Hypersensitivities

The immune reactions that protect us from infection can also inflict a great deal of
damage to our own cells and tissues. The immune response uses multiple strategies to
reduce damage to self by turning off responses once pathogen is cleared, and by avoiding
reactions to self antigens. However, these checks and balances can break down, leading to
immune mediated reactions that are more detrimental than protective.

Under certain circumstances the imfammatory responses can have deleterious effects,
resulting in tissue injury, serious diseases or even death.

Such an inappropriate and damaging immune response is termed hypersensitivity.

1
1. Immune system could respond inappropriately to antigenic challenge was
recognized in the twentieth century.

2. Paul Portier and Charles Richet, two French Scientists investigated the
problem of bathers in Mediterranean reacting violently to the stings of
Portuguese man-of-war jellyfish.

3. They isolated the toxin and prepared vaccines and tested on dogs. They
injected the toxins to dogs and also introduced a booster dose.

4. Instead of reacting to the booster by producing antibodies, the dogs reacted

with vomiting , diarrhea, asphyxia, and death.

5. Thus, the sensitized animal overreacted to the antigen.

6. Richet coined the term anaphylaxis, derived from the Greek and translated
loosely as “against protection” to describe this overreaction of the immune
system, the first description of a hypersensitivity reaction. Richet was
subsequently awarded the Nobel Prize in Physiology or Medicine in 1913.
2
Charles Richet
The Nobel Prize in Physiology or Medicine 1913
Born: 26 August 1850, Paris, France
Died: 4 December 1935, Paris, France
Affiliation at the time of the award: Sorbonne University,
Paris, France
Prize motivation: "in recognition of his work on
anaphylaxis“.
Field: immunity
Prize share: 1/1

3
During a cruise on the yacht of
Prince Albert of Monaco, the
Prince advised Charles Richet to
study Physalia poison. Together
with his friends Georges Richard
and Paul Portier they found that
it was easily dissolved in
glycerol and that by injecting
this glycerol solution, the
symptoms of Physalia poisoning
were reproduced.

Portuguese man-of-war jellyfish

(Physalia physalis)

4
1. Hypersensitive reaction may develop through a humoral or a cell mediated immune
response.

2. Anaphylactic reactions initiated by antibody or antigen antibody complexes are

referred to as immediate hypersensitivity because the symptoms are manifest
within minutes or hours after a sensitized recipient encounters antigen.

3. Delayed-type hypersensitivity (DTH) is named in recognition of the delay of

symptoms until days after exposure.

4. Two immunologists, P. G. H. Gell and R. R. A. Coombs, proposed a classification

scheme to discriminate among the various types of hypersensitivity.
Hypersensitivities are classically divided into four categories (types I–IV) that
differ by the immune molecules and cells that cause them, and the way they induce
damage.

5
Four types of hypersensitive reactions

6
7
IgE-Mediated (Type I) Hypersensitivity

1. This reaction is induced by a certain type of antigens referred to as

allergens.
2. This is an example of allergen induced humoral antibody immune
response.

3. Plasma cells secrete IgE in response to activation of allergen-

specificTH2 cells.

4. These antibodies bind with high affinity to Fc receptors on the surface

of tissue mast cells and blood basophils. Both cells are sensitized. A
later exposure to same allergen cross links the membrane bound
antibodies and cause degranulation of these cells.

5. Pharmacologically active mediators released from the granules act on

the surrounding tissue.

8
General mechanism underlying an immediate type I hypersensitivity reaction.
Exposure to an allergen activates T H2 cells that stimulate B cells to
proliferate, undergo heavy-chain class switching to IgE, and
differentiate into IgE-secreting plasma cells and memory B cells
expressing membrane IgE B-cell receptors (mIgE).
The secreted IgE molecules bind to IgE-specific Fc receptors (FcεRI)
on mast cells and blood basophils. (Many molecules of IgE with
various specificities for this and other allergens can bind to FcεRI.)
A second exposure to the allergen leads to cross-linking of the bound
IgE, triggering the release of pharmacologically active mediators from
mast cells and basophils.
The mediators cause numerous effects, including smooth muscle
contraction, increased vascular permeability, and vasodilation.

