 are mediated by the IgE class of antibodies

 reactions typically occur 15 to 20 minutes after

exposure to an allergen.
 allergic diseases are now among the top three
causes of illness and disability.
 Allergic reactions occur in the:
 skin (urticaria and atopic dermatitis),
 nose and eyes (rhinitis and conjunctivitis),
 lungs (asthma)
 intestine (food allergies).
 characterized by elevated IgE levels directed at common
aeroallergens or food allergens.
 is associated single nucleotide polymorphisms on
chromosomes 5, 7, and 11
 These mutations increase cytokine production,
expression of Fc receptors, IgE synthesis, and bronchial
hyperreactivity.
 Atopic individuals have increased numbers of
 CD4Th2 (T helper) cells
 elevated interleukin 4 (IL-4)
 mast cells and basophils have double the number of Fc receptors
for IgE
 These abnormalities skew the immune response to IgE
production.
 Atopic individuals also have hyperreactive airways that
respond to low levels of cholinergic agonists that bind and
activate acetylcholine receptors in the lung.
 Chromosome 5q genes regulate the production
of cytokines (e.g., IL-4, IL-5, and IL-13).
 IL-4 and IL-13 - isotypic switching to IgE production
 IL-5 - growth and activation of eosinophils
 IL-13 - increases bronchial mucus secretion
 Bronchial hyperreactivity is controlled by the
genes on chromosome 7
allergens are processed by macrophages and allergenic epitopes presented to
CD4Th2 cells in the context of class II molecules.

T cells secrete IL-4, IL-5, and IL-13, which promote the

rapid isotypic switching and IgE production by plasma cells.

Secreted IgE binds specifically to Fc receptors on tissue

mast cells and circulating basophils
 Upon second exposure, the allergen cross-links two
cellbound IgEs, which initiates an energy-dependent
mechanism that culminates in a biphasic immune
response.
 The early phase response
 occurs within 20 minutes of exposure
 involves IgE–antigen interactions
 mediated by preformed pharmacologic mediators.
 A late-phase response
 occurs 4 to 8 hours following exposure,
 does not involve antibodies
 facilitated by the newly synthesized products of the
arachidonic acid pathway.
 The major preformed mediators include histamine, heparin,
eosinophil chemotactic factor (ECF), and neutrophil
chemotactic factor (NCF)
 Histamine
 vasoactive amine interacts with H1 receptor on vascular endothelial
cells to create gaps between adjacent cells
 increases vascular permeability (H2 receptor)
 causing swelling or edema in the tissue
 irritates peripheral nerve endings, causing itching and pain (pruritus).
 reacts with H1 receptors on bronchioles causing bronchoconstriction.
 Heparin
 potentiates the tissue edema by binding to antithrombin
 prevents the activation of the normal coagulation pathway.
 The chemotactic factors ECF and NCF
 cause an influx of eosinophils and granulocytes at the site of the allergic
reaction.
 Mast cells and basophils synthesize and release late-phase
mediators over the course of 4 to 8 hours.
 These mediators include prostaglandins, leukotrienes, and
platelet activating factor (PAF)
 PGD2 and PGE2
 increasing vascular permeability, contracting smooth muscle, and
acting as an NCF.
 Leukotrienes
 20 carbon unsaturated fatty acids (LTA4, LTB4, LTC4, LTD4, and LTE4)
 bronchoconstriction, increased mucus production, and sustained
inflammation.
 PAF
 released from polymorphonuclear cells, endothelial cells, and
monocytes
 causes bronchoconstriction, retraction of endothelial cells, and
vasodilation
 Mast cells release mediators
after cross-linking of the
immunoglobulin E (IgE)
receptors on their surface.
 Preformed mediators are
released rapidly while
arachidonic acid metabolites
such as leukotriene D4 and
prostaglandin D2 are released
more slowly.
