Chapter
16
Hypersensitivity
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„„Definition and Classification
„„Type I Hypersensitivity Reaction
„„Type II Hypersensitivity Reaction
„„Type III Hypersensitivity Reaction
The purpose of immune response is to eliminate the
foreign antigens that have entered into the host. In most
instances, immune response leads to only a subclinical
or localized inflammatory response which just eliminates
the antigen without causing significant damage to
the host. However, at times, this response becomes
abnormal; leads to exaggerated inflammatory response
which causes extensive tissue damage or sometimes even
death.
HYPERSENSITIVITY REACTIONS
Definition
The term hypersensitivity or allergy refers to the injurious
consequences in the sensitized host, following subsequent
contact with specific antigens.
Gell and Coombs Classification
Following an antigen contact, hypersensitivity may
occur immediately or after a few days. It may result from
„„Type IV Hypersensitivity Reaction
abnormality of either humoral or cell-mediated immune
response. Based on the above two features, Gell and R
Coombs classified hypersensitivity reactions into four
types (Table 16.1).
Immediate Hypersensitivity Reactions
These reactions occur immediately, within few minutes
to few hours of antigen contact, as a result of abnormal
exaggerated humoral response (antibody mediated). This
can be further classified into three types based on the type
of effector mechanisms:
1. Type I hypersensitivity reaction: It is IgE-mediated,
which causes mast cell degranulation following a contact
with soluble antigen
2. Type II hypersensitivity reaction: It is IgG (or rarely
IgM) mediated, which causes complement activation
or antibody-dependent cellular cytotoxicity (ADCC) in
response to cell surface bound antigens
3. Type III hypersensitivity reaction: It is immune
complex-mediated; which are formed due to interaction
Table 16.1: Features of various types of hypersensitivity reactions.
Type I
Type II
Type III
Type IV
Immune response altered Humoral
Humoral
Humoral
Cell mediated
Immediate or delayed
Immediate
Immediate
Delayed
Duration between
2–30 minutes
appearance of symptoms
and antigen contact
5–8 hour
2–8 hours
24–72 hours
Antigen
Soluble
Cell surface bound
Soluble
Soluble or bound
Mediator
IgE
IgG
Ag-Ab complex
TDTH cell
Effector mechanism
Mast cell
degranulation
•• ADCC
•• Complementmediated cytolysis
Complement activation and
inflammatory response
Macrophage activation leads to
phagocytosis or cell cytotoxicity
Desensitization to the
allergen
Easy, but shortlasting
Easy, but short-lasting
Easy, but short-lasting
Difficult, but sustained
Typical manifestations
•• Anaphylaxis
•• Asthma
•• Atopic dermatitis
•• Transfusion reactions
•• Rh incompatibility
•• Hemolytic anemia
••
••
••
••
•• Tuberculin test
•• Granuloma formation in
tuberculosis, leprosy, etc.
•• Contact dermatitis
Immediate
Abbreviation: ADCC, antibody- dependent cellular cytotoxicity.
Arthus reaction
Serum sickness
Glomerulonephritis
Rheumatoid arthritis
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between soluble antigen and antibody (usually IgG),
resulting in an abnormal inflammatory response.
Delayed Hypersensitivity Reaction
Delayed hypersensitivity reaction occurs after few
days of antigen contact, as a result of abnormal cellmediated immune response. This is also called type IV
hypersensitivity reaction. It is mediated by a specific
subset of TH cells called delayed hypersensitivity T cells
or TDTH cell.
TYPE I HYPERSENSITIVITY REACTION
The hallmark of type I hypersensitivity reaction is
production of IgE by sensitized B cells following a
contact with an allergen which inturn induces mast cell
degranulation. The pharmacologically active mediators
released from these granules cause vasodilation, vascular
and smooth muscle contraction and increased vascular
permeability. These changes ultimately lead to localized
response (called atopy) and systemic response (called
anaphylaxis).
™™ The wheal and flare response occurs in three stages,
as follows:
1. Begins with the appearance of an erythematous area
at the site of injury, followed by
2. Development of a flare (erythema) surrounding the site
3. Finally, a wheal (swelling and congestion) forms at the
site as fluid leaks under the skin from the surrounding
capillaries.
