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  • Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells.

    Schaub, Bianca; Liu, Jing; Höppler, Sabine; Schleich, Isolde; Huehn, Jochen; Olek, Sven; Wieczorek, Georg; Illi, Sabina; von Mutius, Erika; Department of Pulmonary and Allergy, University Children's Hospital Munich, LMU Munich, Munich, Germany. Bianca.Schaub@med.uni-muenchen.de (2009-04)
    BACKGROUND: Cross-sectional studies suggest that maternal exposure to farming decreases the risk of allergic diseases in offspring. The potential underlying immunologic mechanisms are not understood. OBJECTIVE: We sought to assess whether maternal farm exposure activates regulatory T (Treg) cells in cord blood, exerting T(H)2-suppressive effects after microbial stimulation. METHODS: Eighty-four pregnant mothers were recruited before delivery. Detailed questionnaires (60 nonfarming and 22 farming mothers with 2 exclusions) assessed the farming exposures. Cord blood was stimulated with the microbial stimulus peptidoglycan (Ppg), the mitogen PHA, house dust mite extracts (Der p 1), and combinations. Treg cells (CD4+CD25(high) cells; intracellular forkhead/winged-helix family transcriptional repressor p3 [FOXP3] expression, FOXP3 levels, lymphocyte activation gene 3 mRNA expression, functional studies, and DNA methylation of the FOXP3 locus), proliferation, and T(H)2/T(H)1/T(H)17 cytokines were examined. RESULTS: Cord blood Treg cell counts (both unstimulated and PHA stimulated) were increased with maternal farming exposures and associated with higher FOXP3 (Der p 1 + Ppg stimulation) and trendwise higher lymphocyte activation gene 3 (Ppg) expression. Furthermore, Treg cell function was more efficient with farming exposure (effector cell suppression, P = .004). In parallel, T(H)2 cytokine (IL-5) levels were decreased and associated with decreased lymphoproliferation and increased IL-6 levels (Ppg stimulation, Der p 1 + Ppg stimulation, or both; P < .05). Maternal exposure to increasing numbers of farm animals and stables was discovered to exert distinct effects on Treg cells, T(H)1/T(H)2 cells, or both. Additionally, FOXP3 demethylation in offspring of mothers with farm milk exposure was increased (P = .02). CONCLUSIONS: Farm exposures during pregnancy increase the number and function of cord blood Treg cells associated with lower T(H)2 cytokine secretion and lymphocyte proliferation on innate exposure. One fascinating speculation is that maternal farm exposure might reflect a natural model of immunotherapy, potentially including a selection of innate stimuli in addition to allergen, shaping a child's immune system at an early stage.
  • Mouse Phenotype Database Integration Consortium: integration [corrected] of mouse phenome data resources.

    Hancock, John M; Adams, Niels C; Aidinis, Vassilis; Blake, Andrew; Bogue, Molly; Brown, Steve D M; Chesler, Elissa J; Davidson, Duncan; Duran, Christopher; Eppig, Janan T; Gailus-Durner, Valérie; Gates, Hilary; Gkoutos, Georgios V; Greenaway, Simon; Hrabé de Angelis, Martin; Kollias, George; Leblanc, Sophie; Lee, Kirsty; Lengger, Christoph; Maier, Holger; Mallon, Ann-Marie; Masuya, Hiroshi; Melvin, David G; Müller, Werner; Parkinson, Helen; Proctor, Glenn; Reuveni, Eli; Schofield, Paul; Shukla, Aadya; Smith, Cynthia; Toyoda, Tetsuro; Vasseur, Laurent; Wakana, Shigeharu; Walling, Alison; White, Jacqui; Wood, Joe; Zouberakis, Michalis (2007-03)
    Understanding the functions encoded in the mouse genome will be central to an understanding of the genetic basis of human disease. To achieve this it will be essential to be able to characterize the phenotypic consequences of variation and alterations in individual genes. Data on the phenotypes of mouse strains are currently held in a number of different forms (detailed descriptions of mouse lines, first-line phenotyping data on novel mutations, data on the normal features of inbred lines) at many sites worldwide. For the most efficient use of these data sets, we have initiated a process to develop standards for the description of phenotypes (using ontologies) and file formats for the description of phenotyping protocols and phenotype data sets. This process is ongoing and needs to be supported by the wider mouse genetics and phenotyping communities to succeed. We invite interested parties to contact us as we develop this process further.
  • Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.