9
Many allergens can elicit a Type I response
Individuals without allergies generate IgE antibodies only in response to parasitic infections.
However, individuals who genetically are highly susceptible to allergies, a condition known as
atopy, are predisposed to generate IgE antibodies against common environmental antigens.
Chemical analyses revealed that most, if not all, allergens are highly soluble proteins or
glycoproteins, usually with multiple epitopes, or antigenic determinants.

Common allergens associated with type I hypersensitivity

10
A. First, many allergens have intrinsic enzymatic activity that contributes to the allergic response.

1. Allergens from dust mites (the allergenic component of house dust), cockroaches, pollen, fungi, and
bacteria have protease activity. Some of these proteases have been shown to be capable of
disrupting the integrity of epithelial cell junctions, allowing allergens to access the underlying cells
and molecules of the innate and adaptive immune systems.

2. Others, including a protease (Der p 1) produced by the dust mite (Dermatophagoides

pteronyssinus), cleave and activate complement components at the mucosal surface.

3. Still others cleave and stimulate protease-activated receptors on the surfaces of immune cells,
enhancing inflammation. Several cleave the inactive form of the IL-33 cytokine produced by
epithelial cells, generating active IL-33 that contributes to allergic responses.

One factor that distinguishes allergenic from nonallergenic antigens may be the presence of protease
activity that affects the cells and molecules of the immune system.

B. Second, many allergens contain potential pathogen-associated molecular patterns, or PAMPS

capable of interacting with receptors of the innate immune system and initiating a
cascade of responses that contribute to an allergic response.

C. Third, many allergens enter the host via mucosal tissues at very low concentrations, which tend to
induce TH 2 responses. The IL-4 and IL-13 produced by TH 2 cells induce heavy-chain class
switching to IgE during the generation both of plasma cells secreting allergen-specific antibodies
and of allergen-specific memory B cells
11
Schematic diagrams of the high-affinity FcεRI and low-affinity FcεRII receptors that bind the Fc
region of IgE.
(a) FcεRI consists of an α chain that binds IgE, a β chain that participates in signaling, and two
disulfide-linked γ chains that are the most important component in signal transduction. The β and γ
chains contain cytoplasmic ITAMs, a motif also present in the Igα/Igβ (CD79α/β) heterodimer of the B-
cell receptor and in the CD3 chains of the T-cell receptor complex.
(b) The single-chain FcεRII is unusual because it is a type II transmembrane protein, oriented in the
membrane with its NH terminus directed toward the cell interior and its COOH terminus directed toward
the extracellular space. 12
 Signaling pathways initiated by
IgE allergen cross-linking of
FcεRI receptors.

By cross-linking FcεRI receptors,

IgE initiates signals that lead to
mast cell degranulation and release
of prepackaged mediators, cytokine
production, and leukotriene and
prostaglandin generation.
The signaling cascades initiated by
the FcεRI are generally similar to
those initiated by antigen receptors.

Cross-linking of FcεRI activates the tyrosine kinase Lyn, which phosphorylates the receptor ITAMs and
activates the tyrosine kinase Syk, which phosphorylates adapter molecules that organize signaling
responses.
Multiple kinases are activated, including protein kinase C (PKC) and various mitogen-activated protein
kinases (MAPKs). These, in turn, activate transcription factors (e.g., NF-κB) that regulate cytokine
production. They also activate lipases, including phospholipase D (PLD), and stimulate an increase in
intracellular free calcium ions and a transient increase in cAMP all of which induce degranulation.
Phospholipase A (PLA) is activated, initiating the production of leukotrienes and prostaglandins from the
13
metabolism of arachidonic acid.
 Mast cell activation and degranulation

