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Allergy and Hypersensitivity
I. Introduction
A. Definitions

Allergy




Immune-mediated response to innocuous
environmental antigen
Can be humoral or cell-mediated reaction
Usually involves prior exposure to antigen
resulting in sensitization of individual
Allergen



Innocuous antigen
Universal
Non-reactiving to most people
 Hypersensitivity
reactions
 Harmful
IRs that cause tissue injury and
may cause serious pathologies
 Atopy
 State
of increased susceptibility to
immediate hypersensitivity usually
mediated by IgE Abs
 Over-react to common environmental Ags
B. Four types of immune-mediated
hypersensitivity reactions causing tissue
damage
 Type
I = Anaphylaxis hypersensitivity
(TH2 = IgE)
 Type II = Cytotoxic hypersensitivity
(IgG)
 Type III = Immune complex
hypersensitivity (IgG)
 Type IV = Cell-mediated hypersensitivity
(TH1, TH2, CTL)
II. Type I (Anaphylaxis)
Hypersensitivity
A. Pathway

IgE made during primary response to soluble
Ag  Binds to high affinity FceRI on mast
cells, basophils and activated eosinophils



Sensitizes individual (become allergic)
IgE aka reagin
Secondary exposure  allergen binds to IgE
on sensitized mast cells, basophils or
eosinophils

IgE Ab crosslinking on leads to rapid release of
preformed inflammatory mediators
High affinity FceRI is functional
on mast cells, basophils, and
activated eosinophils. It is
composed of a,b and two g
chains. Crosslinking of FceRI
on cells by Ag and IgE induces
degranulation.


Induces degranulation  Release of inflammatory
mediators [pre-formed substances including
histamine, slow reacting substance of anaphylaxis
(SRS-A), heparin, prostaglandins, plateletactivating factor (PAF), eosinophil chemotactic
factor of anaphylaxis (ECF-A), and various
proteolytic enzymes]
Eosinophils release major basic protein which
induces degranulation of mast cells and basophils
 Tachyphylaxis
 Depletion
of mast cell granules
 Accounts for unresponsiveness of a patient
to a skin test following an anaphylactic
reaction (lasts 72-96 hours after a reaction)
B. Ig-E mediated reactions differ depending
on route of administration and dose
 Connective
tissue mast cells
 Associated
with blood vessels
 IV-high dose  Activated by allergen in the
bloodstream  systemic
Systemic release of histamine
 Systemic anaphylaxis

dose  subcutaneous injection 
local release of histamine
 SC-low

Wheal and flare reaction
 Mucosal
mast cells
– low dose  Activated by
inhaled allergen
 Inhalation
Smooth muscle contraction of lower airways
 Bronchoconstriction




Asthma
Allergic rhinitis (hay fever)
Increased mucosal secretions

Irritations
Fig. 10.24: Allergen-induced release of histamine by mast cells in skin
causes localized swelling. Swellings (wheals) appear 20 min. after
intradermal injection of ragweed pollen (R), histamine (H). Saline bleb
(S) is due to volume of fluid.
Fig. 10.14
Properties of inhaled
allergens that favor TH2
priming that promotes
IgE isotype switching.
Fig. 10.15
Sensitization to an inhaled allergen.
Soluble allergen is processed by APC and displayed to TH2 T cells.
T cells help B cells to produce IgE which then binds to mast cells. IL-4
promotes isotype switching to IgE.
Fig. 10.21: Allergic rhinitis (hay fever) is caused by inhaled allergen
entering the respiratory tract. Sneezing, runny nose – nasal discharge is full
of eosinophils. Allergic conjunctivitis results if the conjunctiva of the eye is
affected (itchy, watery, and swelling of eyes).
 Ingestion
– Activated by ingested allergen
Food allergy
 Gut epithelial cells are involved
 Intestinal smooth muscle contraction




Vomiting
Diarrhea
Dissemination through bloodstream causes
urticaria (hives) or anaphylaxis (rare)
Fig. 10.25: Ingested allergen can cause vomiting, diarrhea and urticaria.
Summary of Type I Hypersensitivity Reactions
Fig 10.12
C. Hereditary predisposition for IgE
synthesis


