Allergic Asthma: Overview, Immunology, Experimental Models

Allergic Asthma

OVERVIEW

The human lung provides the fundamental function of gas exchange. As the terminal level of the respiratory tract after the nasal cavity and pharynx, it is constantly exposed to airborne particulate matter. Allergic asthma is the manifestation of a pul-monary immune response to various inhaled substances.Clinically,thecardinalsymptoms include (1) generalized but reversible air-way obstruction, (2) wheeze, (3) dyspnea, and (4) cough. Symptoms can range from mild to life threatening. Typical allergens include house dust mite, pollen, cockroach epithelium, animal dander, and fungi.

As in allergic rhinitis, recent advances in understanding the immunology of asthma have important therapeutic value, and immune manipulation will likely become an important modality in the treatment of asthma.

Immunology of Asthma

From a histopathological standpoint, the inflammation in allergic asthma involves the entire thickness of the airway. Findings include generalized edema, denudation of the epithelium, subbasement mem-brane thickening, and smooth muscle and mucous gland hypertrophy. This process begins when dendritic cells, a subset of antigen-presenting cells found in the lung tissue, process inhaled antigens and pres-ent them to T lymphocytes through the interaction of the receptor molecule CD28 on T cells and its ligand CD80 (B7.1) on dendritic cells. This interaction results in T lymphocyte development down the TH2 pathway. TH2 lymphocytes are char-acterized by release of a family of pro-inflammatory cytokines, including IL-3, IL-4, IL-5, IL-13, tumor necrosis factor-α (TNF-α), and granulocyte-macrophage colony-stimulating factor. These cytokines promote development, activation, and sur-vival of eosinophils. In addition, IL-4, IL-5, IL-13, and TNF-α activate endothelial cell adhesion proteins, ICAM-1 and VCAM-1, which assist inflammatory cell movement from blood vessels into the airway. IL-4 and IL-13 are key stimuli of B cells for antigen-specific IgE production, which initiates the allergic cascade. As a whole, these complex immunological processes lead to the pathologic processes that char-acterize asthma.

Treatment is multifactorial. Environ-mental measures to eliminate allergen

exposure should always be attempted. Inhaled corticosteroids (ICS) remain the mainstay of medical treatment as they down-regulate multiple inflammatory reactions in the lungs. Other adjuncts such as leukotriene receptor antagonists modify significant mediators of allergic inflamma-tion present in asthmatic airways. Newer treatments include monoclonal antibod-ies directed against IgE (anti-IgE therapy), which have shown some success in decreasing asthma symptoms and the need for oral or inhaled corticosteroids.

Experimental Models

Although our understanding of the pathogenesis of allergic asthma is incom-plete, animal models have been of great utility in elucidating the mechanisms of this disease.

A major topic of current research has revolved around airway changes in the chronic asthmatic. This process, known as remodeling, is believed to result in irreversible changes in the lung. McMillan and Lloyd induced acute pulmonary eosinophilia and bronchial hyperreactivity in mice using multiple allergen challenges. They subsequently induced a chronic phase in a subset of mice using Ova chal-lenge. Evaluation at one month after Ova challenge showed significant changes in the Ova-challenged mice. Compared with the acutely challenged mice, the Ova group showed deposition of collagen as well as airway smooth muscle and goblet cell hyperplasia. Cytokine profiles in the chronic phase revealed increases of IL-4, transforming growth factor beta 1 (TGF-β1), and IFN-γ . These findings strongly support the concept of airway remodeling and reveal a dual TH1 and TH2 cytokine profile in the chronic phase of asthma.

Another important focus of asthma research centers on so-called inner-city asthma, an increasing epidemic in devel-oped countries. Many epidemiological studies have shown disproportional rates of asthma in urban, lower socioeconomi-cally stratified patients. Although many socioeconomic factors are thought to play a role, distinct allergic triggers specific to these environments appear to be impor-tant. Using recombinant proteins, Sarpong, Zhang, and Kleeberger (2004) evaluated two such allergens, cockroach (Bla g 2) and dust mite (Der f 1), in inbred mouse strain (A/J). Mice were immunized with Bla g 2 and Der f 1 or a combination on days 0 and 7 and were inhalant challenged on day 14. Airway hyperreactivity and airway cellular content were subsequently studied. Findings included dose-related statistically significant increases in airway reactivity and inflammatory and epithe-lial cell measurements. Compared with individual antigens, however, enhanced inflammatory cell levels and epithelial cell numbers, but not airway reactivity, were noted in the combined group. This model, which has been subsequently validated, has practical implications for preventing asthma.