Mechanism of Type I Hypersensitivity
Type I hypersensitivity reaction occurs through two phases; the sensitization and effector phases, both occurring
with an interval of 2–3 weeks (Fig. 16.1).
Sensitization Phase
This occurs when an individual is exposed for the first time
to the sensitizing or priming dose of an allergen.
™™ Sensitization is most effective when the allergen is
introduced parenterally, but may occur by any route,
including ingestion or inhalation
™™ In susceptible individuals, very minute doses can be
sufficient to sensitize the host
Allergens
Allergens are foreign antigens that induce allergy. List of
allergens is given in Table 16.2.
Experiments to Demonstrate Type I Reaction
Several experiments were conducted in the past to
demonstrate type I hypersensitivity reactions; out of which,
the most popular was P–K Reaction.
P–K Reaction
K Prausnitz and H Kustner (1921) were the first to
demonstrate that antibody in the serum responsible for the
allergy, and named it as P-K antibody or reaginic antibody;
which later was known as IgE (in 1960), after its discovery.
The experiment was as follows.
™™ Serum from an allergic person is injected intradermally
into a nonallergic individual. Later when the appropriate
allergen is injected at the same site, a wheal and flare
reaction is developed at the site
Table 16.2: Common allergens associated with type I
hypersensitivity reaction.
Allergen types
Examples
Food
Nuts, egg, peas, sea food, beans, milk
Plants and pollens
Rye grass, rag weed
Proteins
Foreign serum, vaccines
Drugs
Penicillin, sulfonamides, local anesthetics
and salicylates
Insect bite products
Venom of bee, wasp, ant, cockroach calyx
and dust mites
Others
Mold spores, animal hair and dander
Fig. 16.1: Mechanism of type I hypersensitivity reaction.
Chapter 16  Hypersensitivity
™™ The allergen is processed by the antigen presenting cells
and the antigenic peptides are presented to the CD4
helper T cells
™™ Activated TH cells are differentiated into TH2 cells which
in turn secrete interleukin 4 (IL-4)
™™ IL-4 induces the B cells to differentiate into IgE producing
plasma cells and memory cells. Many molecules of IgE
with specificities against various epitopes of the allergen
may be produced
™™ Secreted IgE migrate to the target sites, and coat on
the surface of mast cells and basophils. Fc region (the
CH3 and CH4 domains) of IgE binds to high affinity Fc
receptors (e.g. FcεR1) present on mast cell surface
™™ Such sensitized mast cells (coated with IgE) will be waiting
for interaction with the subsequent antigenic challenge.
Effector Phase
When the same allergen is introduced subsequently
(shocking dose), it directly encounters with the Fab region
of IgE coated on mast cells.
™™ IgE cross linkage initiates degranulation: Allergen bound
to IgE triggers the mast cells (and basophils) activation
and degranulation. Granules in turn release a number of
pharmacologically active chemical mediators that lead
to the various manifestations of type-1 reaction
™™ The memory B cells further differentiate into plasma cells
that produce IgE
™™ Degranulation in two phases: Mast cells and basophils
undergo degranulation in two phases
1. Primary mediators: The preformed chemical
mediators which are already synthesized by mast
cells, are immediately released, e.g. histamine and
serotonin (Table 16.3)
2. Secondary mediators: The mast cells synthesize them
following stimulation by allergen and release, e.g.
prostaglandins and leukotrienes (Table 16.3).
™™ Pharmacological actions: The chemical mediators
perform several pharmacological actions, such as
bronchial and other smooth muscle contraction,
increased vascular permeability and vasodilation (Table
16.3)
™™ Symptoms: These actions in combinations, produce
symptoms such as breathlessness, hypotension and
shock leading to death at times.
Manifestations of Type I Reaction
Manifestations are grouped into immediate and late.
Immediate Manifestations
Systemic Anaphylaxis
It is an acute medical emergency condition, characterized
by severe dyspnea, hypotension, and vascular collapse
leading to death at times.
™™ It occurs within minutes of exposure to allergen and
unless treated promptly, may lead to fatality
Table 16.3: Mediators of type I hypersensitivity.
