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JLJ Dissertation.pdf (2.74 MB)

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Bacterial Exposure and Immune Homeostasis: A Mechanistic View of the Hygiene Hypothesis

Johnson, Jenny Lynn
http://rave.ohiolink.edu/etdc/view?acc_num=case1427988771

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Pathology.
Recently, drastic increases in the prevalence of allergic diseases and asthma have been observed in western societies. This dramatic increase has been tied to an increased emphasis on sterility and a lack of early bacterial exposure, a phenomenon known as the hygiene hypothesis. Bacteria colonization or bacterial antigens to modulate the immune response has been clearly shown; however, the mechanism behind these changes is not understood, and previously published work has little connection with human diseases known to be influenced by bacterial exposure. Utilizing the capsular polysaccharide PSA from the commensal bacterium Bacteroides fragilis, we strove to understand the alterations to the immune system following bacterial exposure, how that affects peripheral immune homeostasis, and identify potential mechanisms for the hygiene hypothesis. Prior work has identified CD4+ T cells as the responding population to Bacteroides fragilis and PSA, we examined responding T cells following PSA treatment. Through phenotypic and functional analysis we identified this population as effector memory (TEM) CD45RbLow cells with increased IL-10 production. Next generation sequencing novelly demonstrated that polysaccharide antigens are capable of clonally expanding T cells, similarly to a protein antigen. To study these cells in the context of a condition associated with the hygiene hypothesis, we utilized a murine model of asthma. We showed PSA capable of suppressing multiple etiologies of asthma through CD4+ T cells induced by PSA in an IL-10 dependent manner; however, further analysis revealed the source of suppressive IL-10 to be tissue resident Foxp3+ regulatory T cells (Tregs), and not the PSA induced T cells. Analysis of in vitro and in vivo data showed PSA expanded TEM cells interact with Tregs through a soluble mediator. Therein, we show one potential mechanism for the hygiene hypothesis in which T cells activated by a bacterial polysaccharide in the gut microenvironment inhibit peripheral inflammation. Additionally, we show the first evidence that polysaccharide A from Bacteroides fragilis induces clonal proliferation of T cells, similar to conventional protein antigens. Understanding how T cell interactions can modulate immune homeostasis yields yet another platform for developing novel therapeutics for multiple inflammatory conditions, including asthma.
Brian Cobb, PhD (Advisor)
Eric Pearlman, PhD (Committee Chair)
George Dubyak, PhD (Committee Member)
Kristie Ross, MD (Committee Member)
Clive Hamlin, PhD (Committee Member)
92 p.
Immunology
Hygiene hypothesis; asthma; polysaccharide A; T cell

Recommended Citations

Citations

  • Johnson, J. L. (2015). Bacterial Exposure and Immune Homeostasis: A Mechanistic View of the Hygiene Hypothesis [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1427988771

    APA Style (7th edition)

  • Johnson, Jenny. Bacterial Exposure and Immune Homeostasis: A Mechanistic View of the Hygiene Hypothesis. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1427988771.

    MLA Style (8th edition)

  • Johnson, Jenny. "Bacterial Exposure and Immune Homeostasis: A Mechanistic View of the Hygiene Hypothesis." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1427988771

    Chicago Manual of Style (17th edition)

case1427988771
364
© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.