FceR genes
Cytokine genes involved in





Isotype switching
Eosinophil survival
Mast cell proliferation
Example: IL-4 promoter mutation which leads to elevated IL4 can favor IgE
MHC class II


MHC:peptide combinations may favor TH2 response
Example: ragweed pollen associates with HLA-DRB1*1501
D. Type I hypersensitivity reactions can be
divided into immediate and late stages
 Acute
(minutes) versus Chronic (5-12
hours) Reactions
 Immediate
allergic reactions is then
followed by a late-phase response
 Acute
– Immediate
 Peaks
within minutes after allergen
injection or inhalation and then subsides
 Wheal and flare
 Bronchial constriction in asthma
 IgE crosslinking  rapid degranulation

Release of preformed inflammatory mediators



Histamine, serotonin
Mast cell chymase, tryptase, carboxypeptidase and
cathepsin G  breaks down tissue matrix proteins
(remodeling of connective tissue matrix)
TNF-a
Mast cell stained for protease
chymase demonstrating
abundant granules residing
in the cytoplasm.
Chronic
 Caused
– Late
by influx of inflammatory
leukocytes (including eosinophils)
 Chronic allergic inflammation
 Tissue damage
 Edema, long-lasting



Chemokines
Heparin
Lipid mediators derived from membrane
phospholipids

Form a precursor called arachidonic acid


Many anti-inflammatory agents inhibit arachidonic acid
metabolism (e.g. aspirin)
Arachidonic acid forms:




Leukotrienes
Prostaglandins
Thromboxanes
Platelet activating factor
Fig. 10.5: Mast cell products involved in allergic reactions.
Fig. 10.7
Mast cell
production of
prostaglandins
and leukotrienes
by different enzyme
pathways starting
with arachidonic
acid.
Fig. 10.8: Eosinophils display a unique staining pattern with bilobed
nuclei and stain pink with eosin.
Eosinophils are specialized granulocytes that release toxic mediators
in IgE-mediated responses.
Fig. 10.9:
Products of
activated
eosinophils.
Fig 10.16: Immediate and late-phase reactions to house dust mite
allergen (HDM) injected intradermally. Saline injection = control.
Wheal = raised area of skin around injection site; flare = redness
(erythema) spreading out from the wheal.
E. Two types of anaphylaxis

1. Systemic anaphylaxis



Generalized response to systemically
administered Ag (e.g. IV) or rapidly absorbed from
gut
Immediate: a lot of mast cell products released
quickly
Smooth muscle constriction of bronchioles 
breathing difficulties


Epiglottal swelling  Asphyxiation
Can be fatal
 Arterioles
dilate
Arterial blood pressure decreases
 Capillary permeability increases (increases
vascular permeability





Fluid loss into tissue spaces
Edema
Late phase reaction = sustained edema
Circulatory shock

Can be fatal
 Examples

of allergens:
Penicillin (or cephalosporins)

Penicillin = hapten  beta lactam ring reacts with
amino groups on host proteins  conjugates form
Bee, wasp or hornet venom
 Peanuts or brazil nuts
 Anti-sera


2. Localized anaphylaxis


Atopic (out of place) allergy
Examples:

Allergic rhinitis (hay fever) – URT


Airborne allergens: pollen, spores, animal dander, house
dust mite feces
Allergens diffuse across the mucus membranes of nasal
passages
 Mast cells sensitized in mucus membrane upon
primary exposure
 Upon secondary exposure – itchy, runny eyes and
nose, sneezing coughing

Bronchial asthma = allergic asthma – LRT




Air sacs (alveoli) fill with fluid and mucus
Wall of bronchi constricted
Bronchodilators relax muscles, making breathing
easier (inhalers)
 Anticollinergic
 Sympathetic activators
 Metaproterenol
 Albuterol
Hives (food allergy)


