MECHANISMS OF UPPER AIRWAY ALLERGIC REACTIONS

Upon exposure to an allergen, atopic individuals respond by producing allergen-

specific IgE. These IgE antibodies bind to IgE receptors on mast cells in the respiratory mucosa
and to basophils in the peripheral blood. When the same allergen is subsequently inhaled, the IgE
antibodies are bridged on the cell surface by allergen, resulting in activation of the cell. Mast
cells in the nasal tissues release preformed and granule-associated chemical mediators, which
cause the symptoms of allergic rhinitis.

Immunogenetics The expression of allergic diseases of the upper airways reflects an

autosomal dominant pattern of inheritance with incomplete penetrance. This inheritance pattern
is manifested as a propensity to respond to inhalant allergen exposure by producing high levels
of allergen specific immunoglobulin E (IgE). The IgE response appears to be controlled by
immune response genes located within the major histocompatibility complex (MHC) on
chromosome 6.

The immunologic mechanisms of atopy have been studied in murine models and in humans.
These mechanisms involve the expression of a repertoire of responses associated with the Th2
type of T-helper lymphocyte. There are probably multiple genetic and environmental influences
that lead to overexpression of Th2 type T cell responses relative to Th1 responses.

Th2 lymphocytes and IgE production Sensitization to allergen is necessary to elicit an IgE
response. After inhalation, the allergen must first be internalized by antigen presenting cells,
which include macrophages, CD1+ dendritic cells, B-lymphocytes, and possibly epithelial cells.
After allergen processing, peptide fragments of the allergen are exteriorized and presented with
class II (MHC) molecules of host antigen presenting cells to CD4+ T lymphocytes.

Nasal provocation with allergen has been associated with increases of such HLA-DR and HLA-
DQ positive cells in the lamina propria and epithelium in allergic subjects. These lymphocytes
have receptors specific for the particular MHC peptide complex and this interaction results in the
release of cytokines by the CD4+ cell.

The switch from the Th1 phenotype to the Th2 phenotype is the crucial early event in allergic
sensitization and is key to the development of allergic inflammation. Allergic inflammation
conceptually derives from two major Th2 mediated pathways:

One involves the secretion of interleukin-4 (IL-4) and IL-13 that results in isotypic
switching of B-lymphocytes to secrete IgE.
The second pathway involves the secretion of the eosinophil growth factor, IL-5.

Thus, the release of IL-4, IL-5, and IL-13 are cardinal features of allergic inflammation.
B-lymphocytes require two signals for isotypic switch to IgE. In the first signal, IL-4 or IL-13
stimulate transcription at the Ce locus, the site of exons that encode the constant region of the
IgE heavy chain. Interaction of CD40 on the B cell membrane with CD40 ligand on the surface
of T lymphocytes provides the second signal that activates genetic recombination in the
functional IgE heavy chain. IL-4 and IL-13 also up-regulate vascular cell adhesion molecule-1
(VCAM-1) on endothelial cells promoting adhesion of inflammatory cell populations and
facilitate their migration into areas of allergic inflammation.

In situ hybridization and/or antibody studies have demonstrated increased numbers of cells with
messenger RNA for and/or expression of IL-3, IL-4, IL-5, IL-13, eotaxin, and GM-CSF within
the nasal mucosa after allergen provocation. Interferon-gamma (IFN-gamma), a Th1 type
cytokine that inhibits B-lymphocyte activation and IgE synthesis is absent. Il-12 and IL-18,
major inducers of IFN-gamma, are also absent.

Thus, atopy appears to be the result of a predisposition toward Th2 type responses, which results
in the formation of large quantities of allergen specific IgE.

Mast cell activation After IgE antibodies specific for a certain allergen are synthesized and
secreted, they bind to high-affinity receptors on mast cells (and basophils). When allergen is
inhaled into the nose, it cross links these allergen specific cell bound IgE antibodies on the mast
cell surface in a calcium dependent process, resulting in rapid degranulation and mediator
release. The mediators stimulate blood vessels, nerves, and glands to cause the clinical
manifestations of allergic rhinitis and feed back to other elements of the immune system to
perpetuate the process.

The superficial nasal epithelium in patients with allergic rhinitis has 50-fold more basophilic
cells (mast cells and basophils) per specimen than does epithelium from nonallergic subjects.
Increased concentrations of mast cells are found near post capillary venules, where they increase
vascular permeability; near sensory nerves, where they initiate the sneeze reflex; and near
glands, where they facilitate secretion. Nasal mast cells are predominately located in the nasal
lamina propria as connective tissue mast cells, although 15 percent are epithelial and called
mucosal mast cells. Mucosal mast cells express tryptase without chymase and proliferate in
allergic rhinitis under the influence of Th2 cytokines.

