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  • 1
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    Online Resource
    EGFR Signaling Blunts Allergen-Induced IL-6 Production and Th17 Responses in the Skin and Attenuates Development and Relapse of Atopic Dermatitis
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 192, No. 3 ( 2014-02-01), p. 859-866
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 3 ( 2014-02-01), p. 859-866
    Abstract: Despite the important role for epidermal growth factor (EGF) in epithelial homeostasis and wound healing, it has not been investigated in atopic dermatitis (AD). We used AD animal models to explore the role of EGF in AD. In an acute AD model, skin transepidermal water loss was significantly attenuated in EGF-treated mice. Blockade of EGFR signaling genetically or pharmacologically confirms a protective role for EGFR signaling in AD. In a chronic/relapsing AD model, EGF treatment of mice with established AD resulted in an attenuation of AD exacerbation (skin epithelial thickness, cutaneous inflammation, and total and allergen specific IgE) following cutaneous allergen rechallenge. EGF treatment did not alter expression of skin barrier junction proteins or antimicrobial peptides in the AD model. However, EGF treatment attenuated allergen-induced expression of IL-17A, CXCL1, and CXCL2 and neutrophil accumulation in AD skin following cutaneous allergen exposure. IL-17A production was decreased in the in vitro restimulated skin-draining lymph node cells from the EGF-treated mice. Similarly, IL-17A was increased in waved-2 mice skin following allergen exposure. Whereas IL-6 and IL-1β expression was attenuated in the skin of EGF-treated mice, EGF treatment also suppressed allergen-induced IL-6 production by keratinocytes. Given the central role of IL-6 in priming Th17 differentiation in the skin, this effect of EGF on keratinocytes may contribute to the protective roles for EGFR in AD pathogenesis. In conclusion, our study provides evidence for a previously unrecognized protective role for EGF in AD and a new role for EGF in modulating IL-17 responses in the skin.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1301062
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
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  • 2
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    Online Resource
    Altered natural killer cell responses linked to allergen sensitization in patients with atopic dermatitis
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 147.33-147.33
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 147.33-147.33
    Abstract: Atopic dermatitis (AD) is a common chronic inflammatory disease associated with skin barrier dysfunction. AD often precedes the development of atopic co-morbidities, including food allergy, asthma and allergic rhinitis. The contributions of natural killer (NK) cells to pathogenesis of AD and progression to allergic disease are unclear. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples collected from n=82 children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma (MPAACH) study, a cohort of toddlers with AD. The children underwent skin prick testing to 11 aeroallergens and 6 foods, and wheezing was defined as one or more episodes of wheezing in the past 12 months. We used flow cytometry to evaluate the phenotype of NK cells in patient PBMC from MPAACH subjects. Our analyses revealed that CD56brightNK cells derived from sensitized children expressed significantly less NKG2D (73.8 ± 3.0 % versus 82.3 ± 2.7 %, respectively, p=0.020) and more TIM-3 (440 ± 462 versus 353 ± 391 median fluorescence intensity, respectively, p=0.085) compared to non-sensitized children. Increased expression of TIM-3 on CD56neg NK cells was also associated with wheezing (47.5 ± 0.51 % versus 19.2 ± 0.40 %, p=0.020). Collectively, these observations suggest that changes within the NK-cell repertoire may promote progressive development of AD and atopic co-morbidities in early life.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.147.33
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
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  • 3
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    Online Resource
    IL-13Rα2 Membrane and Soluble Isoforms Differ in Humans and Mice
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 183, No. 12 ( 2009-12-15), p. 7870-7876
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 183, No. 12 ( 2009-12-15), p. 7870-7876
