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Peter J M Openshaw - One of the best experts on this subject based on the ideXlab platform.
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increased nasal mucosal interferon and CCL13 response to a tlr7 8 agonist in asthma and allergic rhinitis
The Journal of Allergy and Clinical Immunology, 2021Co-Authors: Akhilesh Jha, Rj Shattock, Ryan S Thwaites, Tanushree Tunstall, Onn Min Kon, Trevor T Hansel, Peter J M OpenshawAbstract:Background Acute respiratory viral infections are a major cause of respiratory morbidity and mortality, especially in patients with preexisting lung diseases such as asthma. Toll-like receptors are critical in the early detection of viruses and in activating innate immunity in the respiratory mucosa, but there is no reliable and convenient method by which respiratory mucosal innate immune responses can be measured. Objective We sought to assess in vivo immune responses to an innate stimulus and compare responsiveness between healthy volunteers and volunteers with allergy. Methods We administered the Toll-like receptor 7/8 agonist resiquimod (R848; a synthetic analogue of single-stranded RNA) or saline by nasal spray to healthy participants without allergy (n = 12), those with allergic rhinitis (n = 12), or those with allergic rhinitis with asthma (n = 11). Immune mediators in blood and nasal fluid and mucosal gene expression were monitored over time. Results R848 was well tolerated and significantly induced IFN-α2a, IFN-γ, proinflammatory cytokines (TNF-α, IL-2, IL-12p70), and chemokines (CXCL10, C-C motif chemokine ligand [CCL]2, CCL3, CCL4, and CCL13) in nasal mucosal fluid, without causing systemic immune activation. Participants with allergic rhinitis or allergic rhinitis with asthma had increased IFN-α2a, CCL3, and CCL13 responses relative to healthy participants; those with asthma had increased induction of IFN-stimulated genes DExD/H-box helicase 58, MX dynamin-like GTPase 1, and IFN-induced protein with tetratricopeptide repeats 3. Conclusions Responses to nasal delivery of R848 enables simple assessment of mucosal innate responsiveness, revealing that patients with allergic disorders have an increased nasal mucosal IFN and chemokine response to the viral RNA analogue R848. This highlights that dysregulated innate immune responses of the nasal mucosa in allergic individuals may be important in determining the outcome of viral exposure.
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increased nasal mucosal interferon and CCL13 response to a tlr7 8 agonist in asthma and allergic rhinitis
The Journal of Allergy and Clinical Immunology, 2020Co-Authors: Akhilesh Jha, Rj Shattock, Ryan S Thwaites, Tanushree Tunstall, Onn Min Kon, Trevor T Hansel, Peter J M OpenshawAbstract:Abstract: Background Acute respiratory viral infections are a major cause of respiratory morbidity and mortality, especially in patients with pre-existing lung diseases such as asthma. Toll-like receptors (TLRs) are critical in the early detection of viruses and in activating innate immunity in the respiratory mucosa, but there is no reliable and convenient method by which respiratory mucosal innate immune responses can be measured. Objective To assess in vivo immune responses to an innate stimulus and compare responsiveness between healthy and allergic volunteers. Methods We administered the TLR7/8 agonist resiquimod (R848; a synthetic analogue of single-stranded RNA (ssRNA)) or saline by nasal spray to healthy non-allergic participants (n=12), those with allergic rhinitis (n=12), or allergic rhinitis with asthma (n=11). Immune mediators in blood and nasal fluid and mucosal gene expression were monitored over time. Results R848 was well tolerated and significantly induced interferon (IFN)-α2a, IFN-γ, pro-inflammatory cytokines (TNF-α, IL-2, IL-12p70) and chemokines (CXCL10, CCL2, CCL3, CCL4 and CCL13) in nasal mucosal fluid, without causing systemic immune activation. Participants with allergic rhinitis or allergic rhinitis with asthma had increased IFN-α2a, CCL3 and CCL13 responses relative to healthy participants; those with asthma had increased induction of interferon-stimulated genes DDX58, MX1 and IFIT3. Conclusion Responses to nasal delivery of R848 enables simple assessment of mucosal innate responsiveness, revealing that patients with allergic disorders have an increased nasal mucosal interferon and chemokine response to the viral RNA analogue resiquimod. This highlights that dysregulated innate immune responses of the nasal mucosa in allergic individuals may be important in determining the outcome of viral exposure.
Jo Van Damme - One of the best experts on this subject based on the ideXlab platform.
