Genetic variation in HLA-G that regulates HLA-G protein production influences asthma risk, and coding variations in HLA-G receptor genes {LILRBI and LILRB2 and their family member LILRB4) also confer risk for bronchial hyperresponsiveness and/or asthma. While these findings imply that HLA-G - LILRB signaling participates in asthma pathogenesis, they do not reveal the operative mechanisms. HLA-G can modulate immune function, and independently alters airway smooth muscle (ASM) phenotype, raising the possibility that genetic alteration of HLA-G abundance or of LILRB signaling confers asthma risk by affecting the immune system, by modulating effector organ (ASM) function, or both. The major objective of this project is to discern how HLA-G - LILRB signaling participates in asthma pathogenesis. We recently found that HLA-G is secreted from bronchial epithelium, that its abundance in BAL fluid is increased in asthma, and that BAL HLA-G concentration increases with asthma severity (see Project 1). Others have demonstrated that the immune phenotype of lung CD4 T cells reflects predominantly Th17 skewing in severe asthmatics, while more Th2 skewing is found in less severe asthmatics. We hypothesize that prevailing HLA-G abundance modulates immune activation state or alters immunological responses, with higher levels of HLA-G promoting the severe asthmatic immune phenotypes. We have recently associated genetic variations in LILRBI, LILRB2, and LILRB4 with asthma risk. Since HLA-G exerts its effects through LILRB receptors, any functional consequences of LILRB gene variations could modulate the influence of HLA-G on the immune system. Our preliminary data also demonstrate that HLA-G - LILRB signaling modulates ASM function. It is thus also conceivable that functional variation in LILRB receptors modulates asthma severity by influencing the ability of HLA-G to induce asthma-like ASM dysfunction. The goals of Project 2 are therefore to: 1) determine whether and how HLA-G affects immune responses;2) determine the effect of LILBR genotype on immune modulation by HLA-G;and 3) determine the effect of LILBR genotype on HLA-G signaling to airway smooth muscle. We will exploit naturally occurring genetic variation in HLA-G receptors to dissect these possible mechanisms of action. This project relies heavily on biospecimens obtained from human asthmatic volunteers through Core B, and synergistically complements Projects 1 and 3, in which the regulation of HLA-G expression and epigenetic correlates of asthma are determined in the same subjects studied here.

Public Health Relevance

These studies should provide important new insight into how HLA-G - LILRB signaling contributes to the pathogenesis of asthma, and so may suggest new therapeutic strategies based on manipulation of this pathway.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-PA-I)
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University of Chicago
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Denner, Darcy R; Sangwan, Naseer; Becker, Julia B et al. (2016) Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways. J Allergy Clin Immunol 137:1398-1405.e3
Press, Valerie G; Arora, Vineet M; Trela, Kristin C et al. (2016) Effectiveness of Interventions to Teach Metered-Dose and Diskus Inhaler Techniques. A Randomized Trial. Ann Am Thorac Soc 13:816-24
Kessler, Michael D; Yerges-Armstrong, Laura; Taub, Margaret A et al. (2016) Challenges and disparities in the application of personalized genomic medicine to populations with African ancestry. Nat Commun 7:12521
Nicodemus-Johnson, Jessie; Myers, Rachel A; Sakabe, Noburu J et al. (2016) DNA methylation in lung cells is associated with asthma endotypes and genetic risk. JCI Insight 1:e90151
Mathias, Rasika Ann; Taub, Margaret A; Gignoux, Christopher R et al. (2016) A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun 7:12522
Bønnelykke, Klaus; Ober, Carole (2016) Leveraging gene-environment interactions and endotypes for asthma gene discovery. J Allergy Clin Immunol 137:667-79
Ober, Carole (2016) Asthma Genetics in the Post-GWAS Era. Ann Am Thorac Soc 13 Suppl 1:S85-90
Stein, Michelle M; Hrusch, Cara L; Gozdz, Justyna et al. (2016) Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. N Engl J Med 375:411-21
Stevens, Whitney W; Grammer 3rd, Leslie C (2015) Occupational rhinitis: an update. Curr Allergy Asthma Rep 15:487
Kim, Kyung Won; Myers, Rachel A; Lee, Ji Hyun et al. (2015) Genome-wide association study of recalcitrant atopic dermatitis in Korean children. J Allergy Clin Immunol 136:678-684.e4

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