Vomiting and diarrhea = local response
Urticaria = systemic response
Fig. 10.23: Inflammation of the airways in chronic asthma restrict breathing
A = section through bronchus of individual who died from asthma.
MP = mucus plug – restricts airway. White plug depicts remaining passageway in
bronchial lumen.
B = Bronchial wall at higher magnification demonstrating presence of inflammatory
infiltrate consisting of eosinophils, neutrophils, and lymphocytes. L = lumen of
bronchus.
 In
vivo skin testing can help to identify
responsible allergens  rapid
inflammation
 Diameter
of swelling measured
 Wheal-and-flare reactions
 Cutaneous allergic response
 Develops within 1-2 minutes  lasts ~30
minutes
F. Desensitization
Subcutaneous injections of Ag  to produce
IgG Abs  can compete with IgE Ab, and
neutralize allergens before they reach mast
cells
 Tiny amounts injected initially, then dose is
increased  Diverts IR from TH2 to TH1 
Decreases IgE production
 65-75% effective treatment of inhaled
allergens

G. Treatment
 Inhibit
allergic reactions – Examples
 Desensitization
(described above)
 Experimental:
Inhibit IL-4, IL-5 and/or IL-13 or CD40L to
reduce IgE responses
 Use cytokines that enhance TH1 responses



gIFN, aIFN, IL-10, IL-12, and TGF-b
Block FceR (e.g. with modified Fc components
that lack variable domains)
 Block

Epinephrine




Endothelial tight junctions reform
Relaxation of smooth muscle
Stimulation of heart (increase BP)
Anti-histamines



allergic response effector pathways
Block histamine receptors
Decrease urticaria (hives)
Corticosteroids

Reduce inflammation
Figure 10.20: Effect of epinephrine on blood pressure
Time 0 = point at which anaphylactic response began.
Arrows = times when epinephrine was administered.
III. Type II (Cytotoxic)
Hypersensitivity

A. Host cells are killed or lysed

Cell surface antigens

B. IgG (mainly) or IgM Abs react with cell
surface receptors, matrix associated Ag or
modified cell membranes
 Complement is activated



C’ binds Ig (C1q)
C’ cascade results in formation of membrane
attack complex (MAC)
Holes are punched in target cells  Death
 FcR
bind Ig:Ag complexes
 FCR-bearing
accessory cells are activated
(e.g. macrophages, neutrophils and NK
cells)

Especially important mechanism used by
splenic macrophages  clearance of cells
 Opsonization
induced via FcR + CR1
 Antibody-dependent
cell-mediated
cytotoxicity (ADCC) is induced in NK cells
NK cells secrete preformed perforin and
granzyme from cytoplasmic granules
 Perforin forms a pore in target cell –
transmembrane polymerization
 Granzyyme (aka fragmentin) = 3 serine
proteases – digest host proteins and activate
endonucleases  DNA is degraded into ~200
by multimers (subunits) = APOPTOSIS

 Examples
 Hemolytic
disease of the newborn
(Erythroblastosis fetalis) (Abs to Rh Ags)
Hemolytic Disease of the
Newborn (Erythroblastosis
fetalis)
Type II hypersensitivity
Alloantibodies resulting
from Rh incompatibilities
between mother and father
Spacing of Rh antigen is
too far to activate C’ or
cause agglutination.
Fetal RBC destroyed by macrophages causing edema.
This may in turn lead to heart
failure, edema and fetal death
(hydrops fetalis).
More examples:
 Mismatched
blood transfusion (Abs to A/B
Ags)
 Autoimmune hemolytic anemia (Abs to self
Ag on RBC)
 Autoimmune thrombocytopenia purpura
(Abs to platelet integrin  abnormal
bleeding/hemorrhaging)
 Goodpastuer’s Syndrome (renal failure due
to anti-basement membrane collagen Abs)
vulgaris (skin blisters – antiepidermal cadherin Abs)
 Acute rheumatic fever (cross-reactive Abs
to cardiac muscle generated following
Streptococcus group A infection 
myocarditis, arthritis, heart valve scarring)
 Drug allergies (e.g. penicillin) (drug
combines with cell proteins)
 Pemphigus
Penicillin interferes with the
bacterial enzyme transpeptidase
after binding to the active site in
the enzyme.
Penicillin may also bind to surface proteins
on human cells (RBC = most common).
This creates a new epitope that can act
like a foreign Ag.
Fig. 10.27: Penicillin-protein conjugates stimulate the production of
anti-penicillin antibodies.
Penicillin-modified RBC get coated with C3b as a bystander effect of C’ activation by bacterial activating surfaces
for which the penicillin was administered. This initiates the process by inducing opsonization by macrophages.
 RBC
and platelets are especially
susceptible to lytic effects of Type II
hypersensitivity, owing to reduced levels
of C’ regulatory proteins than other cells
have.