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the cc chemokines ccl8 CCL13 and ccl20 are local inflammatory biomarkers of hla b27 associated uveitis
Acta Ophthalmologica, 2019Co-Authors: Ahmed Abu M Elasrar, Nele Berghmans, Saleh A Alobeidan, Ghislain Opdenakker, Jo Van Damme, Priscilla W Gikandi, Sofie StruyfAbstract:Purpose To determine the concentrations of the CC chemokines CCL2, CCL7, CCL8, CCL11, CCL13, CCL20, CCL24 and CCL26 in aqueous humour (AH) samples from patients with specific uveitic entities. Methods Aqueous humour samples from patients with active uveitis associated with Behcet's disease (BD) (n = 13), sarcoidosis (n = 8), HLA-B27-related inflammation (n = 12), Vogt-Koyanagi-Harada (VKH) disease (n = 12) and control patients (n = 9) were assayed with the use of a multiplex assay. Results When considering all uveitis patients as one group, all chemokine levels except CCL2 were significantly increased compared to controls. CCL8, CCL13 and CCL20 were the most strongly upregulated, 48-fold, 118-fold and 173-fold, respectively, above control AH levels. CCL8 and CCL13 levels were significantly higher in HLA-B27-associated uveitis than in sarcoidosis and VKH disease. CCL20 levels were significantly higher in HLA-B27-associated uveitis than in BD, sarcoidosis and VKH disease. In addition, CCL20 levels were significantly higher in BD than in VKH disease. In HLA-B27-associated uveitis, CCL8, CCL13 and CCL20 were upregulated 111-fold, 255-fold and 465-fold, respectively, compared with controls. CCL8, CCL13 and CCL20 levels were significantly higher in nongranulomatous uveitis (BD and HLA-B27-associated uveitis) than in granulomatous uveitis (sarcoidosis and VKH disease). Conclusion Immune responses mediated by CCL8, CCL13 and CCL20 appear to be more potent in nongranulomatous uveitis, particularly in HLA-B27-associated uveitis.
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the cytokine interleukin 6 and the chemokines ccl20 and cxcl13 are novel biomarkers of specific endogenous uveitic entities
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Ahmed Abu M Elasrar, Nele Berghmans, Saleh A Alobeidan, Ahmed Mousa, Ghislain Opdenakker, Jo Van DammeAbstract:PURPOSE The purpose of this study was to determine levels of the cytokines IL-1β, IL-6, IL-21, IL-22, and IL-23 and the chemokines CXCL13, CCL19, CCL20, and CCL21 in aqueous humor (AH) samples from patients with specific uveitic entities. METHODS Paired serum samples (n = 13) and AH samples (n = 111) from patients with active idiopathic granulomatous uveitis (IGU) or with uveitis associated with HLA-B27-related inflammation, Behcet's disease (BD), Vogt-Koyanagi-Harada (VKH) disease, or sarcoidosis and control patients were analyzed in two different multiplex assays. RESULTS Cytokines IL-1β, IL-21, IL-22, and IL-23 were not detected in any AH sample. Chemokine CCL21 concentrations in serum were significantly higher than those in AH. CCL19 levels in AH and serum were not significantly different. Levels of CCL20 and CXCL13 in AH were significantly higher than those in serum. IL-6 was not detected in serum samples. IL-6 AH levels were significantly higher in patients with HLA-B27-associated uveitis and in BD patients than in patients with VKH disease, sarcoidosis, and IGU (P < 0.0001). CCL20 AH levels were significantly higher in HLA-B27-associated uveitis than in BD, VKH, sarcoidosis, and IGU (P = 0.001), whereas CXCL13 AH levels were significantly higher in VKH disease and IGU than in HLA-B27-associated uveitis, BD, and sarcoidosis (P = 0.007). CONCLUSIONS IL-6-driven immune responses are more potent in HLA-B27-associated uveitis and BD than in VKH disease, sarcoidosis, and IGU. CCL20 appears to be a specific biomarker of HLA-B27-associated uveitis, whereas CXCL13 appears to be a biomarker of VKH disease and IGU. Our findings suggest that IL-6, CCL20, and CXCL13 could serve as drug targets for treatment of specific clinical entities of endogenous uveitis.
