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  1. Article ; Online: The association of microbial infection and adaptive immune cell activation in Alzheimer's disease.

    Clement, Mathew

    Discovery immunology

    2023  Volume 2, Issue 1, Page(s) kyad015

    Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Early symptoms include the loss of memory and mild cognitive ability; however, as the disease progresses, these symptoms can present with increased ...

    Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Early symptoms include the loss of memory and mild cognitive ability; however, as the disease progresses, these symptoms can present with increased severity manifesting as mood and behaviour changes, disorientation, and a loss of motor/body control. AD is one of the leading causes of death in the UK, and with an ever-increasing ageing society, patient numbers are predicted to rise posing a significant global health emergency. AD is a complex neurophysiological disorder where pathology is characterized by the deposition and aggregation of misfolded amyloid-beta (Aβ)-protein that in-turn promotes excessive tau-protein production which together drives neuronal cell dysfunction, neuroinflammation, and neurodegeneration. It is widely accepted that AD is driven by a combination of both genetic and immunological processes with recent data suggesting that adaptive immune cell activity within the parenchyma occurs throughout disease. The mechanisms behind these observations remain unclear but suggest that manipulating the adaptive immune response during AD may be an effective therapeutic strategy. Using immunotherapy for AD treatment is not a new concept as the only two approved treatments for AD use antibody-based approaches to target Aβ. However, these have been shown to only temporarily ease symptoms or slow progression highlighting the urgent need for newer treatments. This review discusses the role of the adaptive immune system during AD, how microbial infections may be contributing to inflammatory immune activity and suggests how adaptive immune processes can pose as therapeutic targets for this devastating disease.
    Language English
    Publishing date 2023-09-26
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2754-2483
    ISSN (online) 2754-2483
    DOI 10.1093/discim/kyad015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cytokine-Mediated Induction and Regulation of Tissue Damage During Cytomegalovirus Infection.

    Clement, Mathew / Humphreys, Ian R

    Frontiers in immunology

    2019  Volume 10, Page(s) 78

    Abstract: Human cytomegalovirus (HCMV) is a β-herpesvirus with high sero-prevalence within the human population. Primary HCMV infection and life-long carriage are typically asymptomatic. However, HCMV is implicated in exacerbation of chronic conditions and ... ...

    Abstract Human cytomegalovirus (HCMV) is a β-herpesvirus with high sero-prevalence within the human population. Primary HCMV infection and life-long carriage are typically asymptomatic. However, HCMV is implicated in exacerbation of chronic conditions and associated damage in individuals with intact immune systems. Furthermore, HCMV is a significant cause of morbidity and mortality in the immunologically immature and immune-compromised where disease is associated with tissue damage. Infection-induced inflammation, including robust cytokine responses, is a key component of pathologies associated with many viruses. Despite encoding a large number of immune-evasion genes, HCMV also triggers the induction of inflammatory cytokine responses during infection. Thus, understanding how cytokines contribute to CMV-induced pathologies and the mechanisms through which they are regulated may inform clinical management of disease. Herein, we discuss our current understanding based on clinical observation and
    MeSH term(s) Animals ; Cytokines/immunology ; Cytomegalovirus Infections/immunology ; Humans
    Chemical Substances Cytokines
    Language English
    Publishing date 2019-01-29
    Publishing country Switzerland
    Document type Journal Article ; 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.2019.00078
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Optimal CD8

    Dimonte, Sandra / Gimeno-Brias, Silvia / Marsden, Morgan / Chapman, Lucy / Sabberwal, Pragati / Clement, Mathew / Humphreys, Ian R

    Immunology

    2021  Volume 164, Issue 2, Page(s) 279–291

    Abstract: Cytomegalovirus (CMV) induction of large frequencies of highly functional memory T cells has attracted much interest in the utility of CMV-based vaccine vectors, with exciting preclinical data obtained in models of infectious diseases and cancer. However, ...

    Abstract Cytomegalovirus (CMV) induction of large frequencies of highly functional memory T cells has attracted much interest in the utility of CMV-based vaccine vectors, with exciting preclinical data obtained in models of infectious diseases and cancer. However, pathogenesis of human CMV (HCMV) remains a concern. Attenuated CMV-based vectors, such as replication- or spread-deficient viruses, potentially offer an alternative to fully replicating vectors. However, it is not well understood how CMV attenuation impacts vector immunogenicity, particularly when administered via relevant routes of immunization such as the skin. Herein, we used the murine cytomegalovirus (MCMV) model to investigate the impact of vector attenuation on T-cell memory formation following subcutaneous administration. We found that the spread-deficient virus (ΔgL-MCMV) was impaired in its ability to induce memory CD8
    MeSH term(s) Animals ; Antigens, Viral/immunology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/virology ; Cytomegalovirus/immunology ; Cytomegalovirus Infections/immunology ; Cytomegalovirus Infections/virology ; Dendritic Cells/immunology ; Dendritic Cells/virology ; Immunologic Memory/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Skin/immunology ; Skin/virology ; Virus Replication/immunology
    Chemical Substances Antigens, Viral
    Language English
    Publishing date 2021-06-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80124-0
    ISSN 1365-2567 ; 0019-2805 ; 0953-4954
    ISSN (online) 1365-2567
    ISSN 0019-2805 ; 0953-4954
    DOI 10.1111/imm.13368
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Inhibitory IL-10-producing CD4

    Clement, Mathew / Ladell, Kristin / Miners, Kelly L / Marsden, Morgan / Chapman, Lucy / Cardus Figueras, Anna / Scott, Jake / Andrews, Robert / Clare, Simon / Kriukova, Valeriia V / Lupyr, Ksenia R / Britanova, Olga V / Withers, David R / Jones, Simon A / Chudakov, Dmitriy M / Price, David A / Humphreys, Ian R

    eLife

    2023  Volume 12

    Abstract: Inhibitory ... ...

