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

Abstract

The prevalence and severity of allergic asthma continue to rise, lending urgency to the search for environmental triggers and genetic substrates. Using microarray analysis of pulmonary gene expression and single nucleotide polymorphism–based genotyping, combined with quantitative trait locus analysis, we identified the gene encoding complement factor 5 (C5) as a susceptibility locus for allergen-induced airway hyperresponsiveness in a murine model of asthma. A deletion in the coding sequence of C5 leads to C5-deficiency and susceptibility. Interleukin 12 (IL-12) is able to prevent or reverse experimental allergic asthma. Blockade of the C5a receptor rendered human monocytes unable to produce IL-12, mimicking blunted IL-12 production by macrophages from C5-deficient mice and providing a mechanism for the regulation of susceptibility to asthma by C5. The role of complement in modulating susceptibility to asthma highlights the importance of immunoregulatory events at the interface of innate and adaptive immunity in disease pathogenesis.

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Figure 1: C5 gene expression and genotype correlate with allergen-induced AHR.
Figure 2: C5 allele correlates with allergen-induced AHR across inbred strains.
Figure 3: Effects of C5aR blockade on cytokine production by primary human monocytes.
Figure 4: C5aR signaling and C5aR blockade have mechanistically distinct effects on IL-12 production: serum dependence and pertussis toxin sensitivity of signaling.
Figure 5: IL-12 production by macrophages from A/J and C3H/HeJ mice.

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Acknowledgements

Supported in part by NIH grants AI40507, DE12167 (C.L.K.); ES09606, HL58527 (M.W.-K.); and RR00097 (S.L.E.). BMBF grant 01VM9305 (J.K.); a Michigan State University All-University Research Initiation Grant (S.L.E.); and EPA grant R826724 (M.W.-K.). The authors thank M. Shin for the gift of K-76.

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Correspondence to Marsha Wills-Karp.

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Karp, C., Grupe, A., Schadt, E. et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 1, 221–226 (2000). https://doi.org/10.1038/79759

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