Asthma is a complex inflammatory condition that afflicts 10-15 million people in the US alone. Asthma and its related phenotypes (airway hyperresponsiveness (AHR) and airway inflammation) have a heritable component. Despite this recognition, the genetic mechanisms underlying susceptibility to asthma remain unknown. Identification of susceptibility genes for human asthma has been hampered by variability in clinical phenotype, genetic heterogeneity in human populations and the difficulty in addressing the molecular mechanisms underlying complex processes in humans. To identify asthma genes we have taken advantage of the genetic and experimental tractability of inbred murine models of asthma to provide asthma candidate genes. Using classic genetic analyses and gene profiling, we have identified complement factor 5 (C5) as a strong candidate gene for one of two distinct linkage regions (Abrhl and Abhr2) identified for AHR. We provide evidence that an allelic variant in the C5 locus is closely associated with AHR in this model. Further we show that transfer of these two linkage regions onto the resistant background confers susceptibility. Mechanistically, our preliminary data suggest the novel hypothesis that C5 regulates the type and function of dendritic cells presenting antigen to T cells. Specifically in mice carrying the wildtype allele, antigen is predominantly taken up by tolerogenic plasmacytoid dendritic cells (pDC) expressing high levels of inhibitory molecules (i.e. B7-H1 and B7-DC) on their surface. On the other hand, expression of the variant allele results in uptake of antigen predominantly by myeloid dendritic cells relatively lacking in inhibitory receptor expression. Further, we show that blockade of these inhibitory receptors (B7-H1 and B7-DC) on dendritic cells enhances Th2 cytokine production. Thus, we plan to critically test the novel hypothesis that variants in the C5 gene contribute to susceptibility to AHR through altering dendritic cell phenotype and function.
The specific aims are: 1) To further explore the relationship between C5 genotype, and allergen-induced AHR in mouse strains that carry functionally different alleles at the C5 locus and examine the effect of C5aR blockade on the allergic phenotype in resistant C3H mice; 2) To determine the effects of C5 genotype on the numerical and functional characteristics of dendritic cell subsets in the lung and their relationship to susceptibility to allergen-induced AHR in our mouse model; and 3) To examine the effects of C5 driven alterations in DC subset phenotype on antigen specific CD4+ T cell responses (proliferation, phenotype, cytokine generation) and subsequent susceptibility to AHR. The results of these studies will provide considerable insight into the factors regulating the development of immunogenic responses to inert inhaled antigens in genetically susceptible individuals and may lead to the development of novel therapeutic interventions for the treatment of this debilitating condition. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL067736-06
Application #
7029494
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2000-09-30
Project End
2010-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
6
Fiscal Year
2006
Total Cost
$374,271
Indirect Cost
Name
Children's Hospital Med Ctr (Cincinnati)
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
McAlees, Jaclyn W; Lajoie, Stephane; Dienger, Krista et al. (2015) Differential control of CD4(+) T-cell subsets by the PD-1/PD-L1 axis in a mouse model of allergic asthma. Eur J Immunol 45:1019-29
Lajoie, S; Lewkowich, I; Herman, N S et al. (2014) IL-21 receptor signalling partially mediates Th2-mediated allergic airway responses. Clin Exp Allergy 44:976-85
Lewkowich, I P; Lajoie, S; Stoffers, S L et al. (2013) PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production. Mucosal Immunol 6:728-39
Wills-Karp, Marsha; Rani, Reena; Dienger, Krista et al. (2012) Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med 209:607-22
Wang, Yui-Hsi; Wills-Karp, Marsha (2011) The potential role of interleukin-17 in severe asthma. Curr Allergy Asthma Rep 11:388-94
Schauberger, Eric M; Ewart, Susan L; Arshad, Syed H et al. (2011) Identification of ATPAF1 as a novel candidate gene for asthma in children. J Allergy Clin Immunol 128:753-760.e11
Chen, Gang; Wan, Huajing; Luo, Fengming et al. (2010) Foxa2 programs Th2 cell-mediated innate immunity in the developing lung. J Immunol 184:6133-41
Lajoie, Stephane; Lewkowich, Ian P; Suzuki, Yusuke et al. (2010) Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol 11:928-35
Wills-Karp, M; Nathan, A; Page, K et al. (2010) New insights into innate immune mechanisms underlying allergenicity. Mucosal Immunol 3:104-10
Page, Kristen; Ledford, John R; Zhou, Ping et al. (2010) Mucosal sensitization to German cockroach involves protease-activated receptor-2. Respir Res 11:62

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