    Abstract Inhibitory CD4
    MeSH term(s) Mice ; Animals ; Cytomegalovirus ; Interleukin-10 ; CD4-Positive T-Lymphocytes ; Arginase/genetics ; Muromegalovirus/physiology
    Chemical Substances Interleukin-10 (130068-27-8) ; Arginase (EC 3.5.3.1)
    Language English
    Publishing date 2023-07-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.79165
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Acquisition of suppressive function by conventional T cells limits antitumor immunity upon T

    Whiteside, Sarah K / Grant, Francis M / Alvisi, Giorgia / Clarke, James / Tang, Leqi / Imianowski, Charlotte J / Zhang, Baojie / Evans, Alexander C / Wesolowski, Alexander J / Conti, Alberto G / Yang, Jie / Lauder, Sarah N / Clement, Mathew / Humphreys, Ian R / Dooley, James / Burton, Oliver / Liston, Adrian / Alloisio, Marco / Voulaz, Emanuele /
    Langhorne, Jean / Okkenhaug, Klaus / Lugli, Enrico / Roychoudhuri, Rahul

    Science immunology

    2023  Volume 8, Issue 90, Page(s) eabo5558

    Abstract: Regulatory T ( ... ...

    Abstract Regulatory T (T
    MeSH term(s) Mice ; Humans ; Animals ; T-Lymphocytes, Regulatory ; Interleukin-10/metabolism ; Neoplasms/therapy ; Neoplasms/metabolism ; Immunotherapy ; Forkhead Transcription Factors/metabolism
    Chemical Substances Interleukin-10 (130068-27-8) ; Forkhead Transcription Factors
    Language English
    Publishing date 2023-12-15
    Publishing country United States
    Document type Journal Article
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.abo5558
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: High-affinity CD8 variants enhance the sensitivity of pMHCI antigen recognition via low-affinity TCRs.

    Knezevic, Lea / Wachsmann, Tassilo L A / Francis, Ore / Dockree, Tamsin / Bridgeman, John S / Wouters, Anne / de Wet, Ben / Cole, David K / Clement, Mathew / McLaren, James E / Gostick, Emma / Ladell, Kristin / Llewellyn-Lacey, Sian / Price, David A / van den Berg, Hugo A / Tabi, Zsuzsanna / Sessions, Richard B / Heemskerk, Mirjam H M / Wooldridge, Linda

    The Journal of biological chemistry

    2023  Volume 299, Issue 8, Page(s) 104981

    Abstract: ... ...

    Abstract CD8
    MeSH term(s) CD8 Antigens ; CD8-Positive T-Lymphocytes ; Histocompatibility Antigens Class I/metabolism ; Lymphocyte Activation ; Peptides/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Humans
    Chemical Substances CD8 Antigens ; Histocompatibility Antigens Class I ; Peptides ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2023-06-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.104981
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor.

    Clement, Mathew / Knezevic, Lea / Dockree, Tamsin / McLaren, James E / Ladell, Kristin / Miners, Kelly L / Llewellyn-Lacey, Sian / Rubina, Anzelika / Francis, Ore / Cole, David K / Sewell, Andrew K / Bridgeman, John S / Price, David A / van den Berg, Hugo A / Wooldridge, Linda

    Proceedings of the National Academy of Sciences of the United States of America

    2021  Volume 118, Issue 29

    Abstract: ... ...

    Abstract CD8
    MeSH term(s) Antigens/chemistry ; Antigens/immunology ; CD8 Antigens/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cross Reactions ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/immunology ; Humans ; Kinetics ; Ligands ; Lymphocyte Activation ; Models, Immunological ; Mutation ; Peptides/agonists ; Peptides/immunology ; Receptors, Antigen, T-Cell/immunology
    Chemical Substances Antigens ; CD8 Antigens ; Histocompatibility Antigens Class I ; Ligands ; Peptides ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2021-07-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2019639118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors.

    Thompson, Aiysha / Davies, Luke C / Liao, Chia-Te / da Fonseca, Diogo M / Griffiths, James S / Andrews, Robert / Jones, Adam V / Clement, Mathew / Brown, Gordon D / Humphreys, Ian R / Taylor, Philip R / Orr, Selinda J

    PLoS pathogens

    2019  Volume 15, Issue 6, Page(s) e1007850

    Abstract: Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like ...

