GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    A Longitudinal Biomarker for the Extent of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis
    Wiley ; 2015
    In:  Arthritis & Rheumatology Vol. 67, No. 11 ( 2015-11), p. 3004-3015
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 67, No. 11 ( 2015-11), p. 3004-3015
    Abstract: To define a pharmacodynamic biomarker based on gene expression in skin that would provide a biologic measure of the extent of disease in patients with diffuse cutaneous systemic sclerosis (dcSSc) and could be used to monitor skin disease longitudinally. Methods Skin biopsy specimens obtained from a cohort of patients with dcSSc (including longitudinal specimens) were analyzed by microarray. Expression of genes correlating with the modified Rodnan skin thickness score (MRSS) were examined for change over time using a NanoString platform, and a generalized estimating equation (GEE) was used to define and validate longitudinally measured pharmacodynamic biomarkers composed of multiple genes. Results Microarray analysis of genes parsed to include only those correlating with the MRSS revealed prominent clusters of profibrotic/transforming growth factor β–regulated, interferon‐regulated/proteasome, macrophage, and vascular marker genes. Using genes changing longitudinally with the MRSS, we defined 2 multigene pharmacodynamic biomarkers. The first was defined mathematically by applying a GEE to longitudinal samples. This modeling method selected cross‐sectional THBS1 and longitudinal THBS1 and MS4A4A . The second model was based on a weighted selection of genes, including additional genes that changed statistically significantly over time: CTGF , CD163 , CCL2 , and WIF1 . In an independent validation data set, biomarker levels calculated using both models correlated highly with the MRSS. Conclusion Skin gene expression can be used effectively to monitor changes in SSc skin disease over time. We implemented 2 relatively simple models on a NanoString platform permitting highly reproducible assays that can be applied directly to samples from patients or collected as part of clinical trials.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v67.11
    DOI: 10.1002/art.39287
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2754614-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD ‐1, TIGIT , and TIM ‐3 in Lymphocytes From Patients With Systemic Sclerosis
    Wiley ; 2018
    In:  Arthritis & Rheumatology Vol. 70, No. 4 ( 2018-04), p. 566-577
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 70, No. 4 ( 2018-04), p. 566-577
    Abstract: Immune dysfunction is an important component of the disease process underlying systemic sclerosis ( SS c), but the mechanisms contributing to altered immune cell function in SS c remain poorly defined. This study was undertaken to measure the expression and function of the coinhibitory receptors (co‐ IR s) programmed cell death 1 ( PD ‐1), T cell immunoglobulin and ITIM domain ( TIGIT ), T cell immunoglobulin and mucin domain 3 ( TIM ‐3), and lymphocyte activation gene 3 ( LAG ‐3) in lymphocyte subsets from the peripheral blood of patients with SS c. Methods Co‐ IR expression levels on subsets of immune cells were analyzed using a 16‐color flow cytometry panel. The functional role of co‐ IR s was determined by measuring cytokine production after in vitro stimulation of SS c and healthy control peripheral blood mononuclear cells ( PBMC s) in the presence of co‐ IR –blocking antibodies. Supernatants from cultures of stimulated PBMC s were added to SS c fibroblasts, and their impact on fibroblast gene expression was measured. Mathematical modeling was used to reveal differences between co‐ IR functions in SS c patients and healthy controls. Results Levels of the co‐ IR s PD ‐1 and TIGIT were increased, and each was coexpressed, in distinct T cell subsets from SS c patients compared to healthy controls. Levels of TIM ‐3 were increased in SS c natural killer cells. PD ‐1, TIGIT , and TIM ‐3 antibody blockade revealed patient‐specific roles of each of these co‐ IR s in modulating activation‐induced T cell cytokine production. In contrast to healthy subjects, blockade of TIGIT and TIM ‐3, but not PD ‐1, failed to reverse inhibited cytokine production in SS c patients, indicating that enhanced T cell exhaustion is present in SS c. Finally, cytokines secreted in anti– TIM ‐3–treated PBMC cultures distinctly changed the gene expression profile in SS c fibroblasts. Conclusion The altered expression and regulatory capacity of co‐ IR s in SS c lymphocytes may contribute to disease pathophysiology by modulating the cytokine‐mediated cross‐talk of immune cells and fibroblasts at sites of inflammation and/or fibrosis.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v70.4
    DOI: 10.1002/art.40399
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2754614-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Editorial: Epigenetics in Systemic Sclerosis
    Wiley ; 2016
    In:  Arthritis & Rheumatology Vol. 68, No. 12 ( 2016-12), p. 2841-2844