Mast cell mediators are either preformed, associated with granules, formed during degranulation,
or generated after transcription.

Histamine Histamine is the most important preformed mediator in allergic rhinitis. Histamine
reproduces all of the acute symptoms of allergic rhinitis when sprayed into the noses of normal
volunteers. Histamine causes mucus secretion, vasodilatation leading to nasal congestion,
increased vascular permeability leading to tissue edema, and sneezing through stimulation of
sensory nerve fibers.
Prostaglandins and leukotrienes The cross linking of IgE antibody on mast cells activates
phospholipase A2 and releases arachidonic acid from the A2 position of cell membrane
phospholipids. Mast cells then metabolize arachidonic acid either via the cyclooxygenase
pathway to form prostaglandin and thromboxane mediators or via the lipoxygenase pathway to
form leukotrienes. Prostaglandin D2 (PGD2), the sulfidopeptide leukotrienes LTC4, LTD4, and
LTE4 are thus formed during degranulation. PGD2 is synthesized by mast cells, but not
basophils, and appears to be more potent than histamine in causing nasal congestion. LTB4 is the
most potent chemotactic factor yet described in humans.

Other mediators Platelet activating factor (PAF) and bradykinin (generated by the action of
tryptase) are also formed during degranulation. PAF is a potent chemotactic factor, and the
bradykinins are vasoactive.

Cellular infiltration Once allergic reactions begin, mast cells amplify such reactions by
releasing not only vasoactive agents, but also cytokines, including GM-CSF, tumor necrosis
factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), IL-1 to IL-6, and IL-13.

Tissue eosinophilia is characteristic of allergic rhinitis. It appears that mast cell derived cytokines
promote further IgE production, mast cell and eosinophil growth, chemotaxis, and survival. As
an example, IL-5, TNF-alpha, and IL-1 promote eosinophil movement by increasing the
expression of adhesion receptors on endothelium. In turn, eosinophils secrete a plethora of
cytokines including IL-3, IL-4, IL-5, IL-10, and GM-CSF which favor, among others, Th2 cell
proliferation and mast cell growth. Eosinophils also serve an autocrine function in these reactions
by producing the cytokines IL-3, IL-5, and GM-CSF, which are important in hematopoiesis,
differentiation, and survival of eosinophils themselves.

Eosinophils release oxygen radicals and proteins including eosinophil major basic protein,
eosinophil cationic protein, and eosinophil peroxidases; these have been shown to be associated
with nasal epithelial injury and desquamation, subepithelial fibrosis, and hyperresponsiveness.
As a result of mast cell and eosinophil activation in the allergic response, the following events
occur in succession:

Vascular endothelial cell expression of adhesion molecules

Adhesion of leukocytes to vascular endothelium
Transendothelial migration

Chemotaxis and increased survival of eosinophils occur within areas of allergic inflammation. In
addition to the families of adhesion molecules, chemokine molecules that affect the expression
and function of adhesion molecules on endothelium and leukocytes are also expressed in these
reactions. Increased numbers of cells positive for chemokines, such as RANTES, eotaxins, MCP-
3, and MCP-4 are present in the mucosa after allergen challenge. These chemokines further
enhance the recruitment and activation of inflammatory cells possessing their cell surface
receptors in allergic reactions [6]. Nitric oxide (NO), a vasodilator, is also produced in the nasal
mucosa of patients with allergic rhinitis and may play a role in the production of nasal
obstruction. Nitric oxide synthetase is expressed by mast cells, neutrophils, and endothelial cells,
among others.

IMMEDIATE AND LATE NASAL REACTIONS Exposing the nasal mucosa to ragweed
in ragweed sensitive subjects (nasal challenge) provokes the immediate onset of sneezing and
nasal itching associated with significantly increased concentrations of inflammatory mediators.
The time course of histamine concentration, symptoms (sneezing), and increases in nasal airway
resistance are closely correlated.

Immediate Within seconds to minutes of allergen exposure, an immediate allergic response is

observed, which peaks in 15 to 30 minutes. Sneezing correlates with the appearance of
measurable histamine, the kininogen product tosyl-L-arginine methyl ester (TAME esterase), and
PGD2 in nasal washes. Increased levels of sulfidopeptide leukotrienes C4 and B4, tryptase,
kinins, albumin, eosinophil major basic protein, and platelet activating factor are also present in
nasal washes after allergen challenges. The presence of histamine, tryptase, and prostaglandin
D2 indicate the central role of the mast cell in the early response to allergen.

After about 30 minutes, PGD2 and histamine levels return to baseline, whereas TAME esterase
concentrations remain elevated. Biopsy specimens of the nasal mucosa at this time show an
increased number of degranulated mast cells.