    Abstract Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.
    MeSH term(s) Animals ; Candida albicans/immunology ; Candidiasis/genetics ; Candidiasis/immunology ; Chemokines/genetics ; Chemokines/immunology ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/pathology ; Lectins, C-Type/genetics ; Lectins, C-Type/immunology ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Mice ; Mice, Knockout ; Monocytes/immunology ; Monocytes/pathology ; Neutrophils/pathology
    Chemical Substances Chemokines ; Clecsf8 protein, mouse ; Lectins, C-Type ; Membrane Proteins ; dectin 1 ; dectin-2, mouse
    Language English
    Publishing date 2019-06-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1007850
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  9. Article ; Online: IRF5 Promotes Influenza Virus-Induced Inflammatory Responses in Human Induced Pluripotent Stem Cell-Derived Myeloid Cells and Murine Models.

    Forbester, Jessica L / Clement, Mathew / Wellington, Dannielle / Yeung, Amy / Dimonte, Sandra / Marsden, Morgan / Chapman, Lucy / Coomber, Eve L / Tolley, Charlotte / Lees, Emily / Hale, Christine / Clare, Simon / Udalova, Irina / Dong, Tao / Dougan, Gordon / Humphreys, Ian R

    Journal of virology

    2020  Volume 94, Issue 9

    Abstract: Recognition of influenza A virus (IAV) by the innate immune system triggers pathways that restrict viral replication, activate innate immune cells, and regulate adaptive immunity. However, excessive innate immune activation can exaggerate disease. The ... ...

    Abstract Recognition of influenza A virus (IAV) by the innate immune system triggers pathways that restrict viral replication, activate innate immune cells, and regulate adaptive immunity. However, excessive innate immune activation can exaggerate disease. The pathways promoting excessive activation are incompletely understood, with limited experimental models to investigate the mechanisms driving influenza virus-induced inflammation in humans. Interferon regulatory factor 5 (IRF5) is a transcription factor that plays important roles in the induction of cytokines after viral sensing. In an
    MeSH term(s) Adaptive Immunity/physiology ; Animals ; Disease Models, Animal ; Host-Pathogen Interactions/immunology ; Humans ; Immunity, Innate/physiology ; Induced Pluripotent Stem Cells/immunology ; Influenza A virus/immunology ; Influenza A virus/metabolism ; Influenza A virus/physiology ; Influenza, Human/immunology ; Interferon Regulatory Factors/immunology ; Interferon Regulatory Factors/metabolism ; Interferon Type I/metabolism ; Lung/virology ; Macrophages/virology ; Mice ; Orthomyxoviridae Infections/virology ; Virus Replication/physiology
    Chemical Substances IRF5 protein, human ; Interferon Regulatory Factors ; Interferon Type I ; Irf5 protein, mouse
    Language English
    Publishing date 2020-04-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00121-20
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  10. Article ; Online: Interferon lambda is required for interferon gamma-expressing NK cell responses but does not afford antiviral protection during acute and persistent murine cytomegalovirus infection.

    Gimeno Brias, Silvia / Marsden, Morgan / Forbester, Jessica / Clement, Mathew / Brandt, Cordelia / Harcourt, Katherine / Kane, Leanne / Chapman, Lucy / Clare, Simon / Humphreys, Ian R

    PloS one

    2018  Volume 13, Issue 5, Page(s) e0197596

    Abstract: Interferon lambda (IFNλ) is a group of cytokines that belong to the IL-10 family. They exhibit antiviral activities against certain viruses during infection of the liver and mucosal tissues. Here we report that IFNλ restricts in vitro replication of the ... ...

    Abstract Interferon lambda (IFNλ) is a group of cytokines that belong to the IL-10 family. They exhibit antiviral activities against certain viruses during infection of the liver and mucosal tissues. Here we report that IFNλ restricts in vitro replication of the β-herpesvirus murine cytomegalovirus (mCMV). However, IFNλR1-deficient (Ifnλr1-/-) mice were not preferentially susceptible to mCMV infection in vivo during acute infection after systemic or mucosal challenge, or during virus persistence in the mucosa. Instead, our studies revealed that IFNλ influences NK cell responses during mCMV infection. Ifnλr1-/- mice exhibited defective development of conventional interferon-gamma (IFNγ)-expressing NK cells in the spleen during mCMV infection whereas accumulation of granzyme B-expressing NK cells was unaltered. In vitro, development of splenic IFNγ+ NK cells following stimulation with IL-12 or, to a lesser extent, IL-18 was abrogated by IFNλR1-deficiency. Thus, IFNλ regulates NK cell responses during mCMV infection and restricts virus replication in vitro but is redundant in the control of acute and persistent mCMV replication within mucosal and non-mucosal tissues.
    MeSH term(s) Animals ; Female ; Herpesviridae Infections/immunology ; In Vitro Techniques ; Interferon-gamma/metabolism ; Interferons/metabolism ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Muromegalovirus/immunology ; Muromegalovirus/physiology ; Virus Replication
    Chemical Substances Interferon-gamma (82115-62-6) ; Interferons (9008-11-1)
    Language English
    Publishing date 2018-05-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0197596
    Database MEDical Literature Analysis and Retrieval System OnLINE

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