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  1. Article ; Online: T helper cell immunity in pregnancy and influence on autoimmune disease progression.

    Graham, Jonathon J / Longhi, Maria Serena / Heneghan, Michael A

    Journal of autoimmunity

    2021  Volume 121, Page(s) 102651

    Abstract: Pregnancy presents the maternal immune system with a unique immunological challenge since it has to defend against pathogens while tolerating paternal allo-antigens expressed by fetal tissues. T helper (Th) cells play a central role in modulating immune ... ...

    Abstract Pregnancy presents the maternal immune system with a unique immunological challenge since it has to defend against pathogens while tolerating paternal allo-antigens expressed by fetal tissues. T helper (Th) cells play a central role in modulating immune responses and recent advances have defined distinct contributions of various Th cell subsets throughout each phase of human pregnancy, while dysregulation in Th responses show association with multiple obstetrical complications. In addition to localized decidual mechanisms, modulation of Th cell immunity during gestation is mediated largely by oscillations in sex hormone concentrations. Aberrant Th cell responses also underlie several autoimmune disorders while pregnancy-induced changes in the balance of Th cell immunity has been shown to exert favorable outcomes in the progression Th1 and Th17 driven autoimmune conditions only to be followed by post-partal exacerbations in disease.
    MeSH term(s) Autoimmune Diseases/blood ; Autoimmune Diseases/immunology ; Disease Progression ; Female ; Gonadal Steroid Hormones/blood ; Humans ; Pregnancy ; Pregnancy Complications/blood ; Pregnancy Complications/immunology ; T-Lymphocytes, Helper-Inducer/immunology
    Chemical Substances Gonadal Steroid Hormones
    Language English
    Publishing date 2021-05-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 639452-8
    ISSN 1095-9157 ; 0896-8411
    ISSN (online) 1095-9157
    ISSN 0896-8411
    DOI 10.1016/j.jaut.2021.102651
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2368: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Transcriptome profiling of PBMCs and formalin-fixed autopsy tissues from COVID-19 patients.

    Vuerich, Marta / Wang, Na / Kalbasi, Ahmadreza / Graham, Jonathon J / Longhi, Maria Serena

    STAR protocols

    2022  Volume 3, Issue 1, Page(s) 101156

    Abstract: Here we present an optimized protocol for transcriptome profiling of COVID-19 patient samples, including peripheral blood mononuclear cells (PBMCs) and formalin-fixed paraffin-embedded tissue samples obtained from the lung, liver, heart, kidney, and ... ...

    Abstract Here we present an optimized protocol for transcriptome profiling of COVID-19 patient samples, including peripheral blood mononuclear cells (PBMCs) and formalin-fixed paraffin-embedded tissue samples obtained from the lung, liver, heart, kidney, and spleen, with the matched controls. We describe RNA extraction and subsequent transcriptome analysis using NanoString technology of the patient samples. The protocol provides information about sample preparation, RNA extraction, and NanoString profiling and analysis. It can be also applied to differentiated Th17 and Treg subsets or formalin-fixed colon tissue samples. For complete details on the use and execution of this protocol, please refer to Wang et al. (2021).
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Autopsy ; COVID-19/diagnosis ; COVID-19/genetics ; COVID-19/virology ; Case-Control Studies ; Female ; Formaldehyde/chemistry ; Humans ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; RNA, Viral/analysis ; RNA, Viral/genetics ; SARS-CoV-2/genetics ; SARS-CoV-2/isolation & purification ; Tissue Fixation/methods ; Transcriptome ; Young Adult
    Chemical Substances RNA, Viral ; Formaldehyde (1HG84L3525)
    Language English
    Publishing date 2022-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2022.101156
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  3. Article ; Online: Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies.

    Vuerich, Marta / Wang, Na / Kalbasi, Ahmadreza / Graham, Jonathon J / Longhi, Maria Serena

    Frontiers in immunology

    2021  Volume 12, Page(s) 746436

    Abstract: Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological features of interface hepatitis. AIH therapeutic management still relies on the administration of ... ...