 Mast cells can also be triggered
by opiates, contrast media,
vancomycin, and the
complement components C3a
and C5a.
 Histamine, TNF-α and IL-4
 Mediators released by basophils
 Asthma
 partial airway obstruction that is partially reversible either spontaneously or
with treatment.
 The hallmark of allergic asthma is an early-phase allergic response.
 Chronic airway inflammation, airway injury, and airway repair
(airway remodeling) also contribute to the pathogenesis of asthma
and permanent abnormalities in lung function.
 Chronic asthma has an inflammatory component.
 Cells involved in the inflammatory response include T cells, eosinophils,
and mast cells.
 Cytokines released from activated macrophages mediate the inflammatory
process.
 TNF-α upregulates endothelial cell adhesion factors that bind
neutrophils, monocytes, and eosinophils.
 The accumulation of cells forms the asthma inflammatory nidus.
 The interaction between lymphocyte CD28 and dendritic cell B7
activates dendritic cells and promotes the synthesis of proinflammatory
cytokines.
 In tissue, L-arginine is converted to L-ornithine
 initiates cell proliferation, collagen synthesis, smooth muscle hypertrophy, and
goblet cell hyperplasia.
 These changes culminate in the thickening of the sub-basement membrane,
subepithelial fibrosis, and permanent damage to the bronchioles
 For acute exacerbations of asthma
 Slow-acting β2-agonists and oral corticosteroids
 Therapeutics used to control long-term and chronic pulmonary symptoms
 mast cells stabilizers,
 leukotriene antagonists,
 long-acting β2-agonists,
 inhaled corticosteroids,
 methylxanthines.
 omalizumab
 humanized monoclonal antibody which is directed at IgE
 It binds to soluble IgE and prevents binding to Fc receptors on mast cells/basophils
 For moderate to severe asthma triggered by ubiquitous year round allergens.
 result of early-phase and late phase IgE-mediated reactions
and subsequent inflammation of the nasal passages,
mucus membranes, nose, eyes, sinuses, and eustachian
tubes.
 Early-phase mediators cause nasal edema, mucus
secretion, itching, sneezing, and rhinorrhea.
 In the late phase, lymphocytes, basophils, and eosinophils
accumulate in the area of an allergic reaction.
 AR is often complicated by sinusitis
 Inflammation causes the sinus lining to thicken, which
impedes the flow of air or fluid.
 The chronic inflammation also results in the formation
of nasal polyps found in the ethmoidal sinuses
 Acute sinusitis is usually caused by Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis.
 Infections with Staphylococcus aureus and anaerobic bacteria are
common in individuals with chronic sinusitis.
 Treatment
 second-generation oral antihistamines,
 decongestants,
 nasal steroids,
 leukotriene antagonists such as montelukast sodium
 Intranasal antihistamines, sodium cromolyn, and anticholinergic
agents
 Chronic rhinitis is treated with a short course of nasal steroids.
 is characterized by redness, itching, and excessive
tearing of the eyes
 Conjunctivitis follows the same seasonal patterns of
AR.
 Vernal conjunctivitis is a more serious, persistent form
of conjunctivitis.
 It is characterized by redness and itching of the eyes,
mucus production, and photophobia.
 giant papillary conjunctivitis
 hypertrophy and edema of the upper eyelid form papillae.
 Artificial tear preparations are used to dilute the
allergens and inflammatory mediators.
 Systemic or topical antihistamines reduce some
symptoms.
 a rash characterized by raised, flat-topped areas with associated red
edematous welts
 acute (6 or less weeks in duration) or chronic (6 or more weeks in
duration).
 Acute urticaria is usually caused by food allergens
 eggs, nuts, shellfish, chocolate, tomatoes, berries, and milk, use of aspirin,
ACE inhibitors, and NSAIDs.
 Type I urticaria
 true IgE allergic reaction with both early and late phases
 Type II urticaria
 an aberrant reaction mediated by cytotoxic T cells, antibodies,
complement activation, and the deposition of fibrin.
