Hypersensitivity

Hypersensitivity
• Paul Portier and Charles Richet, investigated the problem of
bathers in the Mediterranean reacting violently to the
stings of Portuguese Man of War jellyfish.
• Portier and Richet concluded that the localized reaction of
the bathers was the result of toxins.
• To counteract this reaction, the scientists experimented
with the use of isolated jellyfish toxins as vaccines.
• Portier and Richet injected dogs with the purified toxins,
followed later by a booster of toxins.
• Instead of reacting to the booster by producing antibodies
against the toxins, the dogs immediately reacted with
vomiting, diarrhea, asphyxia, and, in some instances, death.
 Hypersensitivity
• The animals “overreacted” to the antigen.
• Portier and Richet coined the term
anaphylaxis, loosely translated from Greek to
mean the opposite of prophylaxis, to describe
this overreaction.
• Richet was subsequently awarded the Nobel
Prize in Physiology or Medicine in 1913 for his
work on anaphylaxis.
 Gell and Coombs Classification
• P. G. H. Gell and R. R. A. Coombs proposed a
classification scheme in which hypersensitive reactions
are divided into four types.
• Three types of hypersensitivity occur within the
humoral branch and are mediated by antibody or
antigen-antibody complexes:
– IgE-mediated (type I)
– Antibody-mediated (type II)
– Immune complex–mediated (type III)
• A fourth type of hypersensitivity depends on reactions
within the cell-mediated branch, and is termed
delayed-type hypersensitivity, or DTH
 Type I Hypersensitivity
• IgE mediated
• This class of antibody binds with high affinity to Fc receptors on the
surface of tissue mast cells and blood basophils.
• Mast cells and basophils coated by IgE are said to be sensitized.
• A later exposure to the same allergen cross-links the membrane-
bound IgE on sensitized mast cells and basophils, causing
degranulation of these cells.
• The pharmacologically active mediators released from the granules
act on the surrounding tissues.
• The principal effects—vasodilation and smooth-muscle
contraction—may be either systemic or localized, depending on the
extent of mediator release.
 Components of Type I Reactions
Allergen
• Allergen - The term allergen refers specifically to
nonparasitic antigens capable of stimulating type
I hypersensitive responses in allergic individuals.
• Atopy is a hereditary predisposition to the
development of immediate hypersensitivity
reactions against common environmental
antigens.
• The IgE regulatory defects suffered by atopic
individuals allow nonparasitic antigens to
stimulate inappropriate IgE production, leading to
tissue damaging type I hypersensitivity.
• The abnormal IgE response of atopic
individuals is at least partly genetic—it often
runs in families.
• Atopic individuals have abnormally high levels
of circulating IgE and also more than normal
numbers of circulating eosinophils.
• These individuals are more susceptible to
allergies such as hay fever, eczema, and
asthma.
• Most allergic IgE responses occur on mucous
membrane surfaces in response to allergens
that enter the body by either inhalation or
ingestion.
• Ragweed Pollen - The pollen particles are inhaled, and their
tough outer wall is dissolved by enzymes in the mucous
secretions, releasing the allergenic substances.
• Chemical fractionation of ragweed has revealed a variety of
substances, most of which are not allergenic but are
capable of eliciting an IgM or IgG response.
• Of the five fractions that are allergenic (i.e., able to induce
an IgE response), two evoke allergenic reactions in about
95% of ragweed-sensitive individuals and are called major
allergens; these are designated the E and K fractions.
• The other three, called Ra3, Ra4, and Ra5, are minor
allergens that induce an allergic response in only 20% to
30% of sensitive subjects.
 Components of Type I Reactions
IgE
• The existence of a human serum factor that
reacts with allergens was first demonstrated by K.
Prausnitz and H. Kustner in 1921.
• The local wheal and flare response that occurs
when an allergen is injected into a sensitized
individual is called the P-K reaction.
• Because the serum components responsible for
the P-K reaction displayed specificity for allergen,
they were assumed to be antibodies, but the
nature of these P-K antibodies, or reagins, was
not demonstrated for many years.
• Serum IgE levels in normal individuals fall within
the range of 0.1–0.4 µg/ml; even the most
severely allergic individuals rarely have IgE levels
greater than 1 µg/ml.