    Abstract: Although mice have nanogram per milliliter serum levels of soluble (s) IL-13Rα2, humans lack sIL-13Rα2 in serum. Our data provide a mechanism for this biological divergence. In mice, discrete transcripts encoding soluble and membrane forms of IL-13Rα2 are generated by alternative splicing. We used small interfering RNA to specifically deplete the transcript encoding membrane (mem) IL-13Rα2 (full-length) or sIL-13Rα2 (ΔEx10) in murine cells. Depletion of the full-length transcript decreased memIL-13Rα2 but had no effect on the level of sIL-13Rα2 in cell supernatants at baseline or following cytokine stimulation. Depletion of the ΔEx10 transcript decreased sIL-13Rα2 in supernatants at baseline and following stimulation. In contrast to mice, we were unable to find a transcript encoding sIL-13Rα2 in humans and siRNA-mediated depletion of full-length IL-13Rα2 decreased both sIL-13Rα2 and memIL-13Rα2 in human cells. Inhibition of matrix metalloproteinases (MMP)/MMP-8 abolished production of sIL-13Rα2 from human cells. Thus, sIL-13Rα2 is derived exclusively from the memIL-13Rα2 transcript in humans through MMPs/MMP-8 cleavage of memIL-13Rα2, supporting a limited role for sIL-13Rα2 in humans and highlighting the potential importance of memIL-13Rα2 in human immunity. These observations require consideration when results of murine IL-13 studies are applied to humans.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.0901028
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
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  • 4
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    Online Resource
    Collaborative Interactions between Type 2 Innate Lymphoid Cells and Antigen-Specific CD4+ Th2 Cells Exacerbate Murine Allergic Airway Diseases with Prominent Eosinophilia
    The American Association of Immunologists ; 2015
    In:  The Journal of Immunology Vol. 194, No. 8 ( 2015-04-15), p. 3583-3593
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 194, No. 8 ( 2015-04-15), p. 3583-3593
    Abstract: Type-2 innate lymphoid cells (ILC2s) and the acquired CD4+ Th2 and Th17 cells contribute to the pathogenesis of experimental asthma; however, their roles in Ag-driven exacerbation of chronic murine allergic airway diseases remain elusive. In this study, we report that repeated intranasal rechallenges with only OVA Ag were sufficient to trigger airway hyperresponsiveness, prominent eosinophilic inflammation, and significantly increased serum OVA-specific IgG1 and IgE in rested mice that previously developed murine allergic airway diseases. The recall response to repeated OVA inoculation preferentially triggered a further increase of lung OVA-specific CD4+ Th2 cells, whereas CD4+ Th17 and ILC2 cell numbers remained constant. Furthermore, the acquired CD4+ Th17 cells in Stat6−/−/IL-17–GFP mice, or innate ILC2s in CD4+ T cell–ablated mice, failed to mount an allergic recall response to OVA Ag. After repeated OVA rechallenge or CD4+ T cell ablation, the increase or loss of CD4+ Th2 cells resulted in an enhanced or reduced IL-13 production by lung ILC2s in response to IL-25 and IL-33 stimulation, respectively. In return, ILC2s enhanced Ag-mediated proliferation of cocultured CD4+ Th2 cells and their cytokine production, and promoted eosinophilic airway inflammation and goblet cell hyperplasia driven by adoptively transferred Ag-specific CD4+ Th2 cells. Thus, these results suggest that an allergic recall response to recurring Ag exposures preferentially triggers an increase of Ag-specific CD4+ Th2 cells, which facilitates the collaborative interactions between acquired CD4+ Th2 cells and innate ILC2s to drive the exacerbation of a murine allergic airway diseases with an eosinophilic phenotype.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1400951
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2015
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  • 5
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    Online Resource
    Methylation of STAT6 Modulates STAT6 Phosphorylation, Nuclear Translocation, and DNA-Binding Activity
    The American Association of Immunologists ; 2004
    In:  The Journal of Immunology Vol. 172, No. 11 ( 2004-06-01), p. 6744-6750
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 172, No. 11 ( 2004-06-01), p. 6744-6750
    Abstract: Signal transducer and activator of transcription 6 is a transcription factor important for the development of Th2 cells and regulation of gene expression by IL-4 and IL-13. It has been reported that STAT1 activity is regulated by methylation of a conserved arginine residue in the N-terminal domain. Methylation of STAT6 has not yet been explored. We observed methylation of STAT6 in cells transfected with wild-type STAT6, but not in cells transfected with Arg27Ala mutant, confirming that STAT6 is methylated on Arg27. Transfectants expressing mutant Arg27Ala STAT6 displayed markedly diminished IL-4-dependent STAT6 phosphorylation and nuclear translocation, and no STAT6 DNA-binding activity compared with wild-type STAT6 transfectants. To confirm this, the experiments were repeated using inhibitors of methylation. In the presence of methylation inhibitors, STAT6 methylation was diminished, as was phosphorylation of STAT6 and STAT6 DNA-binding activity. Thus, methylation is a critical regulator of STAT6 activity, necessary for optimal STAT6 phosphorylation, nuclear translocation, and DNA-binding activity. Furthermore, methylation of STAT6 has distinct effects from those reported with STAT1.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.172.11.6744