 Second-generation oral antihistamines
 Topical therapy with doxepin or capsaicin provides relief from refractory
urticaria.
 Glucocorticosteroids are also indicated for the treatment of refractory
urticaria
 a chronic, eczematous skin disease that is characterized by
itching, swelling, cracking, and weeping skin lesions .
 IgE-mediated allergic reaction
 contact dermatitis is a T cell–mediated delayed
hypersensitivity reactio.
 the pathogenesis of atopic dermatitis, allergen-stimulated
Langerhans cells produce large amounts of IL-4, which
causes rapid isotypic switching and the production of
the IgE isotype.
 topical S. aureus infection is the cause of atopic dermatitis.
 Staphylococcal superantigens stimulate Langerhans cells to
produce high concentrations of IL-4 and isotypic switching.
 Low- to medium-potency topical steroids
 calcineurin inhibitors are replacing corticosteroids
 they have fewer adverse effects and can be used on all skin
surfaces, including the skin on the face and neck.
 Over 25% of pollen-
sensitive individuals
develop burning or
pruritus of the lips and
tongue and edema of the
buccal mucosa after
ingestion of certain raw
fruits and vegetables.
 The syndrome is an IgE-
mediated early-phase
reaction caused by
exposure to antigens
shared between pollens
and fruits or vegetables.
 Food allergens
 large, water-soluble glycoproteins that
are resistant to heating at 212°F and
gastric proteolysis at pH 2 to pH 3.
 are absorbed from the intestine and
stimulate the synthesis of allergen-
specific IgE.
 These allergens induce an early-
phase response mediated by heparin
and histamine, which cause
vomiting, diarrhea, malabsorption,
blood loss, and protein loss through
the intestine.
 Acute urticaria, angioedema, and
atopic dermatitis are also common in
individuals with food allergies
 the most severe and often fatal allergic reaction, which
involves total cardiovascular and respiratory collapse.
 This IgE-mediated reaction results in the massive release
of histamine, LTC4, and PGD2.
 Increased vascular permeability
 massive shift of fluids from blood into tissue within 10
minutes of exposure.
 The combination of vasodilation and increased vascular
permeability causes hypovolemic shock and death
within 15 to 60 minutes.
 Penicillin, bee stings, and peanuts are the most common
causes of anaphylaxis.
 Epinephrine
 catecholamine that binds to α-adrenergic and β-adrenergic
receptors to relax smooth muscles, decrease vascular
permeability, and reduce vasodilation.
 Prick and intradermal tests are used in
the diagnosis of allergies.
 prick test
 the allergen is placed on the skin, and
the skin is gently scratched or pricked.
 intradermal test
 small amounts of allergen are injected
subcutaneously under the skin.
 If the patient is sensitive to a specific
allergen, a wheal and- flare reaction
occurs at the skin test site within 15 to
20 minutes.
 Plasma leaking from the vessel into
the skin induces edema, or swelling in
the skin (wheal).
 Blood vessels at the periphery of the
wheal then dilate, and red blood cells
accumulate in the area, causing redness
(flare) in the skin.
 Some individuals who are at a high risk for
anaphylaxis cannot have a skin test.
 in vitro radioallergosorbent test (RAST) is used
to determine the presence of allergen-specific IgE.
 The classic RAST is actually an indirect ELISA, in
which the secondary antibody is labeled with a
radioisotope such as iodine-125.
 Because of the issues related to the handling and
disposal of radioisotopes, secondary antibodies
are now labeled with enzymes or fluorochromes.
 When allergic reactions cannot be effectively controlled with
pharmacologic agents.
 patients are given small amounts of allergens orally or
subcutaneously.
 Over a period of months, the amount of allergen is increased
to a maximum tolerated dose, which is called the
maintenance dose.