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 68, No. 12 ( 2016-12), p. 2841-2844
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v68.12
    DOI: 10.1002/art.39830
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2754614-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    An Autotaxin/Lysophosphatidic Acid/Interleukin‐6 Amplification Loop Drives Scleroderma Fibrosis
    Wiley ; 2016
    In:  Arthritis & Rheumatology Vol. 68, No. 12 ( 2016-12), p. 2964-2974
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 68, No. 12 ( 2016-12), p. 2964-2974
    Abstract: We previously implicated the lipid mediator lysophosphatidic acid (LPA) as having a role in dermal fibrosis in systemic sclerosis (SSc). The aim of this study was to identify the role of the LPA‐producing enzyme autotaxin (ATX), and to connect the ATX/LPA and interleukin‐6 (IL‐6) pathways in SSc. Methods We evaluated the effect of a novel ATX inhibitor, PAT‐048, on fibrosis and IL‐6 expression in the mouse model of bleomycin‐induced dermal fibrosis. We used dermal fibroblasts from SSc patients and control subjects to evaluate LPA‐induced expression of IL‐6, and IL‐6–induced expression of ATX. We next evaluated whether LPA‐induced ATX expression is dependent on IL‐6, and whether baseline IL‐6 expression in fibroblasts from SSc patients is dependent on ATX. Finally, we compared ATX and IL‐6 expression in the skin of patients with SSc and healthy control subjects. Results PAT‐048 markedly attenuated bleomycin‐induced dermal fibrosis when treatment was initiated before or after the development of fibrosis. LPA stimulated expression of IL‐6 in human dermal fibroblasts, and IL‐6 stimulated fibroblast expression of ATX, connecting the ATX/LPA and IL‐6 pathways in an amplification loop. IL‐6 knockdown abrogated LPA‐induced ATX expression in fibroblasts, and ATX inhibition attenuated IL‐6 expression in fibroblasts and the skin of bleomycin‐challenged mice. Expression of both ATX and IL‐6 was increased in SSc skin, and LPA‐induced IL‐6 levels and IL‐6–induced ATX levels were increased in fibroblasts from SSc patients compared with controls. Conclusion ATX is required for the development and maintenance of dermal fibrosis in a mouse model of bleomycin‐induced SSc and enables 2 major mediators of SSc fibrogenesis, LPA and IL‐6, to amplify the production of each other. Our results suggest that concurrent inhibition of these 2 pathways may be an effective therapeutic strategy for dermal fibrosis in SSc.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v68.12
    DOI: 10.1002/art.39797
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2754614-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Skin Gene Expression Is Prognostic for the Trajectory of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis
    Wiley ; 2018
    In:  Arthritis & Rheumatology Vol. 70, No. 6 ( 2018-06), p. 912-919
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 70, No. 6 ( 2018-06), p. 912-919
    Abstract: At present, there are no clinical or laboratory measures that accurately forecast the progression of skin fibrosis and organ involvement in patients with systemic sclerosis ( SS c). The goal of this study was to identify skin biomarkers that could be prognostic for the progression of skin fibrosis in patients with early diffuse cutaneous SS c (dc SS c). Methods We analyzed clinical data and gene expression in skin biopsy samples from 38 placebo‐treated patients, part of the Roche Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis ( FASSCINATE ) phase II study of tocilizumab in SS c. RNA samples were analyzed using nC ounter. A trajectory model based on a modified Rodnan skin thickness score was used to describe 3 skin disease trajectories over time. We examined the association of skin gene expression with skin score trajectory groups, by chi‐square test. Logistic regression was used to examine the prognostic power of each gene identified. Results We found that placebo‐treated patients with high expression of messenger RNA for CD 14, SERPINE 1, IL 13 RA 1, CTGF , and OSMR at baseline were more likely to have progressive skin score trajectories. We also found that those genes were prognostic for the risk of skin progression and that IL 13 RA 1, OSMR , and SERPINE 1 performed the best. Conclusion Skin gene expression of biomarkers associated with macrophages ( CD 14, IL 13 RA 1) and transforming growth factor β activation ( SERPINE 1, CTGF , OSMR ) are prognostic for progressive skin disease in patients with dc SS c. These biomarkers may provide guidance in decision‐making about which patients should be considered for aggressive therapies and/or for clinical trials.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v70.6
    DOI: 10.1002/art.40455
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2754614-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model
    Wiley ; 2015
    In:  Arthritis & Rheumatology Vol. 67, No. 12 ( 2015-12), p. 3146-3157
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 67, No. 12 ( 2015-12), p. 3146-3157
