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 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 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.
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 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 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 — 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]
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 education" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Allergic rhinitis (Beyond the Basics)")
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.)