1. Activation of protein Tyrosine Kinase (PTK)

2. PTK phosphorylates phospholipase C which converts phosphatydillinositol-4,5
bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate(Ip3)
14
2. DAG activated protein kinase C (PKC), which with Ca2+ is necessary for microtubuler
assembly and the fusion of the granules with the plasma membrane. IP3 is a potent
mobilizer of intracellular Ca2+stores.
15
3. Crosss linkage of FcεR1 also activates an enzyme that converts phosphatidylserine (PS)
into phosphatidylethanolamine (PE). PE is methylated toform phosphatidylcholine (PC) by
the phospholipid methyl transferase enzymes I and II (PMT I and II).
16
4. Accumulation of PC on the exterior surface of the plasma membrane causes an increase
in membrane fluidity and facilitates the formation of Ca2+ channels. Influx of calcium and
PTK-activated mitogen-activated protein kinase (MAPK) activates phospholipase A2 which
promoted break dowm of PC into lysophosphatidylcholine Lyso PC and arachidonic acid. 17
5. Arachidonic acid is converted into potent lipid mediators: Prostaglandins and leukotrienes(slow reactive
substance of anaphylaxix, SRS-A).
6. Activated MAPK induces secretion of cytokines by increasing transcription of cytokine genes.
7. Cross linkage of membrane receptors activates membrane Adenylate cyclase leading to transient increase
18
of cAMP-dependent protein kinase required for degranulation.
8. Granule membrane proteins are phosphorylated by C-AMP dependent protein kinase
therby changing permeability of granules to water and Ca2+. Subsequent swelling and
formation of soluble N-ethymaleimide attachment receptor (SNARE) protein complex which
facilitates fusion with the plasma membrane and release of the mediators. 19
Effects of mast cell activation.
(a) Mast cells before (left) and after degranulation (right) induced by IgE
antibodies and antigen that is bound by the antibodies. Resting mast cells
have numerous granules (secretory vesicles) stored in their cytoplasm.
After the mast cell is activated by addition of IgE antibodies (which bind to
FcεRI) and an antigen that cross-links the IgE antibodies, the granules fuse
with the plasma membrane, releasing their contents. Extra membrane from
the granules is seen in the cell’s plasma membrane after degranulation.

(b) Mast cell mediators and their effects. Various

stimuli activate mast cells to secrete different types
and/or amounts of products. Activated mast cells
immediately release preformed, granule-associated
inflammatory mediators (including histamine,
proteases, and heparin) and are induced to generate
lipid mediators (such as leukotrienes and
prostaglandins), chemokines, cytokines, and growth
factors (some of which can also be packaged in
granules). These mediators act on different cell types,
and have both acute and chronic effects. When
produced over long periods of time, mast cell
mediators have a significant influence on tissue
structure by enhancing proliferation of fibroblasts and
epithelial cells, increasing production and
deposition of collagen and other connective tissue
proteins, stimulating the generation of blood vessels,
and more.

20
Principal mediators involved in type I hypersensitivity

21
The early and late
inflammatory responses in
asthma.
Early responses mediated by
IgE binding to mast cells,
triggering degranulation and
mediator release, occur within
about 30 minutes of allergen
inhalation, while late responses
may take 6 to 12 hours.
The effects of various mediators
on an airway, represented in
cross-section, are illustrated in
the center.
Chronic asthma can result in
more serious effects, including
disruption of the epithelial
barrier, thickening of
the basement membrane and
smooth muscle layer, and
increase in mucus-secreting
cells.

22
Localized Hypersensitivity Reactions
In localized hypersensitivity reactions, the effects are limited to a specific target site in a tissue or
organ, often occurring at the epithelial surfaces first exposed to allergens. These localized allergic
reactions include a wide range of IgE-mediated reactions: allergic rhinitis (hay fever), asthma,
atopic dermatitis (eczema), urticaria (hives), angioedema (deep tissue swelling), and food allergies.
The most common localized hypersensitivity reaction is allergic rhinitis or hay fever.
Symptoms result from the inhalation of common airborne allergens (pollens, dust, animal dander,
mold spores),