• Fc portion of the molecule that enables it to bind
to glycoprotein receptors on the surface of
basophils and mast cells.
• Although the half-life of IgE in the serum is only
2–3 days, once IgE has been bound to its receptor
on mast cells and basophils, it is stable in that
state for a number of weeks.
 Components of Type I Reactions
Mast Cells and Basophils
• Mast-cell precursors are formed in the bone marrow
during hematopoiesis and are carried to virtually all
vascularized peripheral tissues, where they
differentiate into mature cells.
• Mast cells are found throughout connective tissue,
particularly near blood and lymphatic vessels.
• Some tissues, including the skin and mucous
membrane surfaces of the respiratory and
gastrointestinal tracts, contain high concentrations of
mast cells; skin, for example, contains 10,000 mast cells
per mm3.
• Mast cells have numerous membrane-
bounded granules distributed throughout the
cytoplasm, which, like those in basophils
contain pharmacologically active mediators.
• After activation, these mediators are released
from the granules, resulting in the clinical
manifestations of the type I hypersensitive
reaction.
Components of Type I Reactions
IgE-BINDING Fc RECEPTORS
 Pharmacological Mediators of Type I
Reaction
• The mediators can be classified as either
primary or secondary.
• The primary mediators are produced before
degranulation and are stored in the granules.
• The most significant primary mediators are
histamine, proteases, eosinophil chemotactic
factor, neutrophil chemotactic factor, and
heparin.
• The secondary mediators either are
synthesized after target-cell activation or are
released by the breakdown of membrane
phospholipids during the degranulation
process.
• The secondary mediators include platelet-
activating factor, leukotrienes, prostaglandins,
bradykinins, and various cytokines.
Pharmacological Mediators of Type I Reaction
Histamine
• Once released from mast cells, histamine
initially binds to specific receptors on various
target cells.
• Three types of histamine receptors—
designated H1, H2, and H3—have been
identified; these receptors have different
tissue distributions and mediate different
effects when they bind histamine.
Pharmacological Mediators of Type I Reaction
Histamine
• Most of the biologic effects of histamine in
allergic reactions are mediated by the binding
of histamine to H1 receptors. This binding
induces contraction of intestinal and bronchial
smooth muscles, increased permeability of
venules, and increased mucus secretion by
goblet cells.
Pharmacological Mediators of Type I Reaction
Histamine
• Interaction of histamine with H2 receptors
increases vasopermeability and dilation and
stimulates exocrine glands.
• Binding of histamine to H2 receptors on mast
cells and basophils suppresses degranulation;
thus, histamine exerts negative feedback on
the release of mediators.
 Leukotrienes and Prostaglandins
• As secondary mediators, the leukotrienes and
prostaglandins are not formed until the mast cell
undergoes degranulation and the enzymatic breakdown of
phospholipids in the plasma membrane.
• An ensuing enzymatic cascade generates the prostaglandins
and the leukotrienes.
• It therefore takes a longer time for the biological effects of
these mediators to become apparent.
• Their effects are more pronounced and longer lasting,
however, than those of histamine.
• The leukotrienes mediate bronchoconstriction, increased
vascular permeability, and mucus production.
• Prostaglandin D2 causes bronchoconstriction.
 Leukotrienes and Prostaglandins
• The contraction of human bronchial and tracheal
smooth muscles appears at first to be mediated by
histamine, but, within 30–60 s, further contraction is
mediated by the leukotrienes and prostaglandins.
• Being active at nanomole levels, the leukotrienes are as
much as 1000 times more potent as
bronchoconstrictors than histamine is, and they are
also more potent stimulators of vascular permeability
and mucus secretion.
• In humans, the leukotrienes are thought to contribute
to the prolonged bronchospasm and buildup of mucus
seen in asthmatics.
 Systemic Anaphylaxis
• Systemic anaphylaxis is a shock-like and often
fatal state whose onset occurs within minutes
of a type I hypersensitive reaction.
 Systemic Anaphylaxis
• Active sensitization in guinea pigs is induced by a single injection of
a foreign protein such as egg albumin.
• After an incubation period of about 2 weeks, the animal is usually
challenged with an intravenous injection of the same protein.
• Within 1 min, the animal becomes restless, its respiration becomes
labored, and its blood pressure drops.
