The allergic form of asthma is driven by an immune response to airborne allergens, and can be exacerbated by a number of factors including exposure to viruses. A typical signature of disease is the accumulation in the lungs of Th2 lymphocytes, eosinophils, mast cells, fibroblasts, and macrophages. Whereas the acute phase of asthma is characterized largely by rapid cell infiltration in the lungs, chronic asthma is characterized by progressive airway remodeling which includes epithelial cell mucus metaplasia, smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis, and increased angiogenesis. Fibrosis is due to deposition of extracellular matrix proteins such as collagen, fibronectin, tenascin, and laminin, thought produced largely from differentiating fibroblasts or epithelial cells, which can additionally be induced to express alpha smooth muscle actin and contribute to the enhanced smooth muscle mass. How all of these cell types are controlled is largely unknown. This proposal will focus on several members of the tumor necrosis factor (TNF) and TNF receptor superfamily, and test the hypotheses that OX40 (CD134) interacting with OX40L (CD252), and LIGHT (CD258) interacting with two receptors, HVEM (CD270) and LTBR (lymphotoxin beta receptor), are signatures of allergen-induced inflammation and remodeling in lungs of patients with varying severity of asthma;that these molecules will be further induced in the lungs of patients that are exposed to rhinovirus, a pathogen that has been associated with asthma exacerbations;and that they will be functionally relevant to the inflammatory and remodeling activities of bronchial epithelial cells, and lung macrophages, fibroblasts, and T cells. The treatment options for asthmatics are currently limited. Understanding when and where these TNF/TNFR family molecules are expressed, and the functional activities that result from their interactions, might lead to new and novel targets for therapeutic intervention in both acute and chronic asthma.

Public Health Relevance

LIGHT, OX40L, and their receptors are expressed on the surface of many immune and some non-immune cells, and are thought to regulate the ability to mount certain immune responses. There is little known about the expression and activities of these proteins in human asthma and in clinical specimens from asthmatics of varying severity. By understanding where and when LIGHT and OX40L and their partners are expressed, and the functional importance of these interactions, we will gain knowledge that might lead to ways to therapeutically suppress asthma and fibrotic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070535-08
Application #
8516970
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$457,267
Indirect Cost
$75,257
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Karta, Maya R; Rosenthal, Peter S; Beppu, Andrew et al. (2018) ?2 integrins rather than ?1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung. J Allergy Clin Immunol 141:329-338.e12
Mehta, A K; Doherty, T; Broide, D et al. (2018) Tumor necrosis factor family member LIGHT acts with IL-1? and TGF-? to promote airway remodeling during rhinovirus infection. Allergy 73:1415-1424
Doherty, Taylor A; Broide, David H (2018) Lipid regulation of group 2 innate lymphoid cell function: Moving beyond epithelial cytokines. J Allergy Clin Immunol 141:1587-1589
da Silva Antunes, Ricardo; Mehta, Amit K; Madge, Lisa et al. (2018) TNFSF14 (LIGHT) Exhibits Inflammatory Activities in Lung Fibroblasts Complementary to IL-13 and TGF-?. Front Immunol 9:576
Unno, Hirotoshi; Miller, Marina; Rosenthal, Peter et al. (2018) Activating transcription factor 6? (ATF6?) regulates airway hyperreactivity, smooth muscle proliferation, and contractility. J Allergy Clin Immunol 141:439-442.e4
Miller, Marina; Vuong, Christine; Garcia, Meghan Farrell et al. (2018) Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? J Allergy Clin Immunol 142:706-709.e4
Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Herro, Rana; Shui, Jr-Wen; Zahner, Sonja et al. (2018) LIGHT-HVEM signaling in keratinocytes controls development of dermatitis. J Exp Med 215:415-422
Chen, Jun; Miller, Marina; Unno, Hirotoshi et al. (2018) Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma. J Allergy Clin Immunol 142:207-218.e6
White, Andrew A; Doherty, Taylor A (2018) Role of group 2 innate lymphocytes in aspirin-exacerbated respiratory disease pathogenesis. Am J Rhinol Allergy 32:7-11

Showing the most recent 10 out of 106 publications