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2004
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  • 6
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    Online Resource
    Importance of Cytokines in Murine Allergic Airway Disease and Human Asthma
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 184, No. 4 ( 2010-02-15), p. 1663-1674
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 184, No. 4 ( 2010-02-15), p. 1663-1674
    Abstract: Asthma is a common, disabling inflammatory respiratory disease that has increased in frequency and severity in developed nations. We review studies of murine allergic airway disease (MAAD) and human asthma that evaluate the importance of Th2 cytokines, Th2 response-promoting cytokines, IL-17, and proinflammatory and anti-inflammatory cytokines in MAAD and human asthma. We discuss murine studies that directly stimulate airways with specific cytokines or delete, inactivate, neutralize, or block specific cytokines or their receptors, as well as controversial issues including the roles of IL-5, IL-17, and IL-13Rα2 in MAAD and IL-4Rα expression by specific cell types. Studies of human asthmatic cytokine gene and protein expression, linkage of cytokine polymorphisms to asthma, cytokine responses to allergen stimulation, and clinical responses to cytokine antagonists are discussed as well. Results of these analyses establish the importance of specific cytokines in MAAD and human asthma and have therapeutic implications.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.0902185
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
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  • 7
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    Online Resource
    TSLP rather than IL-33 signaling drives intestinal mucosal mast accumulation and allergen-induced diarrhea in mice following epicutaneous sensitization to food allergen.
    The American Association of Immunologists ; 2021
    In:  The Journal of Immunology Vol. 206, No. 1_Supplement ( 2021-05-01), p. 94.01-94.01
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 206, No. 1_Supplement ( 2021-05-01), p. 94.01-94.01
    Abstract: A major route of sensitization to food allergen is through an impaired skin barrier. IL33 and TSLP have both been implicated in epicutaneous sensitization and development of food allergy. Method: We assessed the respective contributions of TSLP and IL33 to the development of food allergy in TSLP and IL33 receptor deficient mice following epicutaneous food allergen sensitization, where mice were exposed to thrice weekly skin patches of either saline, OVA or a combination of OVA and Aspergillus fumigatus extract (ASP). Results: ASP+OVA-patched but not OVA-patched mice developed an atopic dermatitis (AD)-like skin phenotype, while sensitization to OVA occurred in both OVA and OVA+ASP patched mice. OVA-specific IgE levels were significantly lower in OVA(±ASP)-patched TSLPR−/− mice compared to wild type mice and ST2−/− mice. Repeated intragastric challenges with 50mg of OVA, induced intestinal accumulation of mast cells but not ILC2s in OVA(±ASP)-patched WT and ST2−/− mice, and to a much lesser degree in TSLPR−/− mice. While OVA-induced mast cell degranulation assessed by measuring MCPT1 blood levels and the development of food allergy (diarrhea occurrences) was observed in almost all WT mice and two thirds of OVA+ASP patched ST2−/− mice, all TSLPR−/− mice were protected from developing food allergy and had significantly lower MCPT1 levels. Conclusion: Epicutaneous sensitization to food allergen and subsequent development of food allergy does not require atopic dermatitis skin lesions and is dependent on TSLP, suggesting that prophylactic targeting of TSLP may be useful in mitigating the development of food allergy early in life.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.206.Supp.94.01
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2021
    detail.hit.zdb_id: 1475085-5
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  • 8
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    Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses
    The American Association of Immunologists ; 2007
    In:  The Journal of Immunology Vol. 179, No. 10 ( 2007-11-15), p. 6429-6438
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 179, No. 10 ( 2007-11-15), p. 6429-6438