Late A late phase nasal allergic reaction develops in approximately 50 percent of patients
with seasonal rhinitis, which peaks at 6 to 12 hours after nasal allergen challenge. This secondary
inflammatory response is thought to be important in establishing the chronicity of the disorder.
During this later phase, symptoms may recur after a second release of mast cell mediators
coincident with maximum mast cell cytokine production.

The late phase allergic reaction is associated with elevated levels of the same mediators noted in
the immediate reaction, except that PGD2 is not detected. Thus, basophils appear to be partly
responsible for such late phase reactions because histamine is generated by both mast cells and
basophils, whereas only mast cells can produce PGD2. In support of this concept, marked
basophil influx into the nasal mucosa has been noted 3 to 11 hours after allergen challenge.
Large numbers of neutrophils, mononuclear cells, and eosinophils also migrate into the nasal
mucosa at this time. Increases in eosinophil cationic protein and other eosinophil products also
become detectable in nasal secretions. After allergen challenge, lymphocytes remain the
predominant cells in the nasal mucosa. These cells actively transcribe messages for IL-3, IL-4,
IL-5, and GM-CSF and have increased expression of the IL-2 receptor. IL-1 through IL-5 and
GM-CSF, among others, have been recovered from nasal washes after allergen challenge.
ALTERATIONS OF NASAL PHYSIOLOGY Under normal conditions, the
nose accounts for one-half to two-thirds of the resistance to airflow in the
airway. It is lined by pseudostratified epithelium resting upon a basement
membrane that separates it from deeper submucosal layers [19]. The
submucosa contains mucous, seromucous, and serous glands. The small
arteries, arterioles, and arteriovenous anastomoses determine regional blood
flow. Capacitance vessels consisting of veins and cavernous sinusoids determine
nasal patency. The cavernous sinusoids lie beneath the capillaries and venules,
are most dense in the inferior and middle turbinates, and contain smooth
muscle cells controlled by the sympathetic nervous system. Withdrawal of
sympathetic tone, or to a lesser degree, cholinergic stimulation, causes this
sinusoidal erectile tissue to become engorged. Cholinergic stimulation causes
arterial dilation and promotes the passive diffusion of plasma protein into glands
and active secretion by mucous glands in cells.

The role of neurotransmitters may be important in the pathogenesis of allergic

rhinitis. Novel neurotransmitters, including substance P, a chemical that
increases vascular permeability, calcitonin gene related peptide, and
vasointestinal peptide, have been detected in nasal secretions after nasal
allergen challenge of patients with allergic rhinitis [11]. Capsaicin, which
depletes sensory nerves of SP and CGRP, reduces symptoms induced by nasal
allergen challenge [29]. Antidromic stimulation of sensory nerve fibers in the
nose can release a variety of neurotransmitters, including substance P.
Neurotransmitters also produce changes in regional blood flow and glandular
secretion.

INVOLVEMENT OF THE PARANASAL SINUSES There are data indicating

that the inflammatory response noted in the mucosa of patients with allergic
rhinitis is often present in the paranasal sinuses as well [6]. There is
concomitant epithelial denudation, extracellular matrix deposition, and
basement membrane disruption.

INFORMATION FOR PATIENTS UpToDate offers two types of patient

education materials, The Basics and Beyond the Basics. The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about
a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical
jargon.
Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
patient info and the keyword(s) of interest.)

Beyond the Basics topic (see "Patient information: Allergic rhinitis

(seasonal allergies)")

SUMMARY

Atopic individuals respond to allergen exposure by producing allergen-

specific IgE. IgE antibodies bind to IgE receptors on mast cells throughout
the respiratory mucosa and to basophils in the peripheral blood. When the
same allergen is subsequently inhaled, the allergen binds to and
crosslinks IgE on the mast cell surface, resulting in activation and release
of inflammatory mediators. (See 'Mechanisms of upper airway allergic
reactions' above.)
Nasal mast cells release histamine, prostaglandins, leukotrienes, PAF, and
bradykinin, among other mediators. These result in the signs and
symptoms of allergic rhinitis. Tissue eosinophilia is also a feature of
allergic rhinitis, and eosinophil-derived mediators are associated with
nasal epithelial injury and desquamation, subepithelial fibrosis, and
hyperresponsiveness. (See 'Mast cell activation' above and 'Cellular
infiltration' above.)
The allergic nasal response consists of an immediate phase, which peaks
at 15 to 30 minutes after allergen exposure and corresponds to mast cell
degranulation and mediator release, and a late phase, which peaks at 6 to
12 hours after exposure and corresponds to infiltration of the nasal
tissues by eosinophils, basophils, and other inflammatory cells.
(See 'Immediate and late nasal reactions' above.)
Patients with allergic rhinitis usually have similar inflammatory changes in
the linings of the paranasal sinuses. (See 'Involvement of the paranasal
sinuses' above.)