Genetic and environmental influences on airway inflammation in asthma.
The clear recognition that asthma has an inflammatory basis has led to a search for genetic and environmental causes. Genetic linkage studies provide evidence for allelic association between polymorphic markers of interleukin-9 on chromosome 5 and a principal component of the allergic phenotype, log IgE. Further studies that intrauterine environmental factors are an important determinant of the allergic phenotype in addition to allergen exposure during the first year of life. Once sensitised, the respiratory mucosa provides the allergic interface between the environment and internal milieux involving autacoid and cytokine release from mast cells. Up-regulation of endothelial cell adhesion molecules, specifically E-selectin and ICAM-1, is responsible for the leucocyte recruitment of the late-phase asthmatic response, while recruitment of T cells and their subsequent activation contribute to the ongoing inflammatory response of asthma. The epithelium is the origin and target tissue for the inflammatory response, resulting in detachment of suprabasal cells, up-regulation of adhesion molecules and enhanced mediator and cytokine secretion. These latter findings, being more evident in severe chronic disease, suggest that the 'formed' airway elements are also important in mediating the ongoing inflammation characteristic of asthma.
Holgate
S T
ST
University Medicine, Southampton General Hospital, UK.
Church
M K
MK
Howarth
P H
PH
Morton
E N
EN
Frew
A J
AJ
Djukanović
R
R
D000485:Allergens / Q000009:adverse effects; D001249:Asthma / Q000196:embryology / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D012898:Autacoids / Q000378:metabolism; D001706:Biopsy; D001980:Bronchi / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid; D015815:Cell Adhesion Molecules / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin; D004781:Environmental Exposure; D008040:Genetic Linkage; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology*; D007223:Infant; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D016906:Interleukin-9 / Q000235:genetics; D008407:Mast Cells / Q000378:metabolism; D018448:Models, Immunological; D009092:Mucous Membrane / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000485:Allergens; D012898:Autacoids; D015815:Cell Adhesion Molecules; D016207:Cytokines; D019040:E-Selectin; D016906:Interleukin-9; D018799:Intercellular Adhesion Molecule-1; D007073:Immunoglobulin E