinated protein antibody (ACPA)-positive RA from controls was evaluated in two cohorts: Wellcome Trust Case Control Consortium (WTCCC: 1,516 cases; 1,647 controls); UK RA Genetics Group Consortium (UKRAGG: 2,623 cases; 1,500 controls). HLA and smoking provided strongest prediction with good discrimination evidenced by an HLA-smoking model area under the curve (AUC) value of 0.813 in both WTCCC and UKRAGG. SNPs provided minimal prediction (AUC 0.660 WTCCC/0.617 UKRAGG). Whilst high individual risks were identified, with some cases having estimated lifetime risks of 86%, only a minority overall had substantially increased odds for RA. High risks from the HLA model were associated with YORA (P<0.0001); ever-smoking associated with older onset disease. This latter finding suggests smoking's impact on RA risk manifests later in life. Our modelling demonstrates that combining risk factors provides clinically informative RA prediction; additionally HLA and smoking status can be used to predict the risk of younger and older onset RA, respectively.
    PLoS Genetics 09/2013; 9(9):e1003808. DOI:10.1371/journal.pgen.1003808
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    ABSTRACT: Allograft rejection is one of several undesirable consequences of the adaptive nature of the mammalian immune response. This review examines adaptive immune responses and allorecognition in animals with very different immune responses - jawless vertebrates, arthropods, and two distinct colonial marine invertebrates - with the goal of understanding how immune adaptation and allograft rejection are linked, and conversely how a system works where allograft rejection is a desired outcome rather than an unforeseen consequence.
    Current opinion in immunology 07/2013; DOI:10.1016/j.coi.2013.07.002
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    ABSTRACT: Prognosis of patients with early inflammatory arthritis (EIA) is highly variable. The aim of this study was to compare, longitudinally and cross-sectionally, the levels of cytokine-expressing cells in peripheral blood (PB) from patients with EIA, to those in established rheumatoid arthritis (RA), and healthy controls (HC). PB mononuclear cells from HC (n=30), patients with EIA (n=20) or RA (n=38) were stimulated with PMA/Ionomycin for 3 hours, and stained for cell markers and cytokines. Serum cytokines and chemokines were measured by Luminex. Patients with EIA were reassessed at 6 and 12 months. The percentage of IL-17+IFNγ- CD4+ T cells (Th17) was increased in RA and EIA vs. HC. Serum IL-1β, IL-2, IL-4 IL-17, and MIP-1α were increased in RA and EIA vs. HC. IL-1Ra, IL-15 and IFN-α were increased in EIA vs. HC. IL-6 and TNFα was increased in RA but not EIA vs. HC. Disease activity scores in EIA patients improved over 12 months' treatment. Th17 percentage at baseline was correlated with both rheumatoid factor (RF) titre and functional deficit at 12 months. Baseline levels of serum GM-CSF, IL-6 and IL-8 were correlated with Larsen score at 12 months. There were no significant changes in cytokine expressing CD4+T cells over time, although the percentage of IL-6+ monocytes increased. IL-17+CD4+ T cells and serum IL-17 levels are increased in EIA. IL-6 expressing monocytes increase during the first year of disease, irrespective of DMARD therapy. We observed incomplete clinical responses, suggesting EIA patients need more intensive early therapy.
    Clinical & Experimental Immunology 07/2013; DOI:10.1111/cei.12167
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    ABSTRACT: Balanced immunoregulatory networks are essential for maintenance of systemic tolerance. Disturbances in the homeostatic equilibrium between inflammatory mediators, immune regulators and immune effector cells are directly implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). In this study we characterise the peripheral blood CD8+CD28- regulatory T cells (Treg) contribution to the immunoregulatory network in health and in RA. In health, CD8+CD28- Treg are suppressive but unlike CD4+Treg, they function predominantly through the action of soluble mediators such as IL-10 and TGF-β. Neutralisation of TGFβ consistently reduced CD8+CD28-Treg suppressor function in vitro. RA, CD8+CD28- Treg are numerically increased but have reduced expression of ICOS and PD-1 compared to healthy or disease controls. They produce more IL-10 but autologous T cells express less IL-10R. This expression was found to be restored following in vitro addition of a TNF inhibitor (TNFi). Deficiencies in both the CD8+CD28- Treg population and reduced sensitivity of the T responder cells impact on their regulatory function in RA. TNFi therapy partially restores CD8+CD28-Treg ability in vivo and in vitro despite the defects in expression of functionally relevant molecules by RA CD8+CD28- Treg compared to healthy controls. This study places CD8+CD28- Treg cells in the scheme of immune regulation alongside CD4+Treg cells, and highlights the importance of understanding impaired responsiveness to regulation that is common to these suppressor subsets and their restored function in response to TNFi therapy.
