Lessons from allergic rhinitis versus asthma pathogenesis and treatment

Allergy is an extremely common manifestation in humans, but the precise mechanism underlying allergic disease is uncertain. The traditional models for allergic rhinitis and asthma pathogenesis are similar, and both are based on the process of antigen processing and presentation and the subsequent development of a predominant T_H2 response in the airway tissues. There are several differences in this process for nasal versus bronchial airways, but one of the most striking new developments is the contribution of the innate immune system and the special programming of airway epithelial cells for antiviral defense and reprogramming of this system in asthma. Airway epithelial cells may be programmed abnormally for permanent proliferation and skewed mucus-cell differentiation by asthmagenic paramyxoviruses. This alteration in the process of epithelial repair exhibits genetic susceptibility and seems to be analogous to abnormal mucosal phenotypes in asthma and other hypersecretory diseases. These concepts can be integrated into a scheme that incorporates epithelial, viral, and allergic components (called an Epi-Vir-All paradigm) for a more complete explanation of the pathogenesis of airway disease. By extension, the same epithelial network is a target for therapy in airway disease and for improving host defense against respiratory viruses. Smart strategies have already been defined for reversing viral mimicry and engineering dominant-negative mutations that alter epithelial behavior, but full use of these approaches depends on the achievement of selective and high-level gene expression in the epithelium. This goal is dependent on determining the critical biology of the airway epithelium in antiviral defense and airway disease and on defining the contributions of specific viral and host genetic components. The extent to which the paradigm shift in asthma may extend to the pathogenesis of nasal airway disease needs to be defined. There are a number of systemic and topical drugs with significant efficacy in the treatment of allergic rhinitis, including the seasonal variety. Perhaps the greatest efficacy and safety has been shown with intranasal glucocorticoids, but patient and physician acceptance of these drugs is not solid. These agents are not effective for associated conjunctivitis and raise some concern for use in children. Recommendations for improvement for existing therapies include: (1) conversion of second-generation antihistamines to over-the-counter status; (2) development of antihistamines with greater anti-inflammatory and decongestant activities; (3) further evaluation of leukotriene antagonists alone and in combination with other agents, especially antihistamines; and (4) evaluation of the efficacy and safety of anti-IgE alone and in combination with other agents. Recommendations for research and development of new therapies include: (1) improving immunotherapy with recombinant or synthetic peptide allergens; (2) testing DNA vaccines with T_H1-stimulating capacity in models of allergic rhinitis and patients with allergic rhinitis; and (3) testing the efficacy of specific anti-inflammatory agents (eg, drugs directed against IL-4, IL-5, chemokines, chemokine receptors) in models of allergic rhinitis and asthma. Further definition of pathogenesis and drug action in models of allergic rhinitis is warranted. Comparison of these data with information on lower airway function would be useful, because an agent that affects both conditions would be valued highly.