    Hömig-Hölzel, Cornelia; Hojer, Caroline; Rastelli, Julia; Casola, Stefano; Strobl, Lothar J; Müller, Werner; Quintanilla-Martinez, Leticia; Gewies, Andreas; Ruland, Jürgen; Rajewsky, Klaus; Zimber-Strobl, Ursula; Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environment and Health, D-81377 Munich, Germany. (2008-06-09)
    CD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T cell-dependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-kappaB pathway and the mitogen-activated protein kinases Jnk and extracellular signal-regulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas.
  • LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1.

    Rastelli, Julia; Hömig-Hölzel, Cornelia; Seagal, Jane; Müller, Werner; Hermann, Andrea C; Rajewsky, Klaus; Zimber-Strobl, Ursula; Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, Munich, Germany. (2008-02-01)
    The Epstein-Barr virus (EBV) protein LMP1 is considered to be a functional homologue of the CD40 receptor. However, in contrast to the latter, LMP1 is a constitutively active signaling molecule. To compare B cell-specific LMP1 and CD40 signaling in an unambiguous manner, we generated transgenic mice conditionally expressing a CD40/LMP1 fusion protein, which retained the LMP1 cytoplasmic tail but has lost the constitutive activity of LMP1 and needs to be activated by the CD40 ligand. We show that LMP1 signaling can completely substitute CD40 signaling in B cells, leading to normal B-cell development, activation, and immune responses including class-switch recombination, germinal center formation, and somatic hypermutation. In addition, the LMP1-signaling domain has a unique property in that it can induce class-switch recombination to IgG1 independent of cytokines. Thus, our data indicate that LMP1 has evolved to imitate T-helper cell function allowing activation, proliferation, and differentiation of EBV-infected B cells independent of T cells.
  • MUGEN mouse database; animal models of human immunological diseases.

    Aidinis, V; Chandras, C; Manoloukos, M; Thanassopoulou, A; Kranidioti, K; Armaka, M; Douni, E; Kontoyiannis, D L; Zouberakis, M; Kollias, G; B.S.R.C. Alexander Fleming, 34 Fleming Street, 16672, Vari, Greece. v.aidinis@fleming.gr (2008-01)
    The MUGEN mouse database (MMdb) (www.mugen-noe.org/database/) is a database of murine models of immune processes and immunological diseases. Its aim is to share and publicize information on mouse strain characteristics and availability from participating institutions. MMdb's basic classification of models is based on three major research application categories: Models of Human Disease, Models of Immune Processes and Transgenic Tools. Data on mutant strains includes detailed information on affected gene(s), mutant allele(s) and genetic background (DNA origin, gene targeted, host and backcross strain background). Each gene/transgene index also includes IDs and direct links to Ensembl, ArrayExpress, EURExpress and NCBI's Entrez Gene database. Phenotypic description is standardized and hierarchically structured, based on MGI's mammalian phenotypic ontology terms. Availability (e.g. live mice, cryopreserved embryos, sperm and ES cells) is clearly indicated, along with handling and genotyping details (in the form of documents or hyperlinks) and all relevant contact information (including EMMA and Jax/IMSR hyperlinks where available). MMdb's design offers a user-friendly query interface and provides instant access to the list of mutant strains and genes. Database access is free of charge and there are no registration requirements for data querying.
  • Serum response factor contributes selectively to lymphocyte development.

    Fleige, Anne; Alberti, Siegfried; Gröbe, Lothar; Frischmann, Ursula; Geffers, Robert; Müller, Werner; Nordheim, Alfred; Schippers, Angela; Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany. (2007-08-17)
    Serum response factor (SRF), is a crucial transcription factor for murine embryonic development and for the function of muscle cells and neurons. Gene expression data show that SRF and its transcriptional cofactors are also expressed in lymphocyte precursors and mature lymphocytes. However, the role of SRF in lymphocyte development has not been addressed in vivo so far, attributed in part to early embryonic lethality of conventional Srf-null mice. To determine the in vivo role of SRF in developing lymphocytes, we specifically inactivated the murine Srf gene during T or B cell development using lymphocyte-specific Cre transgenic mouse lines. T cell-specific Srf deletion led to a severe block in thymocyte development at the transition from CD4/CD8 double to single positive stage. The few residual T cells detectable in the periphery retained at least one functional Srf allele, thereby demonstrating the importance of SRF in T cell development. In contrast, deletion of Srf in developing B cells did not interfere with the growth and survival of B cells in general, yet led to a complete loss of marginal zone B cells and a marked reduction of the CD5+ B cell subset. Our study also revealed a contribution of SRF to the expression of the surface molecules IgM, CD19, and the chemokine receptor 4 in B lymphocytes. We conclude that SRF fulfills essential and distinct functions in the differentiation of different types of lymphocytes.
  • Interleukin-10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA.

