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World Allergy Organization
WAO's mission: To be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies.

Pathophysiology of Allergic Upper Airway Disease

Robert Naclerio
Professor and Chief of Otolaryngology-Head and Neck Surgery
University of Chicago


The mucous membranes of the upper airway are covered by a pseudostratified, columnar epithelium with a continuous basement membrane. They contain a sub-epithelial capillary system, tubuloalveolar, seromucous glands, and goblet cells, parasympathetic and sympathetic innervation, and immunohistochemical evidence of a non-adrenergic, non-cholinergic nervous system. In allergic individuals, allergen stimulation leads to a series of biochemical and cellular events that translate into clinical symptoms.

IgE Response
After repeated low dose exposure to allergens, atopic individuals develop specific IgE antibodies to these allergens. Subsequent exposure initiates a secondary humoral response. The latter has been shown to occur following seasonal exposure and after nasal challenge.

Early Response
Within minutes after exposure of an allergic subject to antigen, an immediate (early) response follows. In the upper airway, the allergic individual begins to sneeze, which is followed closely by an increase in nasal secretions. After about 5 minutes mucosal swelling begins, leading to reduced airflow. These physiologic changes are associated with increases in histamine, leukotrienes, prostaglandins, tryptase and other pro-inflammatory mediators.

Late Response
Besides the immediate response to antigen, there is another response hours later. The late response does not occur in every subject. It appears dose dependent; i.e., the greater the dose of antigen the more likely a late response can be observed. The late response is primarily manifested as airflow obstruction. The physiologic changes are accompanied by mediator release, the pattern, however, differs from the early response. In contrast to the early response to nasal challenge with antigen, the late response is reduced by oral glucocorticosteroids. Since oral steroids are effective in reducing allergic symptoms and do not affect the early response, investigators studied the late response to better understand the pathophysiology of allergic inflammation.

Cellular Infiltration
Eosinophilia has long been associated with allergic diseases. Eosinophils can effect the allergic response by releasing cytotoxic proteins (e.g. major basic protein), lipid mediators (e.g. leukotriene C4), oxygen radicals and cytokines (e.g. IL 3).

Hours after antigen challenge the number of eosinophils and basophils increase in nasal secretions. These recruited cells release mediators. In the submucosa, eosinophils also increase, but the increase in the number of lymphocytes, particularly TH2 cells, is much greater.

The lymphocytes release cytokines, proteins that amplify and regulate local immune responses. For example, IL 4 released mainly by TH2 lymphocytes supports B cell growth and differentiation, increased expression of VCAM (vascular cell adhesion molecule) on endothelial cells, induces uncommitted T cells toward the TH2 phenotype and promotes switching to IgE antibody formation. Other cytokines support eosinophil growth and prevent apoptosis (programmed cell death). The importance of individual cytokines is speculative at this date since cytokines have overlapping function and multiple activities.

Chemokines, chemotactic cytokines, attract and activate lymphocytes, granulocytes and monocytes. They are 7 to 16 kDa proteins with 4 conserved cysteine residues. The CC chemokines, located on chromosome 7q11-q21, contain several eosinophil selective chemoattractants, including RANTES, MCP-1, MCP-3 and eotaxin. While the number of chemokines is great, many activate eosinophils through a shared receptor, CKR-3.

Accumulating evidence supports the importance of leukocyte and vascular endothelial cell adhesion molecules in the migration of inflammatory cells, including eosinophils, into tissue sites during allergic reactions. This involves a sequence of events, which includes margination of leukocytes along the walls of the microvasculature, adhesion to the endothelium, transmigration through the vessel walls and migration along a chemotactic gradient within the extracellular matrix proteins. Adhesion molecules such as integrins, selectins, and members of the immunoglobulin gene super-family mediate these events.

Changes in Responsiveness
One result of the cellular influx following antigen stimulation and the release of pro-inflammatory mediators is changes in responsiveness of the upper airway to other stimuli. The change can be specific (increased responsiveness to the same antigen) or non-specific (increased reactivity to irritants).

Increased responsiveness to antigen, priming, occurs following provocation as well as during seasonal exposure. The increased sensitivity to antigen following a prior antigen challenge is related to inflammation, but is not obligatorily linked to it; i.e., inflammation can occur in the absence of priming. Systemic steroids can effectively suppress the clinical, biochemical and cellular manifestations of antigen-induced hyper-responsiveness.

In allergic individuals, seasonal exposure to pollen can increase methacholine responsiveness in the lower airway. Treatment of the upper airway with topical steroids prevents the shift in reactivity. The mechanisms for these observations are unknown, but they point to the interactions of the upper and lower airway when assessing the response to antigen stimulation.

Microenvironment
Environmental particles greater than 5 microns are almost 100% filtered by the nose. The filtration of the air by the nose probably contributes to the baseline composition of the extracellular lining fluid.