    Abstract: IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4Rα and sIL-13Rα2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4Rα complexes rapidly dissociate, releasing active IL-4, whereas sIL-13Rα2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13Rα2, IL-4, or sIL-4Rα. Approximately 25% of sIL-13Rα2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13Rα2 in serum increase considerably during a Th2 response. sIL-13Rα2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4Rα-dependent while the effect of IL-13 is partially IL-4Rα-independent. Inhalation of an IL-13/sIL-13Rα2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4Rα predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13Rα2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.179.10.6429
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2007
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  • 9
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    Online Resource
    Exacerbation of Allergen-Induced Eczema in TLR4- and TRIF-Deficient Mice
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 191, No. 7 ( 2013-10-01), p. 3519-3525
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 191, No. 7 ( 2013-10-01), p. 3519-3525
    Abstract: Despite its presence on resident skin cells, the role of TLR4 in skin diseases remains poorly understood. This is highly significant because the skin biome is rich with potential TLR4 agonists. We aimed to establish the contribution of TLR4 to atopic dermatitis and determine the mechanism by which TLR4 acts in an experimental model of atopic dermatitis. MyD88, TLR4, or Toll–IL-1R domain-containing adapter-inducing IFN-β (TRIF)–deficient and wild-type mice were epicutaneously exposed to Aspergillus fumigatus allergen over 3 wk. Impaired skin barrier function was assessed by measuring transepidermal water loss (TEWL). Skin levels of innate and adaptive genes were quantified. In an experimental model of atopic dermatitis, TEWL, allergic sensitization, and epidermal thickness were increased following cutaneous allergen exposure, and these were further enhanced in the absence of TLR4. Increased allergen-induced skin levels of innate (S100A8/A9, IL-1β, TNF-α, and CXCL2) and Th17 genes (IL-17A and IL-17F) were observed in TLR4-deficient mice compared with wild-type mice. The absence of MyD88 alleviated disease (decreased TEWL, skin thickness, proinflammatory cytokines), whereas TRIF deficiency exacerbated disease. In conclusion, signaling through the TLR4 and TRIF pathways limits skin barrier dysfunction, cutaneous allergic sensitization, and proinflammatory cytokine production.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1300789
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
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  • 10
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    Online Resource
    Dectin-1 and IL-17A Suppress Murine Asthma Induced by Aspergillus versicolor but Not Cladosporium cladosporioides Due to Differences in β-Glucan Surface Exposure
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 189, No. 7 ( 2012-10-01), p. 3609-3617
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 189, No. 7 ( 2012-10-01), p. 3609-3617
    Abstract: There is considerable evidence supporting a role for mold exposure in the pathogenesis and expression of childhood asthma. Aspergillus versicolor and Cladosporium cladosporioides are common molds that have been implicated in asthma. In a model of mold-induced asthma, mice were repeatedly exposed to either A. versicolor or C. cladosporioides spores. The two molds induced distinct phenotypes, and this effect was observed in both BALB/c and C57BL/6 strains. C. cladosporioides induced robust airway hyperresponsiveness (AHR), eosinophilia, and a predominately Th2 response, whereas A. versicolor induced a strong Th17 response and neutrophilic inflammation, but very mild AHR. Neutralization of IL-17A resulted in strong AHR and eosinophilic inflammation following A. versicolor exposure. In Dectin-1–deficient mice, A. versicolor exposure resulted in markedly attenuated IL-17A and robust AHR compared with wild-type mice. In contrast, C. cladosporioides induced AHR and eosinophilic inflammation independent of IL-17A and Dectin-1. A. versicolor, but not C. cladosporioides, spores had increased exposure of β-glucans on their surface and were able to bind Dectin-1. Thus, the host response to C. cladosporioides was IL-17A– and Dectin-1–independent, whereas Dectin-1– and IL-17A–dependent pathways were protective against the development of asthma after exposure to A. versicolor.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1200589
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
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