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  1. Article ; Online: Spontaneous activation of RNA-sensing pathways in autoimmune disease.

    Crampton, Steve P / Bolland, Silvia

    Current opinion in immunology

    2013  Volume 25, Issue 6, Page(s) 712–719

    Abstract: Multiple intracellular RNA sensing innate immune pathways have been linked to autoimmune disease. RNA-related ligands taken up by the endocytic pathway activate TLRs, and affect primarily immune cells. This type of activation is enhanced by nucleic acid- ... ...

    Abstract Multiple intracellular RNA sensing innate immune pathways have been linked to autoimmune disease. RNA-related ligands taken up by the endocytic pathway activate TLRs, and affect primarily immune cells. This type of activation is enhanced by nucleic acid-specific antibodies and induces an inflammatory program. In contrast, spontaneous activation of cytoplasmic RNA sensing pathways targets mostly non-hematopoietic tissues and their effect on autoimmune disease is secondary to the release of interferon in the circulation. The fact that pathologies result from spontaneous activation of innate pathways implies that endogenous RNA ligands that might be sensed as pathogenic are commonly found in both immune and non-immune cells.
    MeSH term(s) Animals ; Autoimmune Diseases/immunology ; Humans ; Immunity, Innate ; Ligands ; Nucleic Acids/immunology ; RNA/immunology ; Signal Transduction
    Chemical Substances Ligands ; Nucleic Acids ; RNA (63231-63-0)
    Language English
    Publishing date 2013-12-26
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 1035767-1
    ISSN 1879-0372 ; 0952-7915
    ISSN (online) 1879-0372
    ISSN 0952-7915
    DOI 10.1016/j.coi.2013.09.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Spontaneous activation of RNA-sensing pathways in autoimmune disease

    Crampton, Steve P / Bolland, Silvia

    Current Opinion in Immunology. 2013 Dec., v. 25, no. 6

    2013  

    Abstract: Multiple intracellular RNA sensing innate immune pathways have been linked to autoimmune disease. RNA-related ligands taken up by the endocytic pathway activate TLRs, and affect primarily immune cells. This type of activation is enhanced by nucleic acid- ... ...

    Abstract Multiple intracellular RNA sensing innate immune pathways have been linked to autoimmune disease. RNA-related ligands taken up by the endocytic pathway activate TLRs, and affect primarily immune cells. This type of activation is enhanced by nucleic acid-specific antibodies and induces an inflammatory program. In contrast, spontaneous activation of cytoplasmic RNA sensing pathways targets mostly non-hematopoietic tissues and their effect on autoimmune disease is secondary to the release of interferon in the circulation. The fact that pathologies result from spontaneous activation of innate pathways implies that endogenous RNA ligands that might be sensed as pathogenic are commonly found in both immune and non-immune cells.
    Keywords RNA ; antibodies ; autoimmune diseases ; interferons ; tissues
    Language English
    Dates of publication 2013-12
    Size p. 712-719.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 1035767-1
    ISSN 1879-0372 ; 0952-7915
    ISSN (online) 1879-0372
    ISSN 0952-7915
    DOI 10.1016/j.coi.2013.09.011
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  3. Article ; Online: Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus.

    Crampton, Steve P / Morawski, Peter A / Bolland, Silvia

    Disease models & mechanisms

    2014  Volume 7, Issue 9, Page(s) 1033–1046

    Abstract: Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects ... ...

    Abstract Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.
    MeSH term(s) Animals ; Disease Models, Animal ; Genetic Linkage ; Genetic Predisposition to Disease ; Humans ; Lupus Erythematosus, Systemic/genetics ; Mice ; Mice, Inbred C57BL
    Language English
    Publishing date 2014-08-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 2451104-3
    ISSN 1754-8411 ; 1754-8403
    ISSN (online) 1754-8411
    ISSN 1754-8403
    DOI 10.1242/dmm.016451
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Innate pathways to B-cell activation and tolerance.