    Abstract: Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development. Methods K/BxN serum–transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated. K/BxN arthritis was also induced in mice deficient in TRIF, Toll‐like receptor 2 (TLR2), TLR3, TLR4, and TLR7 to determine the pathways through which IRF5 might promote arthritis. In vitro studies were performed to determine the role of IRF5 in interleukin‐1 (IL‐1) receptor and TLR signaling. Results Arthritis severity was reduced in IRF5‐deficient, TRIF‐deficient, TLR3‐deficient, and TLR7‐deficient mice. The expression of multiple genes regulating neutrophil recruitment or function and bioactive IL‐1β formation was reduced in the joints during active arthritis in IRF5‐deficient mice. In vitro studies showed that TLR7 and the TRIF‐dependent TLR3 pathway induce proinflammatory cytokine production in disease‐relevant cell types in an IRF5‐dependent manner. Conclusion Our findings indicate that IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating proinflammatory cytokine production downstream of TLR7 and TLR3. Since TLR7 and TLR3 are both RNA‐sensing TLRs, this suggests that endogenous RNA ligands present in the inflamed joint promote arthritis development. These findings may be relevant to human RA, since RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are up‐regulated in the joints of RA patients.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v67.12
    DOI: 10.1002/art.39321
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2754614-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Resolution of Skin Fibrosis by Neutralization of the Antifibrinolytic Function of Plasminogen Activator Inhibitor 1
    Wiley ; 2016
    In:  Arthritis & Rheumatology Vol. 68, No. 2 ( 2016-02), p. 473-483
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 68, No. 2 ( 2016-02), p. 473-483
    Abstract: Systemic sclerosis (SSc) is a fibrotic disease characterized by an obliterative vasculopathy with thrombosis and impairment of the coagulation–fibrinolysis balance. Plasminogen activator inhibitor 1 (PAI‐1) is the major inhibitor of profibrinolytic plasminogen activators (PAs). This study was undertaken to evaluate the contribution of PAI‐1 to SSc pathology in the skin. Methods PAI‐1 was evaluated in skin from patients with diffuse SSc (dSSc) and those with limited SSc (lSSc) by immunohistochemistry. The contribution of PAI‐1 to SSc pathology was tested in vivo in murine graft‐versus‐host disease (GVHD) and bleomycin models of progressive skin fibrosis and in vitro in dermal human microvascular endothelial cells (HMVECs) using a monoclonal antibody that selectively prevents the binding of PAI‐1 to PA. Results Skin from patients with dSSc and those with lSSc showed increased PAI‐1 levels in the epidermis and microvessel endothelium. PAI‐1 neutralization in the GVHD model led to a dramatic, dose‐dependent improvement in clinical skin score, concomitant with vasculopathy resolution, including a reduction in fibrinolysis regulators and vascular injury markers, as well as reduced inflammation. Resolution of vasculopathy and inflammation was associated with resolution of skin fibrosis, as assessed by reduction in collagen content and expression of key profibrotic mediators, including transforming growth factor β1 and tissue inhibitor of metalloproteinases 1. Similar to the GVHD model, PAI‐1 neutralization reduced dermal inflammation and fibrosis in the bleomycin model. PAI‐1 neutralization stimulated plasmin‐mediated metalloproteinase 1 activation in dermal HMVECs. Conclusion Our findings indicate that neutralization of the antifibrinolytic function of PAI‐1 resolves skin fibrosis by limiting the extent of initial vascular injury and connective tissue inflammation. These data suggest that PAI‐1 represents an important checkpoint in disease pathology in human SSc.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v68.2
    DOI: 10.1002/art.39443
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2754614-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics
    Wiley ; 2016
    In:  Arthritis & Rheumatology Vol. 68, No. 8 ( 2016-08), p. 2003-2015
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 68, No. 8 ( 2016-08), p. 2003-2015
    Abstract: Understanding the pathogenesis of systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not been delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic molecular subsets. Methods Gene expression measured in skin from mice with sclerodermatous graft‐versus‐host disease (GVHD), bleomycin‐induced fibrosis, Tsk1/+ or Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy–derived gene expression. Transforming growth factor β (TGFβ) activation was assessed using a responsive signature in mice, and tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression was measured in SSc patient and mouse skin. Results Gene expression in skin from mice with sclerodermatous GVHD and bleomycin‐induced fibrosis corresponded to that in SSc patients in the inflammatory molecular subset. In contrast, Tsk2/+ mice showed gene expression corresponding to the fibroproliferative SSc subset. Enrichment of a TGFβ‐responsive signature was observed in both Tsk2/+ mice and mice with bleomycin‐induced skin fibrosis. Expression of TNFRSF12A (the TWEAK receptor/fibroblast growth factor–inducible 14) was elevated in skin from patients with fibroproliferative SSc and the skin of Tsk2/+ mice. Conclusion This study reveals similarities in cutaneous gene expression between distinct mouse models of SSc and specific molecular subsets of the disease. Different pathways underlie the intrinsic subsets including TGFβ, interleukin‐13 (IL‐13), and IL‐4. We identify a novel target, Tnfrsf12a , with elevated expression in skin from patients with fibroproliferative SSc and Tsk2/+ mice. These findings will inform mechanistic and translational preclinical studies in SSc.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v68.8