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differential regulation of chemokine production by fcgamma receptor engagement in human monocytes association of ccl1 with a distinct form of m2 monocyte activation m2b type 2
Journal of Leukocyte Biology, 2006Co-Authors: Marina Sironi, Andrea Iellem, Daniele Dambrosio, Marco A. Cassatella, Fernando O Martinez, Marco Gattorno, Nadia Polentarutti, Massimo Locati, Andrea Gregorio, Jo Van DammeAbstract:CC chemokine ligand 1 (CCL1; I-309) is a CC chemokine that interacts with CC chemokine receptor 8, which is preferentially expressed in polarized T helper cell type 2 and Tc2 cells, in eosinophils, and in T regulatory cells. The present study, prompted by transcriptional profiling of human monocytes undergoing different forms of activation, was designed to characterize the production of CCL1 in monocytes compared with the production of other chemokines (CCL2, CCL22, and CCL18) differentially regulated by distinct activation signals. Lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), interleukin (IL)-1beta, tumor necrosis factor alpha, IL-4, IL-13, IL-10, IL-6, IL-18, and combinations thereof did not induce CCL1 production in monocytes, and some of these signals stimulated production of reference chemokines. Induction of CCL1 in monocytes required engagement of Fc receptor for immunoglobulin G (FcgammaR)II and exposure to IL-1beta or LPS. This combination of stimuli results in a form of M2 (M2b, Type 2) macrophage activation. FcgammaR engagement also induced CCL22 and amplified its stimulation by IL-4. In contrast, FcgammaR stimulation inhibited the IL-10- and LPS-mediated induction of CCL18. IL-10, IL-4, and IFN-gamma inhibited induction of CCL1 by FcgammaR ligation and IL-1beta. CCL1 was present in synovial fluids and macrophages in juvenile idiopathic arthritis. Thus, regulation of CCL1 in human monocytes is unique, with an obligate requirement of FcgammaR engagement and costimulation by signals (IL-1beta and LPS), which use the myeloid differentiation primary-response protein 88 adaptor protein. Thus, CCL1 is a CC chemokine with a unique pattern of regulation associated with a distinct form of M2 (Type 2, M2b) monocyte activation, which participates in macrophage-dependent regulatory circuits of innate and adaptive immunity.
Mariecaroline Dieunosjean - One of the best experts on this subject based on the ideXlab platform.
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characterization of chemokines and adhesion molecules associated with t cell presence in tertiary lymphoid structures in human lung cancer
Cancer Research, 2011Co-Authors: Luc De Chaisemartin, Diane Damotte, Pierre Validire, Pierre Magdeleinat, Marco Alifano, Isabelle Cremer, Wolf H Fridman, Catherine Sautesfridman, Mariecaroline DieunosjeanAbstract:De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they represent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found that most TLS T cells were CD62L+ and mainly of CD4+ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins (alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. Intratumoral PNAd+ high endothelial venules also were exclusively associated with TLS and colocalized with CD62L+ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies. Cancer Res; 71(20); 6391–9. ©2011 AACR .
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characterization of chemokines and adhesion molecules associated with t cell presence in tertiary lymphoid structures in human lung cancer
Cancer Research, 2011Co-Authors: Luc De Chaisemartin, Diane Damotte, Pierre Validire, Pierre Magdeleinat, Marco Alifano, Isabelle Cremer, Wolf H Fridman, Catherine Sautesfridman, Jeremy Goc, Mariecaroline DieunosjeanAbstract:De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they represent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found that most TLS T cells were CD62L+ and mainly of CD4+ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins (alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. Intratumoral PNAd+ high endothelial venules also were exclusively associated with TLS and colocalized with CD62L+ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies.
Akhilesh Jha - One of the best experts on this subject based on the ideXlab platform.
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increased nasal mucosal interferon and CCL13 response to a tlr7 8 agonist in asthma and allergic rhinitis
The Journal of Allergy and Clinical Immunology, 2021Co-Authors: Akhilesh Jha, Rj Shattock, Ryan S Thwaites, Tanushree Tunstall, Onn Min Kon, Trevor T Hansel, Peter J M OpenshawAbstract:Background Acute respiratory viral infections are a major cause of respiratory morbidity and mortality, especially in patients with preexisting lung diseases such as asthma. Toll-like receptors are critical in the early detection of viruses and in activating innate immunity in the respiratory mucosa, but there is no reliable and convenient method by which respiratory mucosal innate immune responses can be measured. Objective We sought to assess in vivo immune responses to an innate stimulus and compare responsiveness between healthy volunteers and volunteers with allergy. Methods We administered the Toll-like receptor 7/8 agonist resiquimod (R848; a synthetic analogue of single-stranded RNA) or saline by nasal spray to healthy participants without allergy (n = 12), those with allergic rhinitis (n = 12), or those with allergic rhinitis with asthma (n = 11). Immune mediators in blood and nasal fluid and mucosal gene expression were monitored over time. Results R848 was well tolerated and significantly induced IFN-α2a, IFN-γ, proinflammatory cytokines (TNF-α, IL-2, IL-12p70), and chemokines (CXCL10, C-C motif chemokine ligand [CCL]2, CCL3, CCL4, and CCL13) in nasal mucosal fluid, without causing systemic immune activation. Participants with allergic rhinitis or allergic rhinitis with asthma had increased IFN-α2a, CCL3, and CCL13 responses relative to healthy participants; those with asthma had increased induction of IFN-stimulated genes DExD/H-box helicase 58, MX dynamin-like GTPase 1, and IFN-induced protein with tetratricopeptide repeats 3. Conclusions Responses to nasal delivery of R848 enables simple assessment of mucosal innate responsiveness, revealing that patients with allergic disorders have an increased nasal mucosal IFN and chemokine response to the viral RNA analogue R848. This highlights that dysregulated innate immune responses of the nasal mucosa in allergic individuals may be important in determining the outcome of viral exposure.