    Crampton, Steve P / Voynova, Elisaveta / Bolland, Silvia

    Annals of the New York Academy of Sciences

    2010  Volume 1183, Page(s) 58–68

    Abstract: B cells represent an important link between the adaptive and innate immune systems as they express both antigen-specific B-cell receptors (BCRs) as well as various Toll-like receptors (TLRs). Several checkpoints in B-cell development ensure that self- ... ...

    Abstract B cells represent an important link between the adaptive and innate immune systems as they express both antigen-specific B-cell receptors (BCRs) as well as various Toll-like receptors (TLRs). Several checkpoints in B-cell development ensure that self-specific cells are eliminated from the mature B-cell repertoire to avoid harmful autoreactive responses. These checkpoints are controlled by BCR-mediated events but are also influenced by TLR-dependent signals from the innate immune system. Additionally, B-cell-intrinsic and extrinsic TLR signaling are critical for inflammatory events required for the clearance of microbial infections. Factors secreted by TLR-activated macrophages or dendritic cells directly influence the fate of protective and autoreactive B cells. Additionally, naive and memory B cells respond differentially to TLR ligands, as do different B-cell subsets. We review here recent literature describing intrinsic and extrinsic effects of TLR stimulation on the fate of B cells, with particular attention to autoimmune diseases.
    MeSH term(s) Animals ; Autoantibodies/metabolism ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Humans ; Immune Tolerance/immunology ; Immune Tolerance/physiology ; Immunity, Innate/immunology ; Lymphocyte Activation/physiology ; Mice ; Models, Animal ; Models, Biological ; Signal Transduction/immunology
    Chemical Substances Autoantibodies
    Language English
    Publishing date 2010-02-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 211003-9
    ISSN 1749-6632 ; 0077-8923
    ISSN (online) 1749-6632
    ISSN 0077-8923
    DOI 10.1111/j.1749-6632.2009.05123.x
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    Se 110: Show issues Location:
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  5. Article ; Online: Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity.

    Crampton, Steve P / Deane, Jonathan A / Feigenbaum, Lionel / Bolland, Silvia

    Journal of immunology (Baltimore, Md. : 1950)

    2011  Volume 188, Issue 3, Page(s) 1451–1459

    Abstract: Type I IFNs (IFN-I) are normally produced during antiviral responses, yet high levels of chronic IFN-I expression correlate with autoimmune disease. A variety of viral sensors generate IFN-I in their response, but other than TLRs, it is not fully known ... ...

    Abstract Type I IFNs (IFN-I) are normally produced during antiviral responses, yet high levels of chronic IFN-I expression correlate with autoimmune disease. A variety of viral sensors generate IFN-I in their response, but other than TLRs, it is not fully known which pathways are directly involved in the development of spontaneous immune pathologies. To further explore the link between IFN-I induced by viral pathways and autoimmunity, we generated a new transgenic mouse line containing multiple copies of Ifih1, a gene encoding the cytoplasmic dsRNA sensor MDA5 with proven linkage to diabetes and lupus. We show that MDA5 overexpression led to a chronic IFN-I state characterized by resistance to a lethal viral infection through rapid clearance of virus in the absence of a CD8(+) or Ab response. Spontaneous MDA5 activation was not sufficient to initiate autoimmune or inflammatory pathology by itself, even though every immune cell population had signs of IFN activation. When combined with the lupus-susceptible background of the FcγR2B deficiency, MDA5 overexpression did accelerate the production of switched autoantibodies, the incidence of glomerulonephritis, and early lethality. Thus, MDA5 transgenic mice provide evidence that chronic elevated levels of IFN-I are not sufficient to initiate autoimmunity or inflammation although they might exacerbate an ongoing autoimmune pathology.
    MeSH term(s) Animals ; Autoimmunity/genetics ; Cell Line ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/immunology ; Gene Dosage ; Inflammation/etiology ; Interferon Type I/genetics ; Interferon-Induced Helicase, IFIH1 ; Mice ; Mice, Transgenic ; Virus Diseases/immunology ; Viruses/immunology
    Chemical Substances Interferon Type I ; Ifih1 protein, mouse (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13)
    Language English
    Publishing date 2011-12-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    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.1102705
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    In stock of ZB MED Cologne/Königswinter

    Ud II Zs.37: Show issues Location:
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  6. Article: Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration.

