Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma.
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.
Karp
C L
CL
Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MA, USA. mkarp@wekh.jhu.edu
Grupe
A
A
Schadt
E
E
Ewart
S L
SL
Keane-Moore
M
M
Cuomo
P J
PJ
Köhl
J
J
Wahl
L
L
Kuperman
D
D
Germer
S
S
Aud
D
D
Peltz
G
G
Wills-Karp
M
M
D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003182:Complement C5 / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide
D003182:Complement C5; D018664:Interleukin-12