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Pathogenesis of allergic rhinitis (rhinosinusitis)

Authors: Richard D deShazo, MD, Stephen F Kemp, MD
Section Editor: Jonathan Corren, MD
Deputy Editor: Anna M Feldweg, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2022. | This topic last updated: Apr 09, 2021.

INTRODUCTION

Allergic rhinitis is associated with a symptom complex characterized by paroxysms of sneezing,

rhinorrhea, nasal obstruction, and itching of the eyes, nose, and palate. It is also frequently
associated with postnasal drip, cough, irritability, and fatigue [1-4].

The pathogenesis of allergic rhinitis is presented in this topic review. The clinical manifestations,
diagnosis, and treatment of this condition are discussed separately. (See "Chronic rhinosinusitis:
Clinical manifestations, pathophysiology, and diagnosis" and "Allergic rhinitis: Clinical
manifestations, epidemiology, and diagnosis" and "Pharmacotherapy of allergic rhinitis".)

MECHANISMS OF UPPER AIRWAY ALLERGIC REACTIONS

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

immunoglobulin E (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.

Models of nasal allergen challenge in patients with allergic rhinitis have provided information
about the pathogenesis of allergic rhinitis [5,6]. In this model study system, individuals known
to have allergic rhinitis on exposure to a particular allergen are exposed to incremental doses of
that allergen placed in the nose. The subsequent reaction is then monitored over time with

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nasal biopsies or washes. This allows direct quantitation of cell types by stains and surface
markers, assessment of message for transcription, or direct measurement of cellular cytokines
and other inflammatory mediators [7]. Rhinomanometry, the measurement of nasal airway
resistance, permits measurement of both resistance and airflow following allergen provocative
challenge [8]. (See "Occupational rhinitis", section on 'Rhinomanometry techniques'.)

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 IgE. The IgE response appears to be controlled by immune
response genes located within the major histocompatibility complex (MHC) on chromosome 6.
(See "Major histocompatibility complex (MHC) structure and function".)

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 T helper
type 2 (Th2) lymphocytes. There are probably multiple genetic and environmental influences
that lead to overexpression of Th2 T cell responses relative to T helper type 1 (Th1) cell
responses ( figure 1). (See "The adaptive cellular immune response: T cells and cytokines".)

IgE production — Sensitization to allergen is necessary to elicit an immunoglobulin E (IgE)

response ( figure 2). After inhalation, the allergen must first be internalized by antigen-
presenting cells (APCs), which include macrophages, immature dendritic cells, B lymphocytes,
and epithelial cells [9]. After allergen processing, peptide fragments of the allergen are
exteriorized and presented with class II MHC molecules of host APCs to CD4+ T lymphocytes.
(See "The adaptive cellular immune response: T cells and cytokines".)

Allergenic proteases activate and damage nasal epithelial cells, which then secrete interleukin
(IL)-25, IL-33, thymic stromal lymphopoietin (TSLP), and other cytokines that impact Th2
lymphocytes and group 2 innate lymphoid cells (ILC2s) directly or indirectly via APCs located
within and underneath the nasal epithelium. Activated T lymphocytes proliferate into effector
memory Th2 cells that secrete IL-4, IL-5, IL-9, and IL-13 [9].

B lymphocytes require two signals for isotype switching to IgE (see "Immunoglobulin genetics"
and "Normal B and T lymphocyte development"). 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 [10] (see "The biology of IgE"). Interaction of CD40 on the B cell membrane with CD40
ligand (CD40L) on the surface of T lymphocytes provides the second signal that activates
genetic recombination in the functional IgE heavy chain [11]. IL-4 and IL-13 also upregulate
vascular cell-adhesion molecule-1 (VCAM-1) on endothelial cells, promoting adhesion of

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inflammatory cell populations, and they facilitate their migration into areas of allergic
inflammation. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

In situ hybridization and/or antibody studies have demonstrated increased numbers of cells
with messenger RNA (mRNA) for and/or expression of IL-3, IL-4, IL-5, IL-13, eotaxin, and
granulocyte macrophage colony-stimulating factor (GM-CSF) within the nasal mucosa after
allergen provocation ( picture 1) [5,7]. Interferon-gamma (IFN-gamma), a Th1 cytokine that
inhibits B lymphocyte activation and IgE synthesis is absent. Interleukin-12 (IL-12) and
interleukin-18 (IL-18), major inducers of IFN-gamma, are also absent.