    Wu, Beibei / Crampton, Steve P / Hughes, Christopher C W

    Immunity

    2007  Volume 26, Issue 2, Page(s) 227–239

    Abstract: Wnts are a family of secreted glycoproteins with diverse developmental roles, including regulation of cell migration; however, little is known about wnt signaling in mature T cells. We find that endothelial-cell-derived wnts, acting through Frizzled ... ...

    Abstract Wnts are a family of secreted glycoproteins with diverse developmental roles, including regulation of cell migration; however, little is known about wnt signaling in mature T cells. We find that endothelial-cell-derived wnts, acting through Frizzled receptors, induce matrix metalloproteinase (MMP) 2 and MMP9 expression in effector T cells. Blocking wnt signaling, or MMP activity, reduces T cell migration through the basement membrane in vitro and into inflamed skin in vivo. Wnt signaling stabilizes beta-catenin protein in T cells and directly targets the MMP promoters through tandem TCF sites. Thus, our data support a necessary and previously unexpected role for wnt signaling in T cell extravasation.
    MeSH term(s) Animals ; Chemotaxis, Leukocyte/immunology ; Endothelial Cells/metabolism ; Female ; Frizzled Receptors/immunology ; Frizzled Receptors/metabolism ; Humans ; Matrix Metalloproteinases, Membrane-Associated/biosynthesis ; Matrix Metalloproteinases, Membrane-Associated/immunology ; Mice ; Mice, Inbred BALB C ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/immunology ; T-Lymphocytes/immunology ; Transfection ; Wnt Proteins/immunology ; Wnt Proteins/metabolism
    Chemical Substances Frizzled Receptors ; Wnt Proteins ; Matrix Metalloproteinases, Membrane-Associated (EC 3.4.24.-)
    Language English
    Publishing date 2007-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2006.12.007
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4227: Show issues Location:
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  7. Article ; Online: Isolation of human umbilical vein endothelial cells (HUVEC).

    Crampton, Steve P / Davis, Jaeger / Hughes, Christopher C W

    Journal of visualized experiments : JoVE

    2007  , Issue 3, Page(s) 183

    Abstract: Angiogenesis is a complex multi-step process, where in response to angiogenic stimuli, new vessels are created from the existing vasculature. These steps include: degradation of the basement membrane, proliferation and migration (sprouting) of ... ...

    Abstract Angiogenesis is a complex multi-step process, where in response to angiogenic stimuli, new vessels are created from the existing vasculature. These steps include: degradation of the basement membrane, proliferation and migration (sprouting) of endothelial cells (EC) into the extracellular matrix, alignment of EC into cords, lumen formation, anastomosis, and formation of a new basement membrane. Many in vitro assays have been developed to study this process, but most only mimic certain stages of angiogenesis, and morphologically the vessels often do not resemble vessels in vivo. Here we demonstrate an optimized in vitro angiogenesis assay that utilizes human umbilical vein EC and fibroblasts. This model recapitulates all of the key early stages of angiogenesis, and importantly the vessels display patent intercellular lumens surrounded by polarized EC. Vessels can be easily observed by phase-contrast and time-lapse microscopy, and recovered in pure form for downstream applications.
    MeSH term(s) Cell Separation/methods ; Cells, Cultured ; Endothelial Cells/cytology ; Endothelial Cells/physiology ; Humans ; Neovascularization, Physiologic/physiology ; Umbilical Veins/cytology
    Language English
    Publishing date 2007
    Publishing country United States
    Document type Journal Article ; Video-Audio Media
    ISSN 1940-087X
    ISSN (online) 1940-087X
    DOI 10.3791/183
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  8. Article: Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA.