    Clinical & Experimental Immunology 06/2013; DOI:10.1111/cei.12161
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    ABSTRACT: The fruit-fly Drosophila melanogaster has emerged as a powerful model to study innate immunity against intracellular pathogens. To combat infection, the fly relies on multiple lines of defense, many of which are shared with mammals and arthropod vectors of human diseases. In addition to conserved immune pathways, the ease of performing sophisticated genetic screens has allowed the identification of novel host immune factors and novel pathogen virulence factors. Recently, some groups have exploited this to simultaneously analyze the host and pathogen genetics of intracellular infection. This review aims to unravel the Drosophila immune response against intracellular pathogens, highlighting recent discoveries.
    Developmental and comparative immunology 05/2013; 42(1). DOI:10.1016/j.dci.2013.04.013
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    ABSTRACT: The functions of Nr4a1-dependent Ly6C(low) monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid "danger" signal, which may signify viral infection or local cell death, triggers Gαi-dependent intravascular retention of Ly6C(low) monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7-dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6C(low) monocyte development, crawling, or retention in Nr4a1(-/-), Itgal(-/-), and Tlr7(host-/-BM+/+) and Cx3cr1(-/-) mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7(host+/+BM-/-) mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6C(low) monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris.
    Cell 04/2013; 153(2):362-75. DOI:10.1016/j.cell.2013.03.010
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    ABSTRACT: This unit describes methods for intravital imaging of monocytes in the vasculature of the dermis and the mesentery in vivo using fluorescent reporter mice, fluorescent dyes, and antibodies. Cx3cr1(gfp/gfp (or +)), Rag2(-/-), Il2rg(-/-) mice expressing eGFP at the locus of the Cx3cr1 gene, on the Rag2(-/-) Il2rg(-/-) C57Bl/6 background, are used. Although aimed at specifically tracking Ly6C(low) monocytes, these protocols could readily be adapted to investigate the interaction of other blood leukocytes with the vascular endothelium by use of other fluorescent reporter mice and fluorescently labeled antibodies. Curr. Protoc. Immunol. 101:14.33.1-14.33.16. © 2013 by John Wiley & Sons, Inc.
    Current protocols in immunology / edited by John E. Coligan ... [et al.] 04/2013; Chapter 14:Unit14.33. DOI:10.1002/0471142735.im1433s101
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    ABSTRACT: Microglia, macrophages of the central nervous system, play an important role in brain homeostasis. Their origin has been unclear. Recent fate-mapping experiments have established that microglia mostly originate from Myb-independent, FLT3-independent, but PU.1-dependent precursors that express the CSF1-receptor at E8.5 of embryonic development. These precursors are presumably located in the yolk sac (YS) at this time before invading the embryo between E9.5 and E10.5 and colonizing the fetal liver. Indeed, the E14.5 fetal liver contains a large population of Myb-independent YS-derived myeloid cells. This myeloid lineage is distinct from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development and maintenance. This "yolky" beginning and the independence from conventional HSCs are not unique to microglia. Indeed, several other populations of F4/80-positive macrophages develop also from YS Myb-independent precursors, such as Kupffer cells in the liver, Langerhans cells in the epidermis, and macrophages in the spleen, kidney, pancreas, and lung. Importantly, microglia and the other Myb-independent macrophages persist, at least in part, in adult mice and likely self-renew within their respective tissues of residence, independently of bone marrow HSCs. This suggests the existence of tissue resident macrophage "stem cells" within tissues such as the brain, and opens a new era for the molecular and cellular understanding of myeloid cells responses during acute and chronic inflammation. © 2012 Wiley Periodicals, Inc.
    Glia 01/2013; 61(1). DOI:10.1002/glia.22393
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