Systemic Anaphylaxis
The most severe type of allergic response, anaphylaxis, is a systemic, often fatal state that occurs
within minutes of exposure to an allergen. It is usually initiated by an allergen introduced directly
into the bloodstream or absorbed into the circulation from the gut or skin. Symptoms include a
precipitous drop in blood pressure leading to anaphylactic shock, followed by contraction of smooth
muscles leading to defecation, urination, and bronchiolar constriction causing labored respiration.
This can lead to asphyxiation, which can cause death within 2 to 4 minutes of exposure to the
allergen. These symptoms are all due to rapid and widespread IgE antibody-mediated degranulation
of mast cells and basophils and the systemic effects of their contents.
A wide range of allergens has 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;
foods such as seafood and nuts; and latex. If not treated quickly, these reactions can be fatal.

23
Environmental factors and genetics influence predisposition to allergies. Exposure to environments with
significant microbial content, such as those including farm animals, and diets high in fiber are protective. In contrast,
environmental factors that enhance development of type I hypersensitivities include air pollution (such as smoke from
trucks and factories, second-hand cigarette smoke, and ozone typical of Western industrialized countries), low fiber
diet, and low microbial exposure (e.g., in areas with good sanitation and use of vaccines and antibiotics). These
factors contribute to the disruption of the integrity of epithelial barrier layers. Genetic differences also influence the
mucosal immune system. Development of type 2 immunity, involving dendritic cells, ILC2 cells, and T 2 cells—
which all promote IgE antibody production—leads to H allergic responses. 24
The hygiene hypothesis
The early findings that susceptibility to type I hypersensitivity conditions is high in Western
industrialized societies and reduced in environments where there is early exposure to microbes, as is
found in many developing countries, led to the hygiene hypothesis.
This hypothesis proposes that exposure to some pathogens during infancy and childhood benefits
individuals by stimulating immune responses other than the type 2 responses that induce IgE
responses and allergies.

25
The wheal and flare reaction in the skin and allergy skin test
26
Allergens not always required for
type I hypersensitive reaction

27
Majority of humans mount significant IgE responses only as a defense against parasitic
infections. Level of serum IgE remains high until the parasite is successfully cleared from
the body.

Some people may have abnormality where they produce IgE in response to common
environmental antigens. It is a hereditary predisposition to develop immediate hyper
sensitivity and such abnormality is called atopy.

28
Antibody-Mediated (Type II) Hypersensitivity

Type II hypersensitivity reactions involve antibody-mediated

destruction of cells by IgG and IgM immunoglobulins. Antibody
bound to a cell-surface antigen can induce death of the antibody
bound cell by three distinct mechanisms.

First, certain immunoglobulin subclasses can activate the

complement system, creating pores in the membrane of a foreign
cell.

Second, antibodies can mediate cell destruction by antibody-

dependent cell-mediated cytotoxicity (ADCC), in which cytotoxic
cells bearing Fc receptors bind to the Fc region of antibodies on
target cells and promote killing of the cells.

Third, antibody bound to a foreign cell also can serve as an

opsonin, enabling phagocytic cells with Fc receptors or (after
complement has been activated by the bound antibodies) receptors
for complement fragments such as C3b to bind and phagocytose
the antibody-coated cell.

29
 Transfusion reactions are type II reactions:
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 B blood
cells and mediate their destruction by means of
complement mediated lysis.
Massive intra vascular hemolysis of transfused red
blood cells takes place. Free hemoglobin is detected in
plasma. Antibodies to other blood group antigens may
result from repeated blood transfusion because minor
allelic differences in these antigens can stimulate
antibody production.