    Mestas, Javier / Crampton, Steve P / Hori, Toshiyuki / Hughes, Christopher C W

    International immunology

    2005  Volume 17, Issue 6, Page(s) 737–747

    Abstract: Human endothelial cells (ECs) constitutively express OX40L and co-stimulate memory CD4(+) T cell proliferation that is dependent upon OX40-OX40L interaction. In vivo, OX40 prolongs T cell survival; however, an unanswered question is whether it can also ... ...

    Abstract Human endothelial cells (ECs) constitutively express OX40L and co-stimulate memory CD4(+) T cell proliferation that is dependent upon OX40-OX40L interaction. In vivo, OX40 prolongs T cell survival; however, an unanswered question is whether it can also prolong synthesis of proliferation-sustaining cytokines such as IL-2. Here we show that EC co-stimulation results in the secretion of T cell IL-2, IL-3 and IFN-gamma and that in the absence of OX40 signals synthesis largely ceases by 12-18 h, but is prolonged up to 60 h in the presence of OX40 signaling. Blocking OX40-mediated cytokine expression at later times suppresses T cell proliferation and this can be overcome by addition of exogenous IL-2. We find that OX40 signaling has discrete effects on T cell activation as it does not affect expression of IL-10, CD25, CD69 or soluble IL-2R. Also, OX40 does not appear to alter IL-2 transcription, but rather acts to stabilize a subset of cytokine mRNAs, increasing their half-lives by 3-6-fold. We further show that OX40L induces activation of p38 mitogen-activated protein kinase (MAPK) and phosphotidyl-inositol-3-kinase (PI3K) in T cells, and using specific inhibitors, we find that increased mRNA half-life is dependent upon both these pathways but is independent of c-jun-N-terminal kinase (JNK). Thus, EC co-stimulation through OX40 leads to prolonged T cell cytokine synthesis and enhanced proliferation.
    MeSH term(s) CD4-Positive T-Lymphocytes/immunology ; Cell Communication/immunology ; Cell Proliferation ; Cells, Cultured ; Cytokines/biosynthesis ; Cytokines/immunology ; Endothelial Cells/immunology ; Gene Expression Regulation/immunology ; Humans ; Membrane Glycoproteins/immunology ; Membrane Glycoproteins/metabolism ; OX40 Ligand ; Phosphorylation ; RNA Stability ; RNA, Messenger/immunology ; RNA, Messenger/metabolism ; Receptors, OX40 ; Receptors, Tumor Necrosis Factor/immunology ; Receptors, Tumor Necrosis Factor/metabolism ; Signal Transduction/immunology ; T-Lymphocyte Subsets/immunology ; Tumor Necrosis Factors/immunology ; Tumor Necrosis Factors/metabolism ; Umbilical Veins/immunology ; p38 Mitogen-Activated Protein Kinases/immunology ; p38 Mitogen-Activated Protein Kinases/metabolism
    Chemical Substances Cytokines ; Membrane Glycoproteins ; OX40 Ligand ; RNA, Messenger ; Receptors, OX40 ; Receptors, Tumor Necrosis Factor ; TNFRSF4 protein, human ; TNFSF4 protein, human ; Tumor Necrosis Factors ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2005-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1013745-2
    ISSN 1460-2377 ; 0953-8178
    ISSN (online) 1460-2377
    ISSN 0953-8178
    DOI 10.1093/intimm/dxh255
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2619: Show issues Location:
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  9. Article: Isolation of human umbilical vein endothelial cells (huvec)

    Davis, Jaeger / Crampton, Steve P / Hughes, Christopher C.W

    Journal of visualized experiments. 2007 Apr. 28, , no. 3

    2007  

    Abstract: Angiogenesis is a complex multi-step process, where in response to angiogenic stimuli, new vessels are created from the existing vasculature. These steps include: degradation of the basement membrane, proliferation and migration (sprouting) of ... ...

