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Regulation of Type 2 Immune Responses During Allergic Asthma

Liu, Bo
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406898945

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Immunology.
Allergic asthma is a heterogeneous inflammatory disease of the airway that affects millions of people worldwide. A subgroup of patients with severe asthma often has persistent symptoms and frequent exacerbations, leading to poor disease control and considerable morbidity. Accumulating clinical evidence suggests that airway eosinophilic inflammation is associated with a subphenotype of asthma that is prone to become exacerbated; however, the underlying immunological and molecular mechanisms that preferentially drive the eosinophilic phenotype of severe asthma remain elusive. The first section of this dissertation investigates the relative roles of CD4+Th2, CD4+Th17 cells and type 2 innate lymphoid cells (ILC2s) during repeated Ag re-challenge induced chronic murine allergic airway disease with prominent eosinophilic inflammation. We observed that the increase in airway eosinophils was positively associated with the number of repeated intranasal OVA Ag re-challenges, which preferentially drive the OVA Ag-specific humoral and cellular Th2 immune response. Using IL-4-GFP and IL-17-GFP reporter mice (both in BALB/c background), we found that, although both OVA Ag-specific CD4+Th2 and Th17 cells were induced in the lung of mice that developed acute murine allergic airway disease, repeated Ag re-challenge preferentially drove the increase of lung OVA Ag-specific CD4+Th2, not CD4+Th17, cell numbers. Notably, the increased number of lung CD4+Th2 cells resulted in enhanced IL-13 production by lung ILC2s in response to IL-25 and IL-33 stimulation, which decreased considerably in mice after CD4+ T cell ablation. Reciprocally, ILC2s could facilitate Ag-specific CD4+Th2 cells to mediate the exacerbation of murine allergic airway disease by promoting Ag-specific type 2 cytokine production. The second section of this dissertation investigates the molecular mechanisms underlying the immunological activities of IL-25 in regulating the Ag specific adaptive branch of type 2 immune responses during repeated Ag re-challenge induced chronic murine allergic airway disease. We found that the absence of IL-17RB had a profound effect on the accumulation and function of Ag specific Th2 cells in both lung and draining lymph node after repeated Ag re-challenge. This absence protected mice from chronic allergic airway inflammation and airway hyperresponsiveness, whereas the absence of IL-17RB had a modest effect during acute allergic airway inflammation. IL-17RB expressing Th2 cells in the lung of allergic subjects increased substantially after repeated antigen re-challenges. IL-17RB+Th2 cells was further characterized as highly differentiated and more polarized Th2 cells that exhibit potent Th2 cell effector functions. Enforced over-expression of IL-25R on T cells exacerbated chronic allergic airway inflammation by enhancing Th2 cell effector functions. Notably, activation of mammalian target of rapamycin complex1 (mTORC1) in CD4+Th2 cells was identified as a key mediator for IL-25 mediated enhanced secretion of IL-5 and IL-13, which can be dose dependently inhibited by rapamycin. In summary, our data presented in this dissertation suggest that lung resident Ag-specific Th2 cells are the primary cell type responsible for mounting an allergic recall response and that the collaborative interactions between acquired Ag-specific CD4+Th2 cells and innate ILC2s as well as IL-25 mediated mTORC1 activation in Ag-specific CD4+Th2 cells contribute to the exacerbation of murine allergic airway disease with an eosinophilic phenotype.
Yui-Hsi Wang, Ph.D. (Committee Chair)
George Deepe, M.D. (Committee Member)
Fred Finkelman, M.D. (Committee Member)
David Hildeman, Ph.D. (Committee Member)
Timothy Lecras, Ph.D. (Committee Member)
Marc Rothenberg, M.D. Ph.D. (Committee Member)
164 p.
Immunology

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Citations

  • Liu, B. (2014). Regulation of Type 2 Immune Responses During Allergic Asthma [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406898945

    APA Style (7th edition)

  • Liu, Bo. Regulation of Type 2 Immune Responses During Allergic Asthma. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406898945.

    MLA Style (8th edition)

  • Liu, Bo. "Regulation of Type 2 Immune Responses During Allergic Asthma." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406898945

    Chicago Manual of Style (17th edition)

ucin1406898945
430
© 2014, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.