Ab can alter signaling properties of cells in
autoimmunity

Grave’s Disease



Myasthenia Gravis (MG)



Agonist Ab  Hyperthyroidism
Ab = anti TSH receptor specific  overproduction of
thyroid hormone
Antagonist Ab  Blocks neuromuscular transmission
Anti-acetylcholine receptor specific  progressive
weakness
MORE LATER - AUTOIMMUNITY
IV. Type III (Immune complex)
Hypersensitivity
A. Description of immune
complexes

Form through association of Ab with
multivalent soluble Ag
 Complexes become deposited on blood
vessel walls or tissue sites and activate C’ 
Inflammation induced (C5a)
 Pathogenicity depends on size of complex


Large = cleared by C’ fixation (Ab excess)
Small = deposited (Ag excess)
B. Damage to host tissue
vessels  Vasculitis
 Kidney glomerular basement membrane
 Glomerulonephritis
 Synovial tissue of joints  Arthritis or
Arthralgia
 Skin  Butterfly rash in SLE
 Blood
The pathology of type III hypersensitivity reactions is determined by the sites of
immune-complex deposition.

Mechanism:





C’ is activated
Basophils and platelets degranulate
Histamine and other inflammatory mediators are
released
Vascular permeability increases
Platelets aggregate and form microthrombi (blood
clots) on vessel walls


Burst, hemorrhaging of skin
Recruitment of PMNL by chemotaxis

Further degranulation, enzyme release and host damage
 vasculitis
C. Five types of disease
 Arthus
reaction
 Serum sickness
 Persistent viral, bacterial or protozoan
infection in face of weak Ig response
 Continuous autoantibody production
 Immune complexes formed at body
surfaces
D. Examples

Arthus Reaction


A skin reaction occuring in sensitized (already
immune) individuals where Ag is injected into the
dermis and reacts with IgG in extracellular spaces
This in turn leads to C’ fixation/activation (mast cell
degranulation) and recruitment of phagocytic cells
leading to inflammation




Increased fluid and protein release
Increased phagocytosis
Blood vessel occlusion by platelets
Experimental model for I.C. disease
Localized deposition of immune complexes within a tissue causes a type III
hypersensitivity reaction.
 Serum
Sickness
 Systemic
reaction to a large dose of Ag (710 days after injection)

Ag is poorly catabolized and remains in
circulation long enough to be available
following primary immune response
 Chills,
fever, urticaria, arthritis and
glomerulonephritis
 Examples:
Horse serum used to treat pneumococcal
pneumonia prior to antibiotics usage
 Anti-venin – horse anti snake venom
 Mouse anti-lymphocyte globulin used for
immunosuppression of transplantation (mouse
MoAb)
 Streptokinase (bacterial enzyme) to treat heart
attack victims
 Antibiotics (penicillin or cephalosporin)


Serum sickness is usually a self-limited disease



Symptoms improve as host Abs increase to zone of Ab
excess
Can be fatal if kidneys shut down or hemorrhaging
occurs in brain
Treatment