• As the smooth muscles of the gastrointestinal tract and bladder
contract, the guinea pig defecates and urinates.
• Finally bronchiole constriction results in death by asphyxiation
within 2–4 min of the injection.
• These events all stem from the systemic vasodilation and smooth-
muscle contraction brought on by mediators released in the course
of the reaction.
• Postmortem examination reveals that massive edema, shock, and
bronchiole constriction are the major causes of death.
 Systemic Anaphylaxis
• Systemic anaphylaxis in humans is characterized by a
similar sequence of events.
• A wide range of antigens have been shown to trigger this
reaction in susceptible humans, including the venom from
bee, wasp, hornet, and ant stings; drugs, such as penicillin,
insulin, and antitoxins; and seafood and nuts.
• If not treated quickly, these reactions can be fatal.
• Epinephrine is the drug of choice for systemic anaphylactic
reactions. Epinephrine counteracts the effects of mediators
such as histamine and the leukotrienes by relaxing the
smooth muscles and reducing vascular permeability.
 Systemic Anaphylaxis
• Epinephrine also improves cardiac output,
which is necessary to prevent vascular
collapse during an anaphylactic reaction.
• In addition, epinephrine increases cAMP levels
in the mast cell, thereby blocking further
degranulation.
 Localized Anaphylaxis (Atopy)
• In localized anaphylaxis, the reaction is limited to
a specific target tissue or organ, often involving
epithelial surfaces at the site of allergen entry.
• The tendency to manifest localized anaphylactic
reactions is inherited and is called atopy.
• Atopic allergies, which afflict at least 20% of the
population in developed countries, include a wide
range of IgE-mediated disorders, including allergic
rhinitis (hay fever), asthma, atopic dermatitis
(eczema), and food allergies.
Late Phase Reactions Induce Localized
Inflammatory Response
Detection
 Prevention and Treatment
• Elimination of Allergen
• Immunotherapy with repeated injections of
increasing doses of allergens
hyposensitization) has been known for some
time to reduce the severity of type I reactions,
or even eliminate them completely, in a
significant number of individuals suffering
from allergic rhinitis.
• Use of humanized monoclonal anti-IgE. These
antibodies bind to IgE, but only if IgE is not
already bound to FcRI. The monoclonal
antibodies are specifically selected to bind
membrane IgE on IgE-expressing B cells.
Antibody-Mediated Cytotoxic (Type II)
Hypersensitivity
• ADCC
• Complement mediated killing
 Transfusion Reactions Are Type II
Reactions
• Antibodies to the A, B, and O antigens, called
isohemagglutinins, are usually of the IgM class.
• If a type A individual is transfused with blood
containing type B cells, a transfusion reaction occurs in
which the anti-B isohemagglutinins bind to the B blood
cells and mediate their destruction by means of
complement-mediated lysis.
• Antibodies to other blood-group antigens may result
from repeated blood transfusions because minor allelic
differences in these antigens can stimulate antibody
production. These antibodies are usually of the IgG
class.
• The clinical manifestations of transfusion
reactions result from massive intravascular
hemolysis of the transfused red blood cells by
antibody plus complement.
• These manifestations may be either
immediate or delayed.
• Reactions that begin immediately are most
commonly associated with ABO blood-group
incompatibilities, which lead to complement
mediated lysis triggered by the IgM
isohemagglutinins.
• Within hours, free hemoglobin can be detected in
the plasma; it is filtered through the kidneys,
resulting in hemoglobinuria.
• Some of the hemoglobin gets converted to
bilirubin, which at high levels is toxic.
• Typical symptoms include fever, chills, nausea,
clotting within blood vessels, pain in the lower
back, and hemoglobin in the urine.
• Treatment involves prompt termination of the
transfusion and maintenance of urine flow
with a diuretic, because the accumulation of
hemoglobin in the kidney can cause acute
tubular necrosis.
• Delayed hemolytic transfusion reactions generally
occur in individuals who have received repeated
transfusions of ABO-compatible blood that is
incompatible for other blood group antigens.
• The reactions develop between 2 and 6 days after
transfusion, reflecting the secondary nature of
these reactions.
