Asthma affects over 17 million people in the United States and is a major cause of morbidity. Recently a role for a non-classical HLA class I immune factor, HLA-G. in asthma has been proposed. HLA-G directly or indirectly acts to stimulate the presence and function of T suppressor cells and to down-regulate the activity of T helper 2 (Th2) cells that may be critical to asthma pathogenesis. Studies from our laboratories suggest that is HLA-G an asthma susceptibility gene, that several key single nucleotide polymorphisms (SNPs) correlate with the asthma phenotype, that the presence of HLA-G is increased in the airways of asthmatics, and that airway epithelial cells produce HLA-G. More recent observations from our AADCRC group suggest that HLA-G expression in airway epithelium is regulated by cytokines produced by Th2 cells and that a key receptor for HLA-G is found in airway smooth muscle;activating this receptor stimulates smooth muscle proliferation and differentiation. Thus, HLA-G may have a key role in altering the Immune and structural environment within airways. The overall objectives of this project are to demonstrate the presence of local, airway HLA-G in a longitudinal study of mild and severe asthma and to demonstrate mechanisms that regulate the local production of HLA-G by airway epithelial cells. We propose that HLA-G expressed locally in the lung and in the periphery may contribute to the asthma phenotype. We further propose that HLA-G genotype influences both circulating and airway abundance of HLA-G The increased abundance of HLA-G may lead, as we note in Project 2, to important changes in smooth muscle phenotype that over time worsens asthma. To address our hypotheses in this application, we propose three specific aims: 1) Examine HLA-G levels in asthma based on disease severity and phenotype. We hypothesize that both circulating and local airway HLA-G concentrations are greater in patients with asthma, that these concentrations depend in part on the regulation of HLA-G by a SNP in its 3'-untranslated region (+3142). 2) Determine the regulation of HLA-G expression by Th2 cytokines such as IL-13. We hypothesize that IL-13 increases the expression and secretion of HLA-G in airway epithelium, the principal source of HLA-G in the lung, and that over time this creates a positive feedback for continued airway inflammation. 3) Determine regulation of HLA-G in airway epithelium by miRNA. We hypothesize that the +3142 SNP variably binds microRNA that can suppress HLA-G expression, and that these microRNA are produced by airway epithelial cells. Together, these studies will provide a clear understanding of the role of HLA-G in asthma and its regulation by Th2-associated cytokines and by microRNA, and thus set the stage for the development of novel new therapies.
These studies will provide new insights into the regulation of HLA-G expression in asthma, explore how it relates to asthma severity, and thus suggest new therapeutic strategies based on its expression.
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