    DOI: 10.1002/art.39658
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2754614-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Sustained β‐catenin activity in dermal fibroblasts promotes fibrosis by up‐regulating expression of extracellular matrix protein‐coding genes
    Wiley ; 2015
    In:  The Journal of Pathology Vol. 235, No. 5 ( 2015-04), p. 686-697
    Details
    In: The Journal of Pathology, Wiley, Vol. 235, No. 5 ( 2015-04), p. 686-697
    Abstract: Fibrosis is an end‐stage response to tissue injury that is associated with loss of organ function as a result of excess extracellular matrix ( ECM ) production by fibroblasts. In skin, pathological fibrosis is evident during keloid scar formation, systemic sclerosis ( SSc ) and morphea. Dermal fibroblasts in these fibrotic diseases exhibit increased Wnt/ β ‐catenin signalling, a pathway that is sufficient to cause fibrosis in mice. However, in the context of this complex pathology, the precise pro‐fibrotic consequences of Wnt/ β ‐catenin signalling are not known. We found that expression of stabilized β ‐catenin in mouse dermal fibroblasts resulted in spontaneous, progressive skin fibrosis with thickened collagen fibres and altered collagen fibril morphology. The fibrotic phenotype was predominated by resident dermal fibroblasts. Genome‐wide profiling of the fibrotic mouse dermis revealed elevated expression of matrix‐encoding genes, and the promoter regions of these genes were enriched for Tcf/Lef family transcription factor binding sites. Additionally, we identified 32 β ‐catenin‐responsive genes in our mouse model that are also over‐expressed in human fibrotic tissues and poised for regulation by Tcf/Lef family transcription factors. Therefore, we have uncovered a matrix‐regulatory role for stabilized β ‐catenin in fibroblasts in vivo and have defined a set of β ‐catenin‐responsive genes with relevance to fibrotic disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2015.235.issue-5
    DOI: 10.1002/path.4481
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1475280-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Cp GB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin
    Wiley ; 2015
    In:  Experimental Dermatology Vol. 24, No. 2 ( 2015-02), p. 133-139
    Details
    In: Experimental Dermatology, Wiley, Vol. 24, No. 2 ( 2015-02), p. 133-139
    Abstract: Toll‐like receptor 9 ( TLR 9) drives innate immune responses after recognition of foreign or endogenous DNA containing unmethylated CpG motifs. DNA ‐mediated TLR 9 activation is highly implicated in the pathogenesis of several autoimmune skin diseases, yet its contribution to the inflammation seen in these diseases remains unclear. In this study, TLR 9 ligand, Cp GB DNA , was administered to mice via a subcutaneous osmotic pump with treatment lasting 1 or 4 weeks. Gene expression and immunofluorescence analyses were used to determine chemokine expression and cell recruitment in the skin surrounding the pump outlet. Cp GB DNA skin treatment dramatically induced a marked influx of CD 11b + F4/80 + macrophages, increasing over 4 weeks of treatment, and induction of IFN γ and TNF α expression. Chemokines, CCL 2, CCL 4, CCL 5, CXCL 9 and CXCL 10, were highly induced in Cp GB DNA ‐treated skin, although abrogation of these signalling pathways individually did not alter macrophage accumulation. Flow cytometry analysis showed that TLR 9 activation in the skin increased circulating CD 11b + CD 115 + Ly6C hi inflammatory monocytes following 1 week of Cp GB DNA treatment. Additionally, skin‐resident CD 11b + cells were found to initially take up subcutaneous Cp GB DNA and propagate the subsequent immune response. Using diphtheria toxin‐induced monocyte depletion mouse model, gene expression analysis demonstrated that CD 11b+ cells are responsible for the Cp GB DNA ‐induced cytokine and chemokine response. Overall, these data demonstrate that chronic TLR 9 activation induces a specific inflammatory response, ultimately leading to a striking and selective accumulation of macrophages in the skin.
    Type of Medium: Online Resource
    ISSN: 0906-6705 , 1600-0625
    URL: Issue
    URL: Article
    DOI: 10.1111/exd.2015.24.issue-2
    DOI: 10.1111/exd.12603
    RVK:
    XA 42446
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2026228-0
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...