    Abstract Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological features of interface hepatitis. AIH therapeutic management still relies on the administration of corticosteroids, azathioprine and other immunosuppressants like calcineurin inhibitors and mycophenolate mofetil. Withdrawal of immunosuppression often results in disease relapse, and, in some cases, therapy is ineffective or associated with serious side effects. Understanding the mechanisms underlying AIH pathogenesis is therefore of paramount importance to develop more effective and well tolerated agents capable of restoring immunotolerance to liver autoantigens. Imbalance between effector and regulatory cells permits liver damage perpetuation and progression in AIH. Impaired expression and regulation of CD39, an ectoenzyme key to immunotolerance maintenance, have been reported in Tregs and effector Th17-cells derived from AIH patients. Interference with these altered immunoregulatory pathways may open new therapeutic avenues that, in addition to limiting aberrant inflammatory responses, would also reconstitute immune homeostasis. In this review, we highlight the most recent findings in AIH immunopathogenesis and discuss how these could inform and direct the development of novel therapeutic tools.
    MeSH term(s) Animals ; Hepatitis, Autoimmune/drug therapy ; Hepatitis, Autoimmune/immunology ; Humans
    Language English
    Publishing date 2021-09-28
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.746436
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  4. Article ; Online: An update on the pharmacological management of autoimmune hepatitis.

    Chung, Yooyun / Rahim, Mussarat N / Graham, Jonathon J / Zen, Yoh / Heneghan, Michael A

    Expert opinion on pharmacotherapy

    2021  Volume 22, Issue 11, Page(s) 1475–1488

    Abstract: ... ...

    Abstract Introduction
    MeSH term(s) Chemical and Drug Induced Liver Injury ; Hepatitis, Autoimmune/drug therapy ; Hepatitis, Autoimmune/etiology ; Humans ; Retrospective Studies ; T-Lymphocytes, Regulatory
    Language English
    Publishing date 2021-03-26
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2001535-5
    ISSN 1744-7666 ; 1465-6566
    ISSN (online) 1744-7666
    ISSN 1465-6566
    DOI 10.1080/14656566.2021.1895747
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5130: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Blockade of PGK1 and ALDOA enhances bilirubin control of Th17 cells in Crohn's disease.

    Vuerich, Marta / Wang, Na / Graham, Jonathon J / Gao, Li / Zhang, Wei / Kalbasi, Ahmadreza / Zhang, Lina / Csizmadia, Eva / Hristopoulos, Jason / Ma, Yun / Kokkotou, Efi / Cheifetz, Adam S / Robson, Simon C / Longhi, Maria Serena

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 994

    Abstract: Unconjugated bilirubin (UCB) confers Th17-cells immunosuppressive features by activating aryl-hydrocarbon-receptor, a modulator of toxin and adaptive immune responses. In Crohn's disease, Th17-cells fail to acquire regulatory properties in response to ... ...

    Abstract Unconjugated bilirubin (UCB) confers Th17-cells immunosuppressive features by activating aryl-hydrocarbon-receptor, a modulator of toxin and adaptive immune responses. In Crohn's disease, Th17-cells fail to acquire regulatory properties in response to UCB, remaining at an inflammatory/pathogenic state. Here we show that UCB modulates Th17-cell metabolism by limiting glycolysis and through downregulation of glycolysis-related genes, namely phosphoglycerate-kinase-1 (PGK1) and aldolase-A (ALDOA). Th17-cells of Crohn's disease patients display heightened PGK1 and ALDOA and defective response to UCB. Silencing of PGK1 or ALDOA restores Th17-cell response to UCB, as reflected by increase in immunoregulatory markers like FOXP3, IL-10 and CD39. In vivo, PGK1 and ALDOA silencing enhances UCB salutary effects in trinitro-benzene-sulfonic-acid-induced colitis in NOD/scid/gamma humanized mice where control over disease activity and enhanced immunoregulatory phenotypes are achieved. PGK1 and/or ALDOA blockade might have therapeutic effects in Crohn's disease by favoring acquisition of regulatory properties by Th17-cells along with control over their pathogenic potential.
    MeSH term(s) Animals ; Benzene/metabolism ; Bilirubin ; Crohn Disease/genetics ; Forkhead Transcription Factors/metabolism ; Fructose-Bisphosphate Aldolase/metabolism ; Humans ; Interleukin-10/metabolism ; Mice ; Mice, Inbred NOD ; Phosphoglycerate Kinase/antagonists & inhibitors ; Th17 Cells
    Chemical Substances Forkhead Transcription Factors ; Interleukin-10 (130068-27-8) ; Phosphoglycerate Kinase (EC 2.7.2.3) ; Fructose-Bisphosphate Aldolase (EC 4.1.2.13) ; Benzene (J64922108F) ; Bilirubin (RFM9X3LJ49)
    Language English
    Publishing date 2022-09-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-03913-9
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  6. Article ; Online: Limited TCR repertoire and

