Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma

The prevalence and severity of allergic asthma continue to rise, lending ur gency to the search for environmental triggers and genetic substrates. Usin g microarray analysis of pulmonary gene expression and single nucleotide po lymorphism-based genotyping, combined with quantitative trait locus analysi s, we identified the gene encoding complement factor 5 (CS) as a susceptibi lity locus for allergen-induced airway hyperresponsiveness in a murine mode l of asthma. A deletion in the coding sequence of CS leads to C5-deficiency and susceptibility. Interleukin 12 (IL-12) is able to prevent or reverse e xperimental allergic asthma. Blockade of the C5a receptor rendered human mo nocytes unable to produce IL-12, mimicking blunted IL-12 production by macr ophages from C5-deficient mice and providing a mechanism for the regulation of susceptibility to asthma by C5. The role of complement in modulating su sceptibility to asthma highlights the importance of immunoregulatory events at the interface of innate and adaptive immunity in disease pathogenesis.