26
180.94
6.96
80

Publication History View all

  • [Show abstract] [Hide abstract]
    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;
  • [Show abstract] [Hide abstract]
    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;
  • [Show abstract] [Hide abstract]
    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;
  • [Show abstract] [Hide abstract]
    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;
  • [Show abstract] [Hide abstract]
    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;
  • [Show abstract] [Hide abstract]
    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.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: Despite the high frequency of CD4(+) T cells with a regulatory phenotype (CD25(+) CD127(low) FoxP3(+) ) in the joints of patients with rheumatoid arthritis (RA), inflammation persists. One possible explanation is that human Tregs are converted into pro-inflammatory IL-17-producing cells by inflammatory mediators and thereby lose their suppressive function. We investigated whether activated monocytes, which are potent producers of inflammatory cytokines and abundantly present in the rheumatic joint, induce pro-inflammatory cytokine expression in human Tregs and impair their regulatory function. METHODS: The presence and phenotype of CD4(+) CD45RO(+) CD25(+) CD127(low) T cells (memory Tregs) and CD14(+) monocytes in the peripheral blood (PB) and synovial fluid (SF) from patients with RA was investigated by flow cytometry. FACS-sorted memory Tregs from healthy controls were co-cultured with autologous activated monocytes and stimulated with anti-CD3 monoclonal antibody. Intracellular cytokine expression, phenotype and function of cells were determined by flow cytometry, ELISA and proliferation assays. RESULTS: Patients with RA showed higher frequencies of CD4(+) CD45RO(+) CD25(+) CD127(low) Tregs and activated CD14(+) monocytes in SF relative to PB. In vitro-activated monocytes induced an increase in the percentage of IL-17(+) , IFNγ(+) and TNF-α(+) , but also IL-10(+) Tregs. The observed increase in IL-17(+) and IFNγ(+) Tregs was driven by monocyte-derived IL-1β, IL-6 and TNF-α and was mediated by both CD14(+) CD16(-) and CD14(+) CD16(+) monocyte subsets. Despite enhanced cytokine expression, cells maintained their CD25(+) FoxP3(+) CD39(+) Treg phenotype and showed enhanced capacity to suppress proliferation and IL-17 production by effector T cells. CONCLUSION: Tregs exposed to a pro-inflammatory environment show increased cytokine expression as well as enhanced suppressive activity. © 2012 American College of Rheumatology.
    Arthritis & Rheumatology 12/2012;
  • Source
    [Show abstract] [Hide abstract]
    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 07/2012;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Langerhans cell histiocytosis (LCH) features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or 'LCH cells'. Badalian-Very et al. recently reported the presence of a canonical (V600E)B-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients. Mutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using 'next generation' pyrosequencing. In 9 cases the mutation identified was (V600E)B-RAF. In 2 cases novel polymorphisms were identified. A somatic (600DLAT)B-RAF insertion mimicked the structural and functional consequences of the (V600E)B-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The (600DLAT)B-RAF and (V600E)B-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%-2% relative mutation abundance. A novel germ line (T599A)B-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, (T599A)B-RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation. Our data confirmed presence of the (V600E)B-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that (V600E)B-RAF and (600DLAT)B-RAF mutations are somatic mutants enriched in LCH CD1a(+) cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line (T599A)B-RAF allele.
    PLoS ONE 06/2012; 7(4):e33891.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11b(high) monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80(bright) macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia--cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.
    Science 03/2012; 336(6077):86-90.
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.