In a series of studies, allergic individuals were exposed to different environmental conditions of temperature and humidity , which affected the response to nasal challenge with antigen. Whereas little difference could be detected in the early response to allergen challenges in room air (22° C, 30% RH) and cold, dry environment (4° C, <10% RH), patients in a warm, humid environment (37° C, > 90% RH) responded with significantly less nasal congestion, less increase in nasal airway resistance and less increase in vascular permeability. It also significantly reduced histamine release, sneezing and pruritus. There was no effect on the glandular response. In contrast to the reduction in the early response, the eosinophilic response during the late reaction was greatly augmented during inhalation of hot, humid air. These studies point to potential effects of the microenvironment on the allergic response.

Epithelium
The epithelium, like the skin, has long been considered a barrier between the external environment and the inside of the body. In addition to being a barrier, the epithelium can participate in inflammation. The epithelium can present antigen and produce cytokines such as GM-CSF, IL 6 and IL 8. These cytokines can recruit neutrophils and prolong eosinophil survival. Inducible NO synthethase has also been found in epithelial cells as well as vascular endothelial cells, smooth muscle cells and submucosal glands. NO can contribute to vasodilatation and bacteriostasis.

Nervous System
The neuronal pathways potentially involved in allergic rhinitis include the sympathetic, parasympathetic and peripheral sensory nerves. The presence of sympathetic and parasympathetic nerves and their transmitters in the nasal cavities has been known for decades. Recent evidence has established the presence of neuropeptides in the nasal mucosa. Animal studies highlight the importance of these peptides as well as the enzymes involved in their degradation. Their physiologic role in humans, like that of other mediators, however, remains to be established.

Unlike neuropeptides, the presence of central reflex responses involving the parasympathetic nervous system is firmly established. With respect to unilateral antigen provocation, atropine-sensitive changes in secretions have been routinely seen, whereas changes in airway resistance and albumin have been variably reported. Histamine, which is released only at the site of nasal challenge during the early reaction, increases both at the site of challenge and in the opposite nostril during the late reaction. Also, basophils, the source of histamine during the late response, increase on both the side of challenge and in the opposite nostril.

In sum, this brief review highlights some of the events that occur after antigen stimulation of the upper airway of allergic individuals. The consequence of those responses causes clinical manifestations, though which mediator causes which physiologic change is unknown. Studies of the pathophysiology of other forms of nonallergic rhinitis, such as pollution-induced, will be the task for the future.

A Test of This Pathophysiologic Model of Allergic Rhinitis

Allergic individuals challenged with an appropriate allergen in the laboratory react within minutes with an early response characterized by mast cell degranulation, histamine release, and typical symptoms of sneezing, rhinorrhea, and congestion. This early response is followed hours later by a cellular influx including eosinophils and an increase in nasal reactivity to further antigen exposure, called priming. The late response, with congestion as the primary symptom, is less dramatic than the early reaction. Although histamine is increased during the late reaction, its role is not clearly defined. Antihistamines have not been shown to reduce eosinophil influx into the nasal mucosa, to block priming, or to reduce symptoms of the late reaction. In contrast, intranasal corticosteroids have profound inhibitory effects on the late response.

We reasoned that those allergic individuals who use medications as needed would treat themselves after sensing an early reaction. Taking an antihistamine at this point in time would not affect the symptoms of the immediate response, because the symptoms dissipate within minutes and do not affect the late response. In essence, the antihistamine would be effective against the sneezing and rhinorrhea associated with the next immediate response to antigen exposure, provided the drug is present at therapeutic levels at that time. The effectiveness of antihistamines when given prior to a nasal challenge with antigen has been shown repeatedly. The antihistamine, however, would not prevent allergic inflammation and priming from developing. Thus, as the season progressed, the immediate symptoms in response to further antigen exposure would increase.

Taking an intranasal steroid after sensing the symptoms of an immediate response would be expected to block eosinophil infiltration and priming, as Anderson and colleagues demonstrated in the laboratory. The intranasal steroid would also be expected to reduce any contribution of the symptoms of the late reaction to clinical disease, such as the congestion that occurs upon return to an air-conditioned home after working in the garden. We also speculated that, as the season progresses, priming would not occur, and the symptoms experienced by patients upon repeated pollen exposure would be less severe and last for a shorter interval as the pollen counts dissipated. Therefore, we hypothesized that the as-needed use of intranasal corticosteroids would reduce allergic inflammation and provide superior symptom relief compared to the as-needed use of an antihistamine.

As a first step toward testing the above, we performed a parallel, placebo-controlled, randomized study to test whether symptoms of patients with seasonal allergic rhinitis are reduced by treatment with as-needed intranasal corticosteroids versus placebo. The results of that study showed that the as-needed use of an intranasal steroid (fluticasone) was superior to placebo in reducing eosinophil infiltration and symptoms while improving the quality of life during the ragweed allergy season. The next step toward testing our hypothesis was to compare the as-needed use of H1 antihistamines versus the as-needed use of intranasal corticosteroids. The as-needed use of intranasal steroid provided superior results to the as-needed use of H1 antihistamine. These studies validate the model of pathophysiology presented above.

Slide presentation

 

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