ABO (ABH) blood groups. (a) Structure of terminal sugars, which constitute the distinguishing
epitopes of the A, B, and H blood antigens. All individuals express the H antigen, but not all
individuals express the A or B antigens. The blood group of those who express neither A or B
antigens (but, like all people express the H antigen) is referred to as O. (b) ABO genotypes,
corresponding phenotypes, agglutinins (antigens), and isohemagglutinins (antibodies that react to
nonhost antigens).
30
 The ABO antigens are
carbohydrates, linked to cell
surface lipids and proteins.
These are synthesized by
polymorphic glycosyltransferase
enzymes that vary in activity
depending on the inherited
allele.
Most individuals possess a
fucosyltransferase that
adds a fucose moiety to
the nonterminal sugar
residue of the core glycan.
The fucosylated glycan is
called the H antigen.
Different blood groups are
produced by addition of
different sugars by different
inherited glycosyltransferases.
The O allele gene The A allele encoded
enzyme transfers a The B allele gene product
product is devoid of transfers a terminal galactose
any enzyme activity. terminal N-
acetylgalactosamine moity moiety.
31
onto the H antigen
Transfusion reactions are type II reactions:
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 B blood cells and mediate their destruction by means
of complement mediated lysis.
Massive intra vascular hemolysis of transfused red blood cells takes place. Free hemoglobin is
detected in plasma. Antibodies to other blood group antigens may result from repeated blood
transfusion because minor allelic differences in these antigens can stimulate antibody production.

An Rh mother pregnant by an Rh father is in danger of developing a response to the Rh

antigen that the fetus may have inherited from the father and rejecting the Rh fetus. During
pregnancy, fetal red blood cells are separated from the mother’s circulation by a layer of cells in
the placenta called the trophoblast. During her first pregnancy with an Rh fetus, an Rh woman is
usually not exposed to enough fetal red blood cells to activate her Rh-specific B cells. However, at
the time of delivery, separation of the placenta from the uterine wall allows larger amounts of fetal
umbilical cord blood to enter the mother’s circulation. These fetal red blood cells stimulate
Rhspecific B cells to mount an immune response, resulting in the production of Rh-specific plasma
cells and memory B cells in the mother. The secreted IgM antibody clears the Rh fetal red cells
from the mother’s circulation, but memory cells remain, a threat to any subsequent pregnancy
with an Rh fetus. Importantly, since IgM antibodies do not pass through the placenta, IgM anti-Rh
antigens are no threat to the fetus.

However, activation of IgG-expressing memory cells in a subsequent pregnancy results in the

formation of IgG anti-Rh antibodies, which can cross the placenta and damage the fetal red blood
Cells.

32
33
Hemolytic disease of the newborn caused by Rh incompatibility in a second or later pregnancy
can be almost entirely prevented by administering antibodies against the Rh antigen to the mother
at around 28 weeks of her first pregnancy and within 24 to 48 hours after the first delivery.
Anti-Rh antibodies are also administered to pregnant women after amniocentesis. These antibodies,
marketed as RhoGAM, bind to any fetal red blood cells that may have entered the mother’s
circulation 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 cross the placenta.

Ultraviolet light is used to treat bilirubinemia of the newborn.

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. Because the blood-brain
barrier is not complete until after birth, very young babies can suffer fatal brain damage from bilirubin.
Fortunately, bilirubin is rapidly broken down on exposure of the skin to ultraviolet (UV) light, and
babies who display the telltale jaundiced appearance that signifies high levels of blood bilirubin are
treated by exposure to UV light in their cribs
34
Hemolytic anemia can be drug induced
Certain antibiotics (e.g., penicillin, cephalosporins, and streptomycin), as well as other well known
drugs (including ibuprofen and naproxen), can adsorb nonspecifically to proteins on red blood cell
membranes, forming a drug-protein complex. In some patients, such drug-protein complexes induce
the formation of antibodies. These antibodies then bind to the adsorbed drug on red blood cells,
inducing complement-mediated lysis and thus progressive anemia. When the drug is withdrawn, the
hemolytic anemia disappears. Penicillin is notable in that it can induce all four types of
hypersensitivity with various clinical manifestations.

Penicillin-induced hypersensitivity reactions

35
Immune Complex–Mediated (Type III) Hypersensitivity

The reaction of antibody with antigen generates immune complexes. In general, these
antigenantibody complexes facilitate the clearance of antigen by phagocytic cells and red blood cells.
In some cases, however, the presence of large numbers and networks of immune complexes can lead
to tissue-damaging type III hypersensitivity reactions.

