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. ? ?
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