    Abstract Angiogenesis is a complex multi-step process, where in response to angiogenic stimuli, new vessels are created from the existing vasculature. These steps include: degradation of the basement membrane, proliferation and migration (sprouting) of endothelial cells (EC) into the extracellular matrix, alignment of EC into cords, lumen formation, anastomosis, and formation of a new basement membrane. Many in vitro assays have been developed to study this process, but most only mimic certain stages of angiogenesis, and morphologically the vessels often do not resemble vessels in vivo. Here we demonstrate an optimized in vitro angiogenesis assay that utilizes human umbilical vein EC and fibroblasts. This model recapitulates all of the key early stages of angiogenesis, and importantly the vessels display patent intercellular lumens surrounded by polarized EC. Vessels can be easily observed by phase-contrast and time-lapse microscopy, and recovered in pure form for downstream applications.
    Keywords angiogenesis ; basement membrane ; extracellular matrix ; fibroblasts ; human umbilical vein endothelial cells ; in vitro studies ; microscopy ; models ; sprouting ; umbilical veins
    Language English
    Dates of publication 2007-0428
    Size p. e183.
    Publishing place Journal of Visualized Experiments
    Document type Article
    ZDB-ID 2259946-0
    ISSN 1940-087X
    ISSN 1940-087X
    DOI 10.3791/183
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  10. Article ; Online: Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2.

    Crampton, Steve P / Wu, Beibei / Park, Edward J / Kim, Jai-Hyun / Solomon, Candice / Waterman, Marian L / Hughes, Christopher C W

    PloS one

    2009  Volume 4, Issue 11, Page(s) e7841

    Abstract: Background: THE COMPLEXITY OF WNT SIGNALING LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals ... ...

    Abstract Background: THE COMPLEXITY OF WNT SIGNALING LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and c-jun have recently been implicated in wnt signaling, however their upstream activators have not been identified.
    Methodology/principal findings: Here we identify the adapter protein Grb2, which is itself an integrator of multiple signaling pathways, as a modifier of beta-catenin-dependent wnt signaling. Grb2 synergizes with wnt3A, constitutively active (CA) LRP6, Dvl2 or CA-beta-catenin to drive a LEF/TCF-responsive reporter, and dominant negative (DN) Grb2 or siRNA to Grb2 block wnt3A-mediated reporter activity. MMP9 is a target of beta-catenin-dependent wnt signaling, and an MMP9 promoter reporter is also responsive to signals downstream of Grb2. Both a jnk inhibitor and DN-c-jun block transcriptional activation downstream of Dvl2 and Grb2, as does DN-rac1. Integrin ligation by collagen also synergizes with wnt signaling as does overexpression of Focal Adhesion Kinase (FAK), and this is blocked by DN-Grb2.
    Conclusions/significance: These data suggest that integrin ligation and FAK activation synergize with wnt signaling through a Grb2-rac-jnk-c-jun pathway, providing a context-dependent mechanism for modulation of wnt signaling.
    MeSH term(s) Animals ; COS Cells ; Chlorocebus aethiops ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; GRB2 Adaptor Protein/metabolism ; Gene Expression Regulation ; Genes, Dominant ; Humans ; Integrins/metabolism ; Matrix Metalloproteinase 9/metabolism ; Proto-Oncogene Proteins c-jun/metabolism ; RNA, Small Interfering/metabolism ; Signal Transduction ; Wnt Proteins/metabolism ; beta Catenin/metabolism ; rac1 GTP-Binding Protein/metabolism
    Chemical Substances GRB2 Adaptor Protein ; GRB2 protein, human ; Integrins ; Proto-Oncogene Proteins c-jun ; RAC1 protein, human ; RNA, Small Interfering ; Wnt Proteins ; beta Catenin ; Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; rac1 GTP-Binding Protein (EC 3.6.5.2)
    Language English
    Publishing date 2009-11-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0007841
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