Allergic Rhinitis: Overview, Clinical Disease States, Experimental Models

Allergic Rhinitis

OVERVIEW

The nose has five major functions, including (1) olfaction, (2) aiding speech, (3) airflow to the lungs, (4) humidifying and warming air, and (5) filtering potentially irri-tating particles from the air. Allergic reac-tions occurring in the nose can have severe effects on all levels of function, usually divided into primary and consequential, or secondary symptoms. Typical primary symptoms include nasal congestion, runny nose or rhinorrhea, as well as itchy palate and ears. Secondary symptoms include involvement of the middle ears, eustachian tubes, and sinuses, inducing symptoms such as headache, ear pain, and decreased hearing. Multiple central nervous system complaints may occur, including fatigue, irritability, anxiety, and even depression. As in other atopic diseases, the pathophys-iology of allergic rhinitis involves specific IgE production after exposure to airborne allergens. The clinical manifestations and underlying immunological mechanisms of the disorder will be discussed later.

CLINICAL DISEASE STATES

Allergic rhinitis is the most common allergic disease, affecting 25 percent of the population. It consists of two forms, sea-sonal and perennial. Seasonal allergic rhi-nitis is commonly referred to as “hay fever” or “rose fever” and is triggered by pollens with a typically well-defined season of ger-mination. Perennial allergic rhinitis has similar symptoms, yet involved substances are present year-round, including animal dander, dust mites, and mold. In both forms, allergens interact with mast cells or basal cells in the nasal mucosa. They are then presented by antigen-presenting cells such as dendritic cells and macrophages. CD4+ lymphocytes are stimulated by this presentation to release interleukins includ-ing IL-3, IL-4, IL-5, IL-13, and other cyto-kines that promote local and systemic IgE production by plasma cells. In addition, these cytokines lead to enhanced chemo-taxis, inflammatory cell recruitment, prolif-eration, activation, and prolonged immune cell survival in the airway mucosa.

Within minutes of allergen inhalation in sensitized individuals, IgE antibodies fixed to mast cells and basophils trigger release of acute preformed mediators such as histamine and tryptase in the early-phase response. Shortly afterward, de novo generation of mediators, including cysteinyl-leukotrienes (LTC4, LTD5, and LTE4) as well as prostaglandin D2 (PGD2) occurs. These substances cause a pro-nounced inflammatory response leading to the typical symptoms of paroxysmal sneezing, nasal pruritis and congestion, clear rhinorrhea, and palatal itching.

Over the next four to eight hours, the mediators released during the initial response set off a sequence of events, with enhanced inflammatory responses known as the late-phase response. In this phase, cytokines and various mediators released earlier promote the influx of other immune cells by enhancing expression of vascular cell adhesion molecules (VCAMs) that help traffic circulating eosinophils, neutrophils, and lymphocytes to the nasal endothelium. Although each of these cell types plays a role in the late response, eosinophils appear to be the main effector cell in allergic rhi-nitis. Nasal obstruction and secretions can lead to secondary effects, including ear and sinus infections, sleep apnea, and asthma exacerbations. Furthermore, the inflamma-tory cytokines may circulate to the central nervous system, eliciting malaise, irritabil-ity, and impaired concentration.

Treatment of allergic rhinitis involves environmental control for indoor aller-gens, reduction of swelling and congestion by nasal corticosteroids or oral leukotriene receptor antagonists, and relief of rhinor-rhea and nasal pruritis by oral or nasal antihistamines. Recalcitrant cases may require desensitization by immunotherapy (allergy shots).

EXPERIMENTAL MODELS

Recent research into the underlying immunological mechanisms of rhinitis has borne new insights into the patho-physiology of allergic rhinitis. Prior under-standing favored initial IgE production in regional lymph nodes or bone marrow. Failure of prior experiments to co-localize IgE protein within B cells to the local tis-sue environment weighed heavily against localized tissue IgE production. In the past ten years, however, a growing body of research has challenged the former dogma that IgE production occurred remotely from the allergen–tissue interface. Studies of local messenger RNA (mRNA) sup-port the hypothesis of local protein syn-thesis. Durham and colleagues, using a combination of in situ hybridization and immunohistochemistry, showed that cells expressing epsilon–heavy chain mRNA (Cε) were present in the nasal mucosa of allergic individuals, and marked increases of these cells occurred on exposure to aller-gen. Furthermore, the increases seen in IgE and Cε mRNA after allergen challenge were inhibited by topical corticosteroids, favoring a localized process. In addition, Kleinjan and colleagues used similar tech-niques to demonstrate finally IgE-produc-ing B cells in the nasal mucosa. Biopsies were obtained from normal subjects and from seasonal and perennial subjects dur-ing pollen season and during house dust exposure. The study found no differences in B-cell numbers, either CD19+ (B cells) or CD138+ (immunoglobulin-secreting plasma cells) in allergic and normal patients. Allergic patients, however, exhib-ited significantly greater numbers of IgE-positive B cells than normal patients, and allergen-positive cells were only found in allergics with almost all such cells staining positive for IgE or CD138. The combination of these factors suggests local IgE produc-tion may take place in the mucosa during natural allergen exposure.

Other models focus on the eosinophilic inflammation that characterizes allergic rhinitis as well as modulation of the allergic response. Hussain and col-leagues sensitized BALB/c mice using Ova intraperitoneally. Subsequent challenge with aerosolized Ova took place. Vari-ous outcomes, including nasal symptoms, nasal submucosal eosinophilia, and bone marrow eosinophilia, were measured. Afterward, a subset of mice received CpG oligodeoxynucleotides (ODNs), potent inducers of a TH1 nonallergenic response. Using enzyme-linked immunosorbent assay, cytokine levels were measured. Findings included elevated IL-4 and IL-5 and suppressed IFN-γ in Ova-sensitized mice compared with ODN-treated mice. In addition, the administration of ODNs abrogated nasal symptoms and upper air-way eosinophilia compared with controls. Collectively, these models elucidate the complex immunological basis of allergic rhinitis and demonstrate how manipula-tion of the immune response can be used clinically as a potential treatment.