Pathogenic mechanisms of allergic inflammation: atopic asthma as a paradigm.
Prospective studies tracking birth cohorts over periods of years indicate that the seeds for atopic asthma in adulthood are sewn during early life. The key events involve programming of functional phenotypes within the immune and respiratory systems which determine long-term responsiveness to ubiquitous environmental stimuli, particularly respiratory viruses and aeroallergens. A crucial component of asthma pathogenesis is early sensitization to aeroallergens stemming from a failure of mucosal tolerance mechanisms during the preschool years, which is associated with delayed postnatal maturation of a range of adaptive and innate immune functions. These maturational defects also increase risk for severe respiratory infections, and the combination of sensitization and infections maximizes risk for early development of the persistent asthma phenotype. Interactions between immunoinflammatory pathways stimulated by these agents also sustain the disease in later life as major triggers of asthma exacerbations. Recent studies on the nature of these interactions suggest the operation of an infection-associated lung:bone marrow axis involving upregulation of FcERlalpha on myeloid precursor populations prior to their migration to the airways, thus amplifying local inflammation via IgE-mediated recruitment of bystander atopic effector mechanisms. The key participants in the disease process are airway mucosal dendritic cells and adjacent epithelial cells, and transiting CD4(+) effector and regulatory T-cell populations, and increasingly detailed characterization of their roles at different stages of pathogenesis is opening up novel possibilities for therapeutic control of asthma. Of particular interest is the application of genomics-based approaches to drug target identification in cell populations of interest, exemplified by recent findings discussed below relating to the gene network(s) triggered by activation of Th2-memory cells from atopics.
Holt
Patrick G
PG
Faculty of Medicine and Dentistry, Telethon Institute for Child Health Research and Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
Strickland
Deborah H
DH
Bosco
Anthony
A
Jahnsen
Frode L
FL
D000818:Animals; D018926:Anti-Allergic Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D018926:Anti-Allergic Agents