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  1. Article ; Online: Immunoregulation via Cell Density and Quorum Sensing-like Mechanisms

    Adrian A. Naoun / Itay Raphael / Thomas G. Forsthuber

    Cells, Vol 11, Iss 2442, p

    An Underexplored Emerging Field with Potential Translational Implications

    2022  Volume 2442

    Abstract: Quorum sensing (QS) was historically described as a mechanism by which bacteria detect and optimize their population density via gene regulation based on dynamic environmental cues. Recently, it was proposed that QS or similar mechanisms may have broader ...

    Abstract Quorum sensing (QS) was historically described as a mechanism by which bacteria detect and optimize their population density via gene regulation based on dynamic environmental cues. Recently, it was proposed that QS or similar mechanisms may have broader applications across different species and cell types. Indeed, emerging evidence shows that the mammalian immune system can also elicit coordinated responses on a population level to regulate cell density and function, thus suggesting that QS-like mechanisms may also be a beneficial trait of the immune system. In this review, we explore and discuss potential QS-like mechanisms deployed by the immune system to coordinate cellular-level responses, such as T cell responses mediated via the common gamma chain (γc) receptor cytokines and the aryl hydrocarbon receptors (AhRs). We present evidence regarding a novel role of QS as a multifunctional mechanism coordinating CD4 + and CD8 + T cell behavior during steady state and in response to infection, inflammatory diseases, and cancer. Successful clinical therapies such as adoptive cell transfer for cancer treatment may be re-evaluated to harness the effects of the QS mechanism(s) and enhance treatment responsiveness. Moreover, we discuss how signaling threshold perturbations through QS-like mediators may result in disturbances of the complex crosstalk between immune cell populations, undesired T cell responses, and induction of autoimmune pathology. Finally, we discuss the potential therapeutic role of modulating immune-system-related QS as a promising avenue to treat human diseases.
    Keywords quorum sensing ; immune system ; cytokines ; T cell homeostasis ; macrophage ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Memory CD4 + T Cells in Immunity and Autoimmune Diseases

    Itay Raphael / Rachel R. Joern / Thomas G. Forsthuber

    Cells, Vol 9, Iss 3, p

    2020  Volume 531

    Abstract: CD4 + T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4 + Th cells are ... ...

    Abstract CD4 + T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4 + Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4 + T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4 + tissue-resident memory T cells and of CD4 + memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4 + T cell-mediated autoimmune diseases.
    Keywords cd4 + t cells ; memory t cells ; autoimmune disease ; effector memory t cell ; central memory t cell ; tissue-resident t cell ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Early response index

    Sirajul Salekin / Mehrab Ghanat Bari / Itay Raphael / Thomas G. Forsthuber / Jianqiu (Michelle) Zhang

    BMC Bioinformatics, Vol 18, Iss 1, Pp 1-

    a statistic to discover potential early stage disease biomarkers

    2017  Volume 11

    Abstract: Abstract Background Identifying disease correlated features early before large number of molecules are impacted by disease progression with significant abundance change is very advantageous to biologists for developing early disease diagnosis biomarkers. ...

    Abstract Abstract Background Identifying disease correlated features early before large number of molecules are impacted by disease progression with significant abundance change is very advantageous to biologists for developing early disease diagnosis biomarkers. Disease correlated features have relatively low level of abundance change at early stages. Finding them using existing bioinformatic tools in high throughput data is a challenging task since the technology suffers from limited dynamic range and significant noise. Most existing biomarker discovery algorithms can only detect molecules with high abundance changes, frequently missing early disease diagnostic markers. Results We present a new statistic called early response index (ERI) to prioritize disease correlated molecules as potential early biomarkers. Instead of classification accuracy, ERI measures the average classification accuracy improvement attainable by a feature when it is united with other counterparts for classification. ERI is more sensitive to abundance changes than other ranking statistics. We have shown that ERI significantly outperforms SAM and Localfdr in detecting early responding molecules in a proteomics study of a mouse model of multiple sclerosis. Importantly, ERI was able to detect many disease relevant proteins before those algorithms detect them at a later time point. Conclusions ERI method is more sensitive for significant feature detection during early stage of disease development. It potentially has a higher specificity for biomarker discovery, and can be used to identify critical time frame for disease intervention.
    Keywords Disease correlated features ; Early stage of disease ; Biomarker discovery ; Feature selection ; Gene/protein expression change ; Multiple Sclerosis ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
    Subject code 006
    Language English
    Publishing date 2017-06-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: M-Cells Contribute to the Entry of an Oral Vaccine but Are Not Essential for the Subsequent Induction of Protective Immunity against Francisella tularensis.