    Wang, Na / Vuerich, Marta / Kalbasi, Ahmadreza / Graham, Jonathon J / Csizmadia, Eva / Manickas-Hill, Zachary James / Woolley, Ann / David, Clement / Miller, Eric M / Gorman, Kara / Hecht, Jonathan L / Shaefi, Shahzad / Robson, Simon C / Longhi, Maria Serena

    iScience

    2021  Volume 24, Issue 10, Page(s) 103205

    Abstract: T cell exhaustion and dysfunction are hallmarks of severe COVID-19. To gain insights into the pathways underlying these alterations, we performed a comprehensive transcriptome analysis of peripheral-blood-mononuclear-cells (PBMCs), spleen, lung, kidney, ... ...

    Abstract T cell exhaustion and dysfunction are hallmarks of severe COVID-19. To gain insights into the pathways underlying these alterations, we performed a comprehensive transcriptome analysis of peripheral-blood-mononuclear-cells (PBMCs), spleen, lung, kidney, liver, and heart obtained at autopsy from COVID-19 patients and matched controls, using the nCounter CAR-T-Characterization panel. We found substantial gene alterations in COVID-19-impacted organs, especially the lung where altered TCR repertoires are noted. Reduced TCR repertoires are also observed in PBMCs of severe COVID-19 patients.
    Language English
    Publishing date 2021-09-30
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2021.103205
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  7. Article ; Online: Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis.

    Graham, Jonathon J / Mukherjee, Sujit / Yuksel, Muhammad / Sanabria Mateos, Rebeca / Si, Tengfei / Huang, Zhenlin / Huang, Xiahong / Abu Arqoub, Hadil / Patel, Vishal / McPhail, Mark / Zen, Yoh / Heaton, Nigel / Longhi, Maria Serena / Heneghan, Michael A / Liberal, Rodrigo / Vergani, Diego / Mieli-Vergani, Giorgina / Ma, Yun / Hayee, Bu'Hussain

    Hepatology (Baltimore, Md.)

    2021  Volume 75, Issue 3, Page(s) 518–530

    Abstract: Background and aims: The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, ...

    Abstract Background and aims: The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine "the gut homing theory" in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases.
    Approach and results: Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4β7, αEβ7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. β7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with β7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver.
    Conclusions: These findings refute the widely accepted "gut homing" hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD.
    MeSH term(s) Antigens, CD/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cadherins/metabolism ; Cell Adhesion Molecules/isolation & purification ; Cell Adhesion Molecules/metabolism ; Chemokines, CC/metabolism ; Cholangitis, Sclerosing/immunology ; Cholangitis, Sclerosing/metabolism ; Cholangitis, Sclerosing/pathology ; Gastrointestinal Tract/immunology ; Gastrointestinal Tract/pathology ; Gene Expression Profiling ; Humans ; Immunohistochemistry ; Integrin beta Chains/metabolism ; Liver/metabolism ; Liver/pathology ; Liver Diseases/classification ; Liver Diseases/metabolism ; Liver Diseases/pathology ; Mucoproteins/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Peptide/metabolism
    Chemical Substances Antigens, CD ; CCL25 protein, human ; CDH1 protein, human ; Cadherins ; Cell Adhesion Molecules ; Chemokines, CC ; GPR15 protein, human ; Integrin beta Chains ; MADCAM1 protein, human ; Mucoproteins ; Receptors, G-Protein-Coupled ; Receptors, Peptide ; integrin beta7
    Language English
    Publishing date 2021-12-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604603-4
    ISSN 1527-3350 ; 0270-9139
    ISSN (online) 1527-3350
    ISSN 0270-9139
    DOI 10.1002/hep.32193
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    Zs.A 1660: Show issues Location:
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