The magnitude of the reaction depends on the levels and size of immune complexes, their
distribution within the body, and the ability of the phagocyte system to clear the complexes and thus
minimize the tissue damage.

Failure to clear immune complexes may also result from peculiarities of the antigen itself, or
disorders in phagocytic machinery. The deposition of immune complexes in the blood vessels or
tissues initiates reactions that result in the recruitment of complement components and neutrophils to
the site, with resultant tissue injury.

The conditions which induce type III hyper sensitive response include
(1) the presence of antigens capable of generating particularly extensive antigen-antibody lattices,
(2) a high intrinsic affinity of antigens for particular tissues,
(3) the presence of highly charged antigens (which can affect immune complex engulfment), and
(4) a compromised phagocytic system.

36
Uncleared immune complexes bind to mast cells, neutrophils, and
macrophages via Fc receptors, triggering the release of vasoactive mediators
and inflammatory cytokines, which interact with the capillary epithelium and
increase the permeability of the blood vessel walls.

Immune complexes then move through the capillary walls and into the
tissues, where they are deposited and set up a localized inflammatory
response.

Complement activation results in the production of the anaphylatoxin

chemokines C3a and C5a, which attract more neutrophils and macrophages.
These in turn are further activated by immune complexes binding to their Fc
receptors to secrete proinflammatory chemokines and cytokines,
prostaglandins, and proteases. Proteases attack the basement membrane
proteins collagen and elastin, as well as cartilage.

Tissue damage is further mediated by oxygen free radicals released by the

activated neutrophils. In addition, immune complexes interact with platelets
and induce the formation of tiny clots.

Complex deposition in the tissues can give rise to symptoms such as fever,
urticaria (rashes), joint pain, lymph node enlargement, and protein in the urine.
The resulting inflammatory lesion is referred to as vasculitis if it occurs in a
blood vessel, glomerulonephritis if it occurs in the kidneys, or arthritis if it
occurs in the joints.
37
Formation of circulating immune complexes contributes to the pathogenesis of
number of conditions involving type III hypersensitivity reactions

38
Arthus reactions are localized type III hypersensitivity reactions
One example of a localized type III hypersensitivity reaction has been used extensively as
an experimental tool. If an animal or human subject is injected intradermally with an
antigen to which large amounts of circulating antibodies exist (or have been recently
introduced by intravenous injections), antigen will diffuse into the walls of local blood
vessels and large immune complexes will precipitate close to the injection site. This
initiates an inflammatory reaction that peaks approximately 4 to 10 hours postinjection
and is known as an Arthus reaction. Inflammation at the site of an Arthus reaction is
characterized by swelling and localized bleeding, followed by fibrin deposition.

An Arthus reaction. This photograph shows an Arthus reaction

on the thigh of a 72-year-old woman.
This occurred at the site of injection of a hemotherapeutic drug,
3 to 4 hours after the patient received a second injection
(15 days after the first).
This response was accompanied by fever and significant
discomfort.

39
A sensitive individual may react to an insect bite with a rapid, localized type I allergic
reaction, which can be followed, some 4 to 10 hours later, by the development of a
typical Arthus reaction, characterized by pronounced erythema and edema.

Intrapulmonary Arthus-type reactions in the lung induced by bacterial spores, fungi, or

dried fecal proteins in people with antibodies to these antigens can also cause
pneumonitis or alveolitis.

These reactions are known by a variety of common names reflecting the source of the
antigen.
For example, farmer’s lung develops after inhalation of Diseases is caused due to
inhalation of thermophilic actinomycetes from moldy hay.
Pigeon fancier’s disease results from inhalation of a serum protein in dust derived from
dried pigeon feces.

40
Injection of an antigen intradermally or subcutaneously
into an animal that has circulating antibody specific for
that antigen leads to formation of localized immune
complexes.
Neutrophils adhere to the vascular endothelium and
then migrate to the site of immune complex deposition.
As the reaction continues localized damage results in
accumulation of fluid (edema) and red blood cells
(erythema).

