Severe asthma is a significant health care concern with patients having poorer asthma control, frequent asthma attacks, and increased heath care costs compared to milder asthma phenotypes. Boys have an increased prevalence of severe asthma compared to girls. This increased prevalence of severe asthma switches from boys to women around puberty, suggesting a role for sex hormones. However, it remains unknown how gender and ovarian hormones affect severe asthma pathogenesis. IL-17A, a cytokine secreted by CD4+ T cells and ?? T cells, is increased in the bronchoalveolar lavage fluid of patients with severe asthma compared to milder asthma phenotypes. IL-17A is also associated with increased airway inflammation, airway responsiveness (AR), and mucus production. Our preliminary data show increased IL-17A protein expression in Th17 differentiated cells from women compared to men. We also show 17?-estradiol (E2) and progesterone (P4) administration in ovariectomized female mice increased Th17 differentiated cell expression of IL-17A. We hypothesize that female gender, via ovarian hormones, increases Th17 cell differentiation and IL-17A secretion from Th17 cells and ?? T cells. We further hypothesize that in vivo 17?-E2 and P4 administration increases Th17-mediated airway inflammation, AR, and mucus production in mice.
In Aim 1, we will differentiate Th17 cells from healthy women and men and determine the role of gender in Let-7f regulation of IL-23 receptor (R) and IL-17A protein expression on Th17 differentiating cells.
In Aim 2, memory T cells will be isolated to determine if women with severe asthma have increased IL-17A secreting memory CD4+ T cells compared to men with severe asthma.
In Aim 3, we will delineate the mechanisms by which in vivo administration of 17?-E2 and P4 increases IL-17A-mediated airway inflammation in mice. Our results will be the first to determine the role of gender and ovarian hormones on IL-17A-mediated airway inflammation in severe asthma. Our findings may also be helpful in designing future clinical trials by determining if women and men with severe asthma have differential IL-17A production and responses to therapeutics in clinical trials for moderate to severe asthma.

Public Health Relevance

We will determine how gender, estrogen, and progesterone affect protein secretion from immune cells, CD4+ Th17 cells and gamma delta T cells, associated with airway inflammation in severe asthma. Our research will provide critical mechanistic data which may aid in developing personalized treatments for patients with severe asthma, in particular women.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122554-06
Application #
9613262
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Noel, Patricia
Project Start
2014-12-22
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Fuseini, Hubaida; Yung, Jeffrey A; Cephus, Jacqueline Yvonne et al. (2018) Testosterone Decreases House Dust Mite-Induced Type 2 and IL-17A-Mediated Airway Inflammation. J Immunol 201:1843-1854
Yung, Jeffrey A; Fuseini, Hubaida; Newcomb, Dawn C (2018) Hormones, sex, and asthma. Ann Allergy Asthma Immunol 120:488-494
Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D et al. (2018) PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-?1 production. Sci Transl Med 10:
Stier, Matthew T; Goleniewska, Kasia; Cephus, Jacqueline Y et al. (2017) STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection. J Immunol 199:510-519
Fuseini, Hubaida; Newcomb, Dawn C (2017) Mechanisms Driving Gender Differences in Asthma. Curr Allergy Asthma Rep 17:19
Cephus, Jacqueline-Yvonne; Stier, Matthew T; Fuseini, Hubaida et al. (2017) Testosterone Attenuates Group 2 Innate Lymphoid Cell-Mediated Airway Inflammation. Cell Rep 21:2487-2499
Banathy, Alex; Cheung-Flynn, Joyce; Goleniewska, Kasia et al. (2016) Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of ?2-Adrenergic Receptor. Am J Respir Cell Mol Biol 55:225-33
Toki, Shinji; Goleniewska, Kasia; Reiss, Sara et al. (2016) The histone deacetylase inhibitor trichostatin A suppresses murine innate allergic inflammation by blocking group 2 innate lymphoid cell (ILC2) activation. Thorax 71:633-45
Stier, Matthew T; Bloodworth, Melissa H; Toki, Shinji et al. (2016) Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. J Allergy Clin Immunol 138:814-824.e11
Zhou, Weisong; Zhang, Jian; Goleniewska, Kasia et al. (2016) Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation. J Immunol 197:1577-86

Showing the most recent 10 out of 13 publications