    Siewe, Lisa; Bollati-Fogolin, Mariela; Wickenhauser, Claudia; Krieg, Thomas; Müller, Werner; Roers, Axel (2006-12-01)
    Interleukin-10 (IL-10) is an important regulator of immune responses secreted by different cell types. We have previously shown that mice with selective inactivation of the IL-10 gene in T cells suffer from deregulated T cell responses similar to those observed in IL-10(-/-) animals. Unlike IL-10(-/-) mice, however, T cell-specific mutants do not mount an enhanced innate immune response to LPS, which must, therefore, be subject to control by IL-10 from non-T cells. Herein we show that subcutaneous injection of LPS, which causes moderate local inflammation in WT and T cell-specific IL-10 mutant mice, results in augmented inflammatory infiltration and extensive tissue necrosis in mice with deficiency for IL-10 in macrophages and neutrophils. Correspondingly, we observed an enhanced sensitivity of the macrophage/neutrophil-specific IL-10 mutants to systemic LPS exposure when compared with WT animals. In contrast, the inflammatory response of these mutants to CpG oligodeoxynucleotides was not different from that of WT mice. While IL-10(-/-) mice developed massive inflammation, necrosis and increased serum cytokine levels after subcutaneous CpG injection, only moderate responses were observed in macrophage/neutrophil-specific IL-10 mutant and WT mice. These results show that different innate immune responses can be subject to control by IL-10 from different cellular sources.
  • Adult murine hematopoiesis can proceed without beta1 and beta7 integrins.

    Bungartz, Gerd; Stiller, Sebastian; Bauer, Martina; Müller, Werner; Schippers, Angela; Wagner, Norbert; Fässler, Reinhard; Brakebusch, Cord (2006-09-15)
    The function of alpha4beta1 and alpha4beta7 integrins in hematopoiesis is controversial. While some experimental evidence suggests a crucial role for these integrins in retention and expansion of progenitor cells and lymphopoiesis, others report a less important role in hematopoiesis. Using mice with a deletion of the beta1 and the beta7 integrin genes restricted to the hematopoietic system we show here that alpha4beta1 and alpha4beta7 integrins are not essential for differentiation of lymphocytes or myelocytes. However, beta1beta7 mutant mice displayed a transient increase of colony-forming unit (CFU-C) progenitors in the bone marrow and, after phenylhydrazine-induced anemia, a decreased number of splenic erythroid colony-forming units in culture (CFUe's). Array gene expression analysis of CD4(+)CD8(+) double-positive (DP) and CD4(-)CD8(-) double-negative (DN) thymocytes and CD19(+) and CD4(+) splenocytes did not provide any evidence for a compensatory mechanism explaining the mild phenotype. These data show that alpha4beta1 and alpha4beta7 are not required for blood cell differentiation, although in their absence alterations in numbers and distribution of progenitor cells were observed.
  • Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment

    Vosshenrich, Christian A. J.; Cumano, Ana; Müller, Werner; Di Santo, James P.; Vieira, Paulo (National Academy of Sciences, 2004-07-27)
  • In Vivo Effects of a Synthetic 2-Kilodalton Macrophage-Activating Lipopeptide of Mycoplasma fermentans after Pulmonary Application

    Lührmann, Anke; Deiters, Ursula; Skokowa, Julia; Hanke, Michaela; Gessner, Johannes E.; Mühlradt, Peter F.; Pabst, Reinhard; Tschernig, Thomas (American Society for Microbiology, 2002-07)
  • The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting

    Fingerle-Rowson, G.; Petrenko, O.; Metz, C. N.; Forsthuber, T. G.; Mitchell, R.; Huss, R.; Moll, U.; Müller, W.; Bucala, R. (National Academy of Sciences, 2003-08-05)