• The transfused blood induces clonal selection and
production of IgG against a variety of blood-
group membrane antigens, most commonly Rh,
Kidd, Kell, and Duffy.
• The predominant isotype involved in these
reactions is IgG, which is less effective than
IgM in activating complement.
• Symptoms include fever, low hemoglobin,
increased bilirubin, mild jaundice, and
anemia.
 Hemolytic Disease of the Newborn
Is Caused by Type II Reactions
• Hemolytic disease of the newborn develops
when maternal IgG antibodies specific for fetal
blood-group antigens cross the placenta and
destroy fetal red blood cells.
• Severe hemolytic disease of the newborn,
called erythroblastosis fetalis, most commonly
develops when an Rh+ fetus expresses an Rh
antigen on its blood cells that the Rh– mother
does not express.
• Mild to severe anemia can develop in the
fetus, sometimes with fatal consequences. In
addition, conversion of hemoglobin to
bilirubin can present an additional threat to
the newborn because the lipid-soluble
bilirubin may accumulate in the brain and
cause brain damage.
• Hemolytic disease of the newborn caused by Rh incompatibility in a
subsequent pregnancy can be almost entirely prevented by
administering antibodies against the Rh antigen to the mother
within 24–48 h after the first delivery.
• These antibodies, called Rhogam, bind to any fetal red blood cells
that enter the mother’s circulation at the time of delivery and
facilitate their clearance before B-cell activation and ensuing
memory-cell production can take place.
• In a subsequent pregnancy with an Rh+ fetus, a mother who has
been treated with Rhogam is unlikely to produce IgG anti-Rh
antibodies; thus, the fetus is protected from the damage that would
occur when these antibodies crossed the placenta.
• The presence of maternal IgG on the surface
of fetal red blood cells can be detected by a
Coombs test.
• Isolated fetal red blood cells are incubated
with the Coombs reagent, goat antibody to
human IgG antibody.
• If maternal IgG is bound to the fetal red blood
cells, the cells agglutinate with the Coombs
reagent.
• For a severe reaction, the fetus can be given an intrauterine
blood-exchange transfusion to replace fetal Rh+ red blood
cells with Rh– cells. These transfusions are given every 10–
21 days until delivery.
• In less severe cases, a blood-exchange transfusion is not
given until after birth, primarily to remove bilirubin; the
infant is also exposed to low levels of UV light to break
down the bilirubin and prevent cerebral damage.
• The mother can also be treated during the pregnancy by
plasmapheresis. In this procedure, a cell separation
machine is used to separate the mother’s blood into two
fractions, cells and plasma. The plasma containing the anti-
Rh antibody is discarded, and the cells are reinfused into
the mother in an albumin or fresh-plasma solution.
Drug-Induced Hemolytic Anemia Is
a Type II Response
 Immune Complex–Mediated
(Type III) Hypersensitivity
• Type III hypersensitive reactions develop when immune complexes
activate the complement system’s array of immune effector
molecules.
• C3a, C4a, and C5a complement split products are anaphylatoxins
that cause localized mast-cell degranulation and consequent
increase in local vascular permeability.
• C3a, C5a, and C5b67 are also chemotactic factors for neutrophils,
which can accumulate in large numbers at the site of immune-
complex deposition.
• Larger immune complexes are deposited on the basement
membrane of blood vessel walls or kidney glomeruli, whereas
smaller complexes may pass through the basement membrane and
be deposited in the subepithelium. The type of lesion that results
depends on the site of deposition of the complexes.
• Much of the tissue damage in type III reactions stems from release of
lytic enzymes by neutrophils as they attempt to phagocytose immune
complexes.
• The C3b complement component acts as an opsonin, coating immune
complexes.
• A neutrophil binds to a C3b-coated immune complex by means of the
type I complement receptor, which is specific for C3b.
• Because the complex is deposited on the basement membrane surface,
phagocytosis is impeded, so that lytic enzymes are released during the
unsuccessful attempts of the neutrophil to ingest the adhering immune
complex.
• Further activation of the membrane-attack mechanism of the
complement system can also contribute to the destruction of tissue.
• the activation of complement can induce aggregation of platelets, and
the resulting release of clotting factors can lead to formation of
microthrombi.