Development of localized Arthus reaction (Type III

hypersensitivity reaction.
Complement activation initiated by immune complexes
(Classical pathway) produces complement intermediates
that
1. Mediate mast cell degranulation
2. Chemotactically attract neutrophils
3. Stimulate release of lytic enzymes from neutrophils
trying to phagocytose C3b-coated immune
complexes.

41
 Type IV or Delayed-Type Hypersensitivity (DTH)

When some subpopulations of activated TH cells encounter certain types of antigens, they secrete
cytokines that induce a localized imflammatory reaction called delayed type hypersensitivity
(DTH). ), It is the only hypersensitivity category that is purely cell mediated rather than antibody
mediated

The hallmarks of a type IV reaction are its initiation by T cells (as distinct from antibodies), the
delay required for the reaction to develop (usually 1 to 2 days), and the recruitment of macrophages
(as opposed to neutrophils or eosinophils) as the primary cellular component of the infiltrate that
surrounds the site of inflammation.

In1890, Robert Koch observed that individuals infected with Mycobacterium tuberculosis
developed a localized inflammatory response when injected intradermally (i.e., via the skin) with a
filtrate derived from a mycobacterial culture. He therefore named this localized skin reaction a
tuberculin reaction. Later, as it became apparent that a variety of other antigens could induce this
cellular Response , its name was changed to delayed-type, or type IV, hypersensitivity.

42
43
The DTH response.
(a) In the sensitization phase after initial contact with antigen (e.g., peptides derived from
intracellular bacteria), naïve CD4 cells proliferate and differentiate into T H1 cells.
Cytokines secreted by these T cells are indicated by the black dots.

44
b) In the effector phase after subsequent exposure of sensitized effector T cells to antigen, TH 1 cells
secrete a variety of cytokines and chemokines, including IFN-γ. These factors attract and activate
macrophages and other nonspecific inflammatory cells. Activated macrophages are more effective in
presenting antigen, thus perpetuating the DTH response, and function as the primary effector cells in
this reaction. The TH 17 helper T-cell subset and CD8 T cells also contribute to DTH responses.
45
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 any intracellular pathogens.
in some cases, and especially if the antigen is not easily cleared, a prolonged DTH response can develop
that becomes destructive to the host, causing a visible granulomatous reaction.

Granulomas develop when continuous activation of macrophages induces them to adhere closely to one
another. Under these conditions, macrophages assume an epithelioid shape and sometimes fuse to form
multinucleated giant cells.

These giant cells displace the normal tissue cells, forming palpable nodules, and releasing high
concentrations of lytic enzymes, which destroy surrounding tissue. The granulomatous response can
damage blood vessels and lead to extensive tissue necrosis.

Fig. A prolonged DTH response can lead to

formation of a granuloma, a nodule-like
mass. (a) Lytic enzymes released from
activated macrophages in a granuloma can
cause extensive tissue damage.

46
Poison ivy causes contact dermatitis due to its toxin, urushiol.
(a) Poison ivy and the contact dermatitis form of DTH that it causes in many people.
(b) The structures of the alkylcatechols with varying R-groups, alkyl chains of 15–17 carbon atoms,
that comprise the urushiol toxin family.

47
 The most common type IV hypersensitivity is the contact
dermatitis that occurs after exposure to Toxicodendron species,
which include poison ivy, poison oak, and poison sumac.
Induction of contact dermatitis by
urushiol can be mediated by TH 1, T H17,
and CTL effector T cells.
Skin DTH reactions are caused by three
different effector T cells:
1. effector T H1 cells that recognize
urushiol-modified peptides bound to
MHC class II proteins on
Langerhans cells;
2. effector TH 17 cells that recognize
urushiol bound to CD1a on
Langerhans cells; and
3. CD8 CTL effector cells that
recognize urushiol-modified peptides
presented by MHC class I proteins
on skin cells.
After activation, the T cells produce chemokines and cytokines that recruit and activate
macrophages and neutrophils to release inflammatory cytokines, enzymes, and ROS that cause
local tissue damage. CTLs may also kill skin cells expressing urushiol-modified peptides bound to
MHC class I proteins.
48