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  1. Artikel ; Online: Chemokine Receptor Redundancy and Specificity Are Context Dependent.

    Dyer, Douglas P / Medina-Ruiz, Laura / Bartolini, Robin / Schuette, Fabian / Hughes, Catherine E / Pallas, Kenneth / Vidler, Francesca / Macleod, Megan K L / Kelly, Christopher J / Lee, Kit Ming / Hansell, Christopher A H / Graham, Gerard J

    Immunity

    2019  Band 50, Heft 2, Seite(n) 378–389.e5

    Abstract: Currently, we lack an understanding of the individual and combinatorial roles for chemokine receptors in the inflammatory process. We report studies on mice with a compound deletion of Ccr1, Ccr2, Ccr3, and Ccr5, which together control monocytic and ... ...

    Abstract Currently, we lack an understanding of the individual and combinatorial roles for chemokine receptors in the inflammatory process. We report studies on mice with a compound deletion of Ccr1, Ccr2, Ccr3, and Ccr5, which together control monocytic and eosinophilic recruitment to resting and inflamed sites. Analysis of resting tissues from these mice, and mice deficient in each individual receptor, provides clear evidence for redundant use of these receptors in establishing tissue-resident monocytic cell populations. In contrast, analysis of cellular recruitment to inflamed sites provides evidence of specificity of receptor use for distinct leukocyte subtypes and no indication of comprehensive redundancy. We find no evidence of involvement of any of these receptors in the recruitment of neutrophils or lymphocytes to resting or acutely inflamed tissues. Our data shed important light on combinatorial inflammatory chemokine receptor function and highlight Ccr2 as the primary driver of myelomonocytic cell recruitment in acutely inflamed contexts.
    Mesh-Begriff(e) Animals ; Chemokines/immunology ; Chemokines/metabolism ; Eosinophils/immunology ; Eosinophils/metabolism ; Gene Expression Profiling/methods ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/metabolism ; Lymphocytes/immunology ; Lymphocytes/metabolism ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Monocytes/immunology ; Monocytes/metabolism ; Neutrophils/immunology ; Neutrophils/metabolism ; Receptors, CCR/genetics ; Receptors, CCR/immunology ; Receptors, CCR/metabolism ; Receptors, CCR1/immunology ; Receptors, CCR1/metabolism ; Receptors, CCR2/immunology ; Receptors, CCR2/metabolism ; Receptors, CCR3/immunology ; Receptors, CCR3/metabolism ; Receptors, CCR5/immunology ; Receptors, CCR5/metabolism
    Chemische Substanzen CCR5 protein, mouse ; Ccr1 protein, mouse ; Ccr3 protein, mouse ; Chemokines ; Receptors, CCR ; Receptors, CCR1 ; Receptors, CCR2 ; Receptors, CCR3 ; Receptors, CCR5
    Sprache Englisch
    Erscheinungsdatum 2019-02-19
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2019.01.009
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: The Atypical Chemokine Receptor Ackr2 Constrains NK Cell Migratory Activity and Promotes Metastasis.

    Hansell, Christopher A H / Fraser, Alasdair R / Hayes, Alan J / Pingen, Marieke / Burt, Claire L / Lee, Kit Ming / Medina-Ruiz, Laura / Brownlie, Demi / Macleod, Megan K L / Burgoyne, Paul / Wilson, Gillian J / Nibbs, Robert J B / Graham, Gerard J

    Journal of immunology (Baltimore, Md. : 1950)

    2018  Band 201, Heft 8, Seite(n) 2510–2519

    Abstract: Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and ... ...

    Abstract Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and spontaneous models. Further analysis reveals that this relates to increased expression of the chemokine receptor CCR2, specifically by KLRG1
    Mesh-Begriff(e) Animals ; Carcinoma, Lewis Lung ; Cell Movement ; Chemokine CCL2/metabolism ; Cytotoxicity, Immunologic ; Killer Cells, Natural/immunology ; Lectins, C-Type ; Melanoma, Experimental ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasm Metastasis ; Neoplasms, Experimental/immunology ; Receptors, CCR2/metabolism ; Receptors, Chemokine/genetics ; Receptors, Chemokine/metabolism ; Receptors, Immunologic/metabolism
    Chemische Substanzen Ackr2 protein, mouse ; Ccr2 protein, mouse ; Chemokine CCL2 ; Klrg1 protein, mouse ; Lectins, C-Type ; Receptors, CCR2 ; Receptors, Chemokine ; Receptors, Immunologic
    Sprache Englisch
    Erscheinungsdatum 2018-08-29
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1800131
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Influenza nucleoprotein delivered with aluminium salts protects mice from an influenza A virus that expresses an altered nucleoprotein sequence.

    Macleod, Megan K L / David, Alexandria / Jin, Niyun / Noges, Laura / Wang, Jieru / Kappler, John W / Marrack, Philippa

    PloS one

    2013  Band 8, Heft 4, Seite(n) e61775

    Abstract: Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the ... ...