Thus, atopy appears to be the result of a predisposition toward Th2 responses, which results in
the formation of large quantities of allergen-specific IgE [5].

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 postcapillary 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. (See "Mast cells: Development,
identification, and physiologic roles".)

Mast cell mediators are either preformed, associated with granules, formed during
degranulation, or generated after transcription [12]. (See "Mast cell-derived mediators".)

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.

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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), as well as the sulfidopeptide leukotrienes LTC4,
LTD4, and LTE4, are 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 described in humans [13].  

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 [14-
16].

Tissue eosinophilia is characteristic of allergic rhinitis [17]. 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 hyper-
responsiveness [7,18]. 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
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reactions. Increased numbers of cells positive for chemokines, such as RANTES (regulated on
activation, normal T cell expressed and secreted), eotaxins, monocyte chemotactic protein-3
(MCP-3), and MCP-4 are present in the mucosa after allergen challenge [5,19]. These
chemokines further enhance the recruitment and activation of inflammatory cells possessing
their cell surface receptors in allergic reactions [7]. 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 [20]. NO 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 ( figure 3) [21,22].

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

is observed, which peaks in 15 to 30 minutes [17]. Sneezing correlates with the appearance of
measurable histamine, the kininogen product tosyl-L-arginine methyl ester (TAME esterase),
and prostaglandin D2 (PGD2) in nasal washes. Increased levels of sulfidopeptide leukotrienes C4
and B4, tryptase, kinins, albumin, eosinophil major basic protein, and platelet-activating factor
(PAF) are also present in nasal washes after allergen challenges [9,23]. The presence of
histamine, tryptase, and PGD2 indicate the central role of the mast cell in the early response to
allergen [22].

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 [17]. 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 that is coincident with maximum mast cell cytokine production [22].

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

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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
[9,24]. 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
interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), and granulocyte macrophage colony-
stimulating factor (GM-CSF) and have increased expression of the interleukin-2 (IL-2) receptor.
Interleukin-1 (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 [17]. 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 gland 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 (CGRP), and vasointestinal peptide, have been detected in nasal
secretions after nasal allergen challenge of patients with allergic rhinitis [25]. Capsaicin, which
depletes sensory nerves of substance P and CGRP, reduces symptoms induced by nasal allergen
challenge [26]. 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

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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 [7]. There is concomitant
epithelial denudation, extracellular matrix deposition, and basement membrane disruption.

UNANSWERED QUESTIONS

● How do genetic and environmental factors (eg, pollution and infection) promote IgE
production?

● Why do some antigens stimulate Th2 lymphocytes and become allergens and others do
not? (In general, allergens do not stimulate Th1 inducing cytokines by macrophages and
dendritic cells as antigens do.)

● What are the specific roles of Th2 cells and Type 2 innate lymphoid cells (both secrete IL-5
and IL-13) as well as Toll-like receptor ligands from injured cells (some activate mast cells)
in allergic inflammation?

● What are the differences in IL-4 secreting Th2 cells (supporting the allergic diathesis) and
CD25+ regulatory T-cells (suppressing the allergic diathesis) among allergic and
nonallergic individuals? [9,27]

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● Beyond the Basics topic (see "Patient education: Allergic rhinitis (Beyond the Basics)")

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SUMMARY

● Atopic individuals respond to allergen exposure by producing allergen-specific

immunoglobulin E (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 cross-links 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, platelet-activating factor

(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 hyper-responsiveness. (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.)

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