    Aimee L Cunningham / M Neal Guentzel / Jieh-Juen Yu / Chiung-Yu Hung / Thomas G Forsthuber / Christopher S Navara / Hideo Yagita / Ifor R Williams / Karl E Klose / Tonyia D Eaves-Pyles / Bernard P Arulanandam

    PLoS ONE, Vol 11, Iss 4, p e

    2016  Volume 0153402

    Abstract: M-cells (microfold cells) are thought to be a primary conduit of intestinal antigen trafficking. Using an established neutralizing anti-RANKL (Receptor Activator of NF-κB Ligand) antibody treatment to transiently deplete M-cells in vivo, we sought to ... ...

    Abstract M-cells (microfold cells) are thought to be a primary conduit of intestinal antigen trafficking. Using an established neutralizing anti-RANKL (Receptor Activator of NF-κB Ligand) antibody treatment to transiently deplete M-cells in vivo, we sought to determine whether intestinal M-cells were required for the effective induction of protective immunity following oral vaccination with ΔiglB (a defined live attenuated Francisella novicida mutant). M-cell depleted, ΔiglB-vaccinated mice exhibited increased (but not significant) morbidity and mortality following a subsequent homotypic or heterotypic pulmonary F. tularensis challenge. No significant differences in splenic IFN-γ, IL-2, or IL-17 or serum antibody (IgG1, IgG2a, IgA) production were observed compared to non-depleted, ΔiglB-vaccinated animals suggesting complementary mechanisms for ΔiglB entry. Thus, we examined other possible routes of gastrointestinal antigen sampling following oral vaccination and found that ΔiglB co-localized to villus goblet cells and enterocytes. These results provide insight into the role of M-cells and complementary pathways in intestinal antigen trafficking that may be involved in the generation of optimal immunity following oral vaccination.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610 ; 570
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: A T cell epitope-based vaccine protects against chlamydial infection in HLA-DR4 transgenic mice

    Li, Weidang / Ashlesh K. Murthy / Bernard P. Arulanandam / Gopala Krishna Lanka / Guangming Zhong / James P. Chambers / Jieh-Juen Yu / M. Neal Guentzel / Senthilnath L. Chetty / Thomas G. Forsthuber

    Vaccine. 2013 Nov. 19, v. 31, no. 48

    2013  

    Abstract: Vaccination with recombinant chlamydial protease-like activity factor (rCPAF) has been shown to provide robust protection against genital Chlamydia infection. Adoptive transfer of IFN-γ competent CPAF-specific CD4+ T cells was sufficient to induce early ... ...

    Abstract Vaccination with recombinant chlamydial protease-like activity factor (rCPAF) has been shown to provide robust protection against genital Chlamydia infection. Adoptive transfer of IFN-γ competent CPAF-specific CD4+ T cells was sufficient to induce early resolution of chlamydial infection and reduction of subsequent pathology in recipient IFN-γ-deficient mice indicating the importance of IFN-γ secreting CD4+ T cells in host defense against Chlamydia. In this study, we identify CD4+ T cell reactive CPAF epitopes and characterize the activation of epitope-specific CD4+ T cells following antigen immunization or Chlamydia challenge. Using the HLA-DR4 (HLA-DRB1*0401) transgenic mouse for screening overlapping peptides that induced T cell IFN-γ production, we identified at least 5 CPAF T cell epitopes presented by the HLA-DR4 complex. Immunization of HLA-DR4 transgenic mice with a rCPAFep fusion protein containing these 5 epitopes induced a robust cell-mediated immune response and significantly accelerated the resolution of genital and pulmonary Chlamydia infection. rCPAFep vaccination induced CPAF-specific CD4+ T cells in the spleen were detected using HLA-DR4/CPAF-epitope tetramers. Additionally, CPAF-specific CD4+ clones could be detected in the mouse spleen following Chlamydia muridarum and a human Chlamydia trachomatis strain challenge using these novel tetramers. These results provide the first direct evidence that a novel CPAF epitope vaccine can provide protection and that HLA-DR4/CPAF-epitope tetramers can detect CPAF epitope-specific CD4+ T cells in HLA-DR4 mice following C. muridarum or C. trachomatis infection. Such tetramers could be a useful tool for monitoring CD4+ T cells in immunity to Chlamydia infection and in developing epitope-based human vaccines using the murine model.
    Keywords animal models ; CD4-positive T-lymphocytes ; cell-mediated immunity ; Chlamydia muridarum ; Chlamydia trachomatis ; clones ; epitopes ; humans ; interferon-gamma ; mice ; monitoring ; peptides ; screening ; spleen ; splenocytes ; transgenic animals ; vaccination ; vaccines
    Language English
    Dates of publication 2013-1119
    Size p. 5722-5728.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 605674-x
    ISSN 1873-2518 ; 0264-410X
    ISSN (online) 1873-2518
    ISSN 0264-410X
    DOI 10.1016/j.vaccine.2013.09.036
    Database NAL-Catalogue (AGRICOLA)

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