    Abstract Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the current recirculating strains. A universal influenza vaccine that primes specific memory cells that recognise conserved parts of the virus could prove to be effective against both annual influenza variants and newly emergent potentially pandemic strains. Such a vaccine will have to contain a safe and effective adjuvant that can be used in individuals of all ages. We examine protection from viral challenge in mice vaccinated with the nucleoprotein from the PR8 strain of influenza A, a protein that is highly conserved across viral subtypes. Vaccination with nucleoprotein delivered with a universally used and safe adjuvant, composed of insoluble aluminium salts, provides protection against viruses that either express the same or an altered version of nucleoprotein. This protection correlated with the presence of nucleoprotein specific CD8 T cells in the lungs of infected animals at early time points after infection. In contrast, immunization with NP delivered with alum and the detoxified LPS adjuvant, monophosphoryl lipid A, provided some protection to the homologous viral strain but no protection against infection by influenza expressing a variant nucleoprotein. Together, these data point towards a vaccine solution for all influenza A subtypes.
    Mesh-Begriff(e) Animals ; B-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; Influenza A virus/immunology ; Influenza A virus/metabolism ; Influenza A virus/pathogenicity ; Influenza Vaccines/immunology ; Influenza Vaccines/therapeutic use ; Mice ; Mice, Inbred C57BL ; Nucleoproteins/genetics ; Nucleoproteins/metabolism ; T-Lymphocytes/immunology
    Chemische Substanzen Influenza Vaccines ; Nucleoproteins
    Sprache Englisch
    Erscheinungsdatum 2013-04-16
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0061775
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Antigen-specific suppression of humoral immunity by anergic Ars/A1 B cells.

    Aviszus, Katja / Macleod, Megan K L / Kirchenbaum, Greg A / Detanico, Thiago O / Heiser, Ryan A / St Clair, James B / Guo, Wenzhong / Wysocki, Lawrence J

    Journal of immunology (Baltimore, Md. : 1950)

    2012  Band 189, Heft 9, Seite(n) 4275–4283

    Abstract: Autoreactive anergic B lymphocytes are considered to be dangerous because of their potential for activation and recruitment into autoimmune responses. However, they persist for days and constitute ∼5% of the B cell pool. We assessed their functional ... ...

    Abstract Autoreactive anergic B lymphocytes are considered to be dangerous because of their potential for activation and recruitment into autoimmune responses. However, they persist for days and constitute ∼5% of the B cell pool. We assessed their functional potential in the Ars/A1 transgene model, where anergic B cells express a dual-reactive Ag receptor that binds, in addition to a self-Ag, the hapten p-azophenylarsonate (Ars). When Ars/A1 B cells were transferred into adoptive recipients that were immunized with foreign proteins covalently conjugated with Ars, endogenous IgG immune responses to both were selectively and severely diminished, and the development of T helper cells was impaired. Approximately 95% inhibition of the anti-Ars response was attained with ∼4000 transferred Ars/A1 B cells through redundant mechanisms, one of which depended on their expression of MHC class II but not upon secretion of IL-10 or IgM. This Ag-specific suppressive activity implicates the autoreactive anergic B cell as an enforcer of immunological tolerance to self-Ags.
    Mesh-Begriff(e) Adoptive Transfer ; Animals ; Antibody Formation ; Autoantigens/biosynthesis ; Autoantigens/metabolism ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; B-Lymphocyte Subsets/transplantation ; Cells, Cultured ; Clonal Anergy/immunology ; Epitopes, B-Lymphocyte/immunology ; Epitopes, B-Lymphocyte/metabolism ; Immunoglobulin G/biosynthesis ; Immunosuppression/methods ; Mice ; Mice, 129 Strain ; Mice, Inbred A ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Self Tolerance/genetics ; Self Tolerance/immunology ; Spleen/immunology ; Spleen/metabolism ; Spleen/transplantation ; p-Azobenzenearsonate/biosynthesis ; p-Azobenzenearsonate/metabolism
    Chemische Substanzen Autoantigens ; Epitopes, B-Lymphocyte ; Immunoglobulin G ; p-Azobenzenearsonate (7334-23-8)
    Sprache Englisch
    Erscheinungsdatum 2012-09-24
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1201818
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel: Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation.

    Adams, Claire L / Macleod, Megan K L / James Milner-White, E / Aitken, Robert / Garside, Paul / Stott, David I

    Immunology

    2003  Band 108, Heft 3, Seite(n) 274–287

    Abstract: Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the ... ...

    Abstract Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4+ T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system in vivo. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody-antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation.
    Mesh-Begriff(e) Animals ; Antibody Affinity ; Antigen-Antibody Reactions/immunology ; B-Lymphocytes/immunology ; Base Sequence ; Clone Cells/immunology ; Genes, Immunoglobulin/immunology ; Germinal Center/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Sequence Data ; Muramidase/immunology ; Ovalbumin/immunology ; Protein Conformation ; Proteins/immunology ; Somatic Hypermutation, Immunoglobulin/immunology
    Chemische Substanzen Proteins ; Ovalbumin (9006-59-1) ; hen egg lysozyme (EC 3.2.1.-) ; Muramidase (EC 3.2.1.17)
    Sprache Englisch
    Erscheinungsdatum 2003-09-05
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80124-0
    ISSN 1365-2567 ; 0019-2805 ; 0953-4954
    ISSN (online) 1365-2567
    ISSN 0019-2805 ; 0953-4954
    DOI 10.1046/j.1365-2567.2003.01583.x
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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