Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms.
While asthma is an inflammatory disorder of the airways usually associated with atopy, an important additional component is involvement of the epithelium and underlying mesenchyme acting as a trophic unit (EMTU). In addition to allergens, a wide range of environmental factors interact with the EMTU, such as virus infections, environmental tobacco smoke and pollutants, to initiate tissue damage and aberrant repair responses that are translated into remodelling of the airways. While candidate gene association studies have revealed polymorphic variants that influence asthmatic inflammation, positional cloning of previously unknown genes is identifying a high proportion of novel genes in the EMTU. Dipeptidyl peptidase (DPP) 10 and disintegrin and metalloproteinase (ADAM)33 are newly identified genes strongly associated with asthma that are preferentially expressed in the airway epithelium and underlying mesenchyme, respectively. Also of increasing importance is the recognition that genes associated with asthma and atopy have important interactions with the environment through epigenetic mechanisms that influence their expression. This type of research will not only identify biomarkers of different types of asthma across the full range of phenotypic expression, but will also identify novel therapeutic targets that could influence the natural history of the heterogenes lung disease.
Holgate
S T
ST
Allergy and Inflammation Research, Southampton General Hospital, Southampton SO16 6YD, UK. sth@soton.ac.uk
Davies
D E
DE
Powell
R M
RM
Howarth
P H
PH
Haitchi
H M
HM
Holloway
J W
JW
D051722:ADAM Proteins / Q000235:genetics; D000485:Allergens; D001249:Asthma / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics; D018450:Disease Progression; D004777:Environment; D004848:Epithelium / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation; D008954:Models, Biological; D008957:Models, Genetic; D012307:Risk Factors; D013997:Time Factors
D000485:Allergens; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D051722:ADAM Proteins; C450441:ADAM33 protein, human