 Hyposensitization therapy induces the synthesis of IgG
antibodies, which are called blocking antibodies
 The IgG binds the allergen, thus preventing interaction with
mast cell–bound IgE.
 Evidence has shown that hyposensitization therapy also
increases the number of T regulatory cells that inhibit the
production of allergen-specific IgE.
 Hyposensitization results in the reduction, but not
elimination, of clinical symptoms in 60% to 90% of patients
• During desensitization or immunotherapy, a
patient with an allergy receives regular SQ
injections of the relevant allergen.
•The immunologic changes that occur include an
initial increase in (IgE) antibodies followed by a
gradual decline.
• Antibodies of the IgG and specifically IgG4
isotype increase progressively and may reach
concentrations 10 times those present before
treatment.
•Symptoms decline starting as early as 3
months but generally not maximally until 2
years.
• decreased in vitro response to allergens and
increased production of IL-10
 Symptoms similar to allergic asthma, food
allergies, and anaphylaxis can be elicited by
nonimmunologic reactions.
 Respiratory infections, exercise, and aspirin
ingestion can cause asthma in some patients.
 High histamine levels in foods can cause
symptoms consistent with a food allergy.
 some chemicals can induce anaphylactoid
reactions that are similar to life-threatening
anaphylaxis
 Nonallergic asthma can be caused by influenza, respiratory
syncytial virus (RSV), or parainfluenza viruses.
 The replication of viruses often destroys the epithelial layers of the
respiratory tract and exposes the sensory nerve endings.
 Stimulation of nerve endings by cold air or irritants causes
a reflex bronchoconstriction.
 Rhinovirus and enterovirus (common cold viruses)
 disrupt the control mechanisms for smooth muscle contraction by
inhibiting the synthesis of the M2 muscarinic receptors.
 M2 receptors act in a negative feedback loop that controls
the release of acetylcholine.
 The lack of M2 receptors allows the release of acetylcholine
and increases the contraction of smooth muscle, causing
symptoms that mimic asthma.
 exercise triggers an acute bronchospasm and
symptoms similar to those of asthma
 In individuals with bronchial hyperreactivity
 After vigorous exercising, individuals tend to
become mouth breathers.
 Mouth breathing evaporates water from the
bronchioles, which alters airway humidity and
temperature.
 When combined with existing airway edema,
these changes induce a reflex
bronchoconstriction.
 occur within 1 hour of aspirin ingestion
 often accompanied by rhinorrhea and conjunctival
irritation.
 Sensitive individual have defects in the metabolism of
aspirin and the control of leukotriene production.
 Aspirin-sensitive individuals are poor aspirin
metabolizers, and large concentrations of parental
acetylsalicylic acid accumulate in the blood.
 In lung tissue, acetylsalicylic acid stimulates mast cells to
produce leukotrienes.
 Aspirin-sensitive patients have a single nucleotide
polymorphism in the LTC4 synthetase gene that causes
the overproduction of LTC4.
 The C4 leukotriene is converted to LTD4
 causes airway narrowing, mucus secretion, and increased
vascular permeability.
 severe gastrointestinal reactions occur following
the ingestion of foods with high concentrations
of histamine.
 Eggplant, spinach, cheese, vinegar, strawberry,
and red wine (Chianti), tuna and mackerel
 If these fish are improperly refrigerated,
Klebsiella species decarboxylate tissue
histidine to histamine, which causes a clinical
syndrome called scromboid fish poisoning.
 Symptoms include diarrhea, facial flushing, dizziness,
and vomiting.
 Anaphylactoid reactions are not mediated by IgE, but
the symptoms mimic severe anaphylaxis.
 Most anaphylactoid agents activate the complement
cascade or react directly with mast cells or basophils.
 Opiates, vancomycin, polymyxins, and ciprofloxacin
 associated with anaphylactoid reactions resulting from
complement activation.