Prednisone (anti-inflammatory – corticosteroid) and
Benadryl (anti-histamine)
Prior sensitization is NOT prerequisite  Reaction can
occur on first encounter if Ag isn’t readily cleared from
circulation and is present at high concentration
Serum sickness is a classic example of a transient immune-complex mediated syndrome.
 Persistent
viral, bacterial or protozoan
infections
 Results
in chronic immune complex
formation (IC)
 Examples:
Subacute bacterial endocarditis
 Acute glomerulonephritis
 Chronic viral hepatitis

 Autoantibody
produced continuously
 Prolonged
IC formation
 Systemic lupus erythematosus (SLE)
Glomerulonephritis, arthritis, vasculitis
 AutoAbs to DNA, RNA and proteins associated
with nucleic acids

 Immune
complex formed at body
surfaces (lungs) (IgG not IgE)
 Exposure
to very large doses of inhaled
allergens  Inflammation of alveolar wall
of lung
 Farmer’s lung  Inhalation of hay dust or
mold spores  Gas exchange
compromised
V. Type IV Hypersensitivity
A. Features
 T-cell
mediated immune responses
 Includes:
Delayed-type hypersensitivity
 Contact hypersensitivity
 Gluten-sensitive enteropathy (Celiac disease)

B. Mechanism
 Delayed-type
hypersensitivity = DTH
TDTH recruited
 Soluble Ag  macrophages, TH1 activation
 Cell-associated Ag  TH1 activation  Tcyt
cytotoxicity
 Cytokines and chemokines produced



Other cells recruited


IL-2, gIFN, IL-3, TNFa, TNFb and GM-CSF
Macrophages, basophils, other lymphocytes
Tissue can be severely damaged

Cytokines, chemokines and cytotoxins made
by TH1 during Type IV Hypersensitivity
Reactions

Chemokines


Recruitment of macrophages to the site of Ag deposition
Cytokine

gIFN


Macrophage activation, release of inflammatory mediators
IL-3/GM-CSF

Increased monocyte synthesis in bone marrow
 Cytotoxins
– TNFa and TNFb
TNFa activates macrophage
 TNFa and TNFb  blood vessel adhesion
molecules expressed (activation of endothelial
cells)  cells infiltrate, edema
 TNFb  cytotoxic to macrophages and other
cells

 Tcyt
may also be involved in Type IV
hypersensitivity reactions
 Cell-mediated
cytotoxicity and gIFN
production
 Modified peptides associate with class I
(e.g. pentadecacatechol of poison ivy =
lipid soluble)
 The
time course of a delayed type
hypersensitivity reaction
 Acquired

1st phase:


IR
Uptake, processing and presentation of Ag
2nd phase:


Previously primed TH1 cells migrate to site of
infection and become activated
T cells secrete mediators that result in recruitment of
macrophages  Inflammation ensues fluid and
protein accumulate  Lesion  Induration
C. Examples
 Tuberculin
hypersensitivity
 Tuberculosis
skin test (Mantoux test, Heath
test – multipronged skin prick)
 Purified protein derivative (PPD) from
Mycobacterium tuberculosis
Injected intradermally
 After 48 hours, induration (swelling/lesion)
indicates positive reaction


Related to degree of sensitivity
 Indicates prior exposure to M. tuberculosis

Other microbial products used in Type IV skin
testing include




Histoplasmic (for histoplasmosis – Histoplasma
capsulatum – fungus)
Coccidiodin (for coccidiodomycosis – fungus)
Lepromin (for Hansen’s disease – Mycobacterium
leprae)
Brucellergen (for brucellosis – bacteria – Brucella
spp.)
 Allergic
contact dermatitis
 Haptens
combine with skin proteins
Pentadecacatechol (poison ivy)
 Cosmetics
 Metals (jewelry)



Nickel
Gold
 Transplantation
(Graft) Rejection

Autoimmune diseases




Rheumatoid arthritis (joint inflammation)
Multiple sclerosis and Experimental allergic
encephalomyelitis (EAE) (demyelination)
Diabetes mellitus (IDDM) (pancreatic beta cell
destruction)
Gluten-sensitive enteropathy – Celiac disease


Ag = Gliadin
Malabsorption results from villous atrophy in small
intestine
Fig. 10.33: Summary