Type III Reactions Can Be Localized
• Injection of an antigen intradermally or
subcutaneously into an animal that has high
levels of circulating antibody specific for that
antigen leads to formation of localized
immune complexes, which mediate an acute
Arthus reaction within 4–8 h.
• Microscopic examination of the tissue reveals
neutrophils adhering to the vascular endothelium
and then migrating into the tissues at the site of
immune complex deposition.
• As the reaction develops, localized tissue and
vascular damage results in an accumulation of
fluid (edema) and red blood cells (erythema) at
the site.
• The severity of the reaction can vary from mild
swelling and redness to tissue necrosis.
 Type III Reactions Can Also Be
Generalized
• When large amounts of antigen enter the bloodstream
and bind to antibody, circulating immune complexes
can form.
• Generalized type III reactions were often observed
after the administration of antitoxins containing
foreign serum, such as horse antitetanus or
antidiphtheria serum.
• In such cases, the recipient of a foreign antiserum
develops antibodies specific for the foreign serum
proteins; these antibodies then form circulating
immune complexes with the foreign serum antigens.
 `
• Within days or weeks after exposure to foreign
serum antigens, an individual begins to
manifest a combination of symptoms that are
called serum sickness.
• These symptoms include fever, weakness,
generalized vasculitis (rashes) with edema and
erythema, lymphadenopathy, arthritis, and
sometimes glomerulonephritis.
 Type IV or Delayed Type
Hypersensitivity
• When some subpopulations of activated TH
cells encounter certain types of antigens, they
secrete cytokines that induce a localized
inflammatory reaction called delayed-type
hypersensitivity (DTH).
• The reaction is characterized by large influxes
of nonspecific inflammatory cells, in particular,
macrophages.
• The hallmarks of a type IV reaction are the
delay in time required for the reaction to
develop and the recruitment of macrophages
as opposed to neutrophils, as found in a type
III reaction.
• Macrophages are the major component of the
infiltrate that surrounds the site of
inflammation.
• The development of the DTH response begins
with an initial sensitization phase of 1–2
weeks after primary contact with an antigen.
• During this period, TH cells are activated and
clonally expanded by antigen presented
together with the requisite class II MHC
molecule on an appropriate antigen
presenting cell.
• Generally, the T cells activated during the
sensitization phase are CD4+, primarily of the TH1
subtype, but in a few cases CD8+ cells have also
been shown to induce a DTH response.
• The activated T cells previously were called TDTH
cells to denote their function in the DTH
response, although in reality they are simply a
subset of activated TH1 cells (or, in some cases, TC
cells).
• A subsequent exposure to the antigen induces
the effector phase of the DTH response.
• In the effector phase, TH1 cells secrete a variety
of cytokines that recruit and activate
macrophages and other nonspecific inflammatory
cells.
• A DTH response normally does not become
apparent until an average of 24 h after the
second contact with the antigen; the response
generally peaks 48–72 h after second contact.
• Macrophages are the principal effector cells of
the DTH response.
• Cytokines elaborated by TH1 cells induce blood
monocytes to adhere to vascular endothelial
cells and migrate from the blood into the
surrounding tissues.
• During this process the monocytes
differentiate into activated macrophages.
• Activated macrophages exhibit increased
levels of phagocytosis and an increased ability
to kill microorganisms through various
cytotoxic mediators.
• In addition, activated macrophages express
increased levels of class II MHC molecules and
cell-adhesion molecules and therefore
function more effectively as antigen-
presenting cells.
• The heightened phagocytic activity and the
buildup of lytic enzymes from macrophages in
the area of infection lead to nonspecific
destruction of cells, and thus of the
intracellular pathogen.
• Generally, the pathogen is cleared rapidly with
little tissue damage.
• However, in some cases, especially if the antigen
is not easily cleared, a prolonged DTH response
can itself become destructive to the host as the
intense inflammatory response develops into a
visible granulomatous reaction.
• A granuloma develops when continuous
activation of macrophages induces the
macrophages to adhere closely to one another,
assuming an epithelioid shape and sometimes
fusing to form multinucleated giant cells
• These giant cells displace the normal tissue
cells, forming palpable nodules, and release
high concentrations of lytic enzymes, which
destroy surrounding tissue.
Contact Dermatitis
 Reference and Further Reading
• Kuby’s Immunology