 Activation of the complement cascade produces C3a,
C4a, and C5a anaphylatoxins, which release mediators
from mast cells and basophils.
 rashes, urticaria, angioneurotic edema, and smooth
muscle spasms, some individuals develop hypotension,
pulmonary edema, and cardiac arrest.
 Latex is a milky fluid produced by rubber trees (Hevea
brasiliensis)
 latex preparations are often contaminated with
allergenic plant proteins called hevein and hevein
amine.
 Persons sensitized to latex allergens develop IgE-
mediated urticaria, rhinitis, asthma.
 Populations at risk for latex allergy are hospital workers
and patients with spina bifida or congenital urogenital
disease.
 thiuram, mercaptobenzothiazoles, and carbamates
and vulcanization (sulfur) elicit an irritant dermatitis
caused by disruption of the skin or a delayed
hypersensitivity response resembling poison ivy.
 Mites are microscopic insects that inhabit bedding, upholstered
furniture, draperies, and carpets.
 The two species of house dust mites are
(1) Dermatophagoides pteronyssinus (Europe)
(2) Dermatophagoides farinae (United States)
 The most significant allergens (Der p1 and Der p2) are cysteine
proteases.
 In the lung, these proteases degrade the tight junctions in the
vascular epithelium and allow the entry of allergens into the blood
and the stimulation of an immune response.
 Der p1 also cleaves the low-affinity IgE receptor (CD23) on B cells,
which normally acts as a control mechanism for IgE synthesis.
 Uncontrolled IgE synthesis and the release of proinflammatory
cytokines and pharmacologically active mediators from basophils
and mast cells
 cause contraction of smooth muscle and asthmatic symptoms.
A mite is shown with pollen grains (lower left) and fecal particles (upper right).
The mite is approximately 300 μm in length (i.e., just visible but not small
enough to become airborne).
Mite fecal particles are approximately 10 to 40 μm in diameter and become
airborne during any disturbance of surfaces in the house. Pollen grains are
similar in size to mite fecal particles
 Allergens come from the saliva, fecal matter,
secretions, cast skins, and dead bodies of
cockroaches.
 The major cockroach-related allergens are Bla g1,
2, 4, and 5.
 Bla g1 is the major allergen that elicits IgE
synthesis in 60% to 80% of sensitized individuals.
 The structure of Bla g1 is similar to that of an
aspartic proteinase, but it has no enzymatic
activity.
 pharmaceuticals are not usually involved in IgE-
mediated immediate allergic reactions.
 Except: penicillins and beta lactam antibiotics
 drugs may evoke delayed hypersensitivity
reactions
 The major lesion in drug hypersensitivity is
morbilliform rash
 consists of macules and papules of differing sizes
that begin on the trunk and spread to the
extremities.
 individuals with endemic parasitic helminthic
infections
 have increased CD4Th2 lymphocytes
 high levels of parasite-specific IgE
 In the intestine, the release of preformed
mediators causes violent peristaltic
contractions that expel the intestinal worms.
 IL-4, IL-5, and IL-13 cause the release of
cytotoxic proteins from eosinophils
 Immediate allergic reactions that occur 15 to 20 minutes after exposure to
an allergen are mediated by IgE antibodies.
 Most allergic responses have an early-and late-phase reaction.
 Early-phase reactions are mediated by preformed histamine and heparin.
Late-phase reactions are caused by the products of the arachidonic acid
pathway.
 Asthma, urticaria, allergic rhinitis, and atopic dermatitis are examples of
IgE-mediated allergic reactions.
 Some forms of asthma are induced by infection, exercise, and aspirin.
These forms of asthma do not have an immunologic basis.
 Immediate allergic reactions can occur in the skin, lungs, or intestine.
 Food allergens differ from common aeroallergens in their chemical
characteristics and response to physical stressors.
 Anaphylaxis and anaphylactoid reactions are life threatening, but only
anaphylaxis is an IgE-mediated allergic reaction.
 New emerging allergens include latex, house dust mites, and cockroaches.