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increased nasal mucosal interferon and CCL13 response to a tlr7 8 agonist in asthma and allergic rhinitis
The Journal of Allergy and Clinical Immunology, 2020Co-Authors: Akhilesh Jha, Rj Shattock, Ryan S Thwaites, Tanushree Tunstall, Onn Min Kon, Trevor T Hansel, Peter J M OpenshawAbstract:Abstract: Background Acute respiratory viral infections are a major cause of respiratory morbidity and mortality, especially in patients with pre-existing lung diseases such as asthma. Toll-like receptors (TLRs) are critical in the early detection of viruses and in activating innate immunity in the respiratory mucosa, but there is no reliable and convenient method by which respiratory mucosal innate immune responses can be measured. Objective To assess in vivo immune responses to an innate stimulus and compare responsiveness between healthy and allergic volunteers. Methods We administered the TLR7/8 agonist resiquimod (R848; a synthetic analogue of single-stranded RNA (ssRNA)) or saline by nasal spray to healthy non-allergic participants (n=12), those with allergic rhinitis (n=12), or allergic rhinitis with asthma (n=11). Immune mediators in blood and nasal fluid and mucosal gene expression were monitored over time. Results R848 was well tolerated and significantly induced interferon (IFN)-α2a, IFN-γ, pro-inflammatory cytokines (TNF-α, IL-2, IL-12p70) and chemokines (CXCL10, CCL2, CCL3, CCL4 and CCL13) in nasal mucosal fluid, without causing systemic immune activation. Participants with allergic rhinitis or allergic rhinitis with asthma had increased IFN-α2a, CCL3 and CCL13 responses relative to healthy participants; those with asthma had increased induction of interferon-stimulated genes DDX58, MX1 and IFIT3. Conclusion Responses to nasal delivery of R848 enables simple assessment of mucosal innate responsiveness, revealing that patients with allergic disorders have an increased nasal mucosal interferon and chemokine response to the viral RNA analogue resiquimod. This highlights that dysregulated innate immune responses of the nasal mucosa in allergic individuals may be important in determining the outcome of viral exposure.
Xingbing Wang - One of the best experts on this subject based on the ideXlab platform.
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ccl19 and cxcl13 synergistically regulate interaction between b cell acute lymphocytic leukemia cd23 cd5 b cells and cd8 t cells
Journal of Immunology, 2007Co-Authors: He Yuling, Xingbing Wang, Jiang Yanping, Tan Xinti, Yang Yaofang, Yu Feng, Xiao Ruijin, Chen LangAbstract:Interacting with T cells, cytokine-producing B cells play a critical protective role in autoimmune diseases. However, the interaction between malignant B and T cells remains to be fully elucidated. In a previous study, we have reported that ligation of CCL19-CCR7 and CXCL13-CXCR5 activates paternally expressed gene 10 (PEG10), resulting in an enhancement of apoptotic resistance in B-cell acute lymphocytic leukemia (B-ALL) CD23+CD5+ B cells. Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell-derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells. The impairment of cytotoxicity of syngeneic CD8+ T cells is escalated by means of CCL19/CXCL13-induced up-regulation of IL-10 from B-ALL CD23+CD5+ B cells. Moreover, using a short hairpin RNA to knockdown PEG10, we provide direct evidence that increased expression of PEG10 in B-ALL CD23+CD5+ B cells is involved in malignant B-T cell interaction, contributing to the up-regulation of IL-10 expression, as well as to the impairment of cytotoxicity of syngeneic CD8+ T cells. Thus, malignant B-ALL CD23+CD5+ B cells play an immunoregulatory role in controlling different inflammatory cytokine expressions. IL-10 may be one of the critical cellular factors conferring B-ALL CD23+CD5+ B cells to escape from host immune surveillance.