Primary mediators
Action
Histamine, heparin and
↑Vascular permeability
serotonin
↑Smooth-muscle contraction
Eosinophil chemotactic
Eosinophil chemotaxis
factor (ECF-A)
Neutrophil chemotactic
Neutrophil chemotaxis
factor (NCF-A)
Proteases
Bronchial mucous secretion
Degradation of blood-vessel and
basement membrane
Secondary mediators
Action
Platelet-activating factor
Platelet aggregation and
degranulation;
Contraction of pulmonary smooth
muscles
Leukotrienes
↑ Vascular permeability; contraction
(slow reactive substance of of pulmonary smooth muscles
anaphylaxis, SRS-A)
Prostaglandins
↑Vasodilation;
Contraction of pulmonary smooth
muscles
Platelet aggregation
Bradykinin
↑Vascular permeability; smoothmuscle contraction
Cytokines
Systemic anaphylaxis;
(IL-1 and TNF-α)
↑ Expression of cell adhesion
molecules (CAMs) on venular
endothelial cells
™™ Allergens: Wide range of allergens have been shown to
trigger anaphylaxis in susceptible humans, including the
venom (from bee, wasp, and ant stings); drugs (such as
penicillin, insulin), antitoxins, seafood and nuts
™™ Epinephrine (adrenalin) is the drug of choice for systemic
anaphylactic reactions.
Localized Anaphylaxis (Atopy)
Here, the reaction is limited to a specific target tissue or
organ, mostly the epithelial surfaces at the entry sites of
allergen. These allergies afflict more than 20% of people.
They almost always run in families (i.e. inherited) and are
collectively called atopy. Examples include:
™™ Allergic rhinitis (or hay fever): It is the most common
atopic disorder, affecting 10% of the population. This
results from exposure to airborne allergens with the
conjunctiva and nasal mucosa leading to appearance
of various symptoms such as ↑watery secretions of the
conjunctiva, nasal mucosa, and upper respiratory tract,
as well as sneezing and coughing
™™ Asthma: It is the second most common atopic
manifestation. It differs from hay fever in involvement of
lower respiratory mucosa, resulting in contraction of the
bronchial smooth muscles and airway edema, ↑mucus
secretion; all together leading to bronchoconstriction
and dyspnea. The stimulus may or may not be an allergen.
Accordingly, asthma can be classified as:
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Allergic asthma: It is induced by air-borne or bloodborne allergens, such as pollens, dust, fumes, insect
products, or viral antigens
„„ Intrinsic asthma: It is independent of allergen
stimulation; induced by exercise or cold.
™™ Food allergy: Various foods also can induce localized
anaphylaxis in atopic individuals. The food allergens (e.g.
nuts, egg, seafood, etc.) can either stimulate the mast
cells lining gut mucosa to cause GI symptoms such as
diarrhea and vomiting or may be carried in the blood
stream to distant sites (e.g. when the allergen is deposited
on skin, causes local wheal and flare like reaction called
atopic urticaria (or hives)
™™ Atopic dermatitis (allergic eczema): It is an
inflammatory disease of skin that is frequently associated
with young children with family history of atopy. It often
develops during infancy, manifested as erythematous
skin eruptions which are filled with pus.The skin lesions
have an increased response of TH2 cells and eosinophils
™™ Drug allergy: Various drugs (such as penicillin,
sulfonamides, etc.) may produce type I hyper-sensitivity
responses which may be either local reactions or even
sometimes produce systemic anaphylaxis.
„„
Late Manifestations
The immediate phase of type 1 reaction is followed, 4–6
hours later, by an inflammatory response. This phase lasts
for 1–2 days and leads to tissue damage.
™™ Mediators: They are released in acute phase along
with cytokines (IL-3, IL-5, IL-8), ECF and NCF;
induce recruitment of various inflammatory cells,
such as neutrophils, eosinophils, macrophages, and
lymphocytes, etc. Among the infiltrates, eosinophils and
neutrophils predominate; each accounting for 30% of the
total inflammatory cells influx
™™ Eosinophil influx: It is favored by ECF (eosinophil
chemotactic factor), IL-5 and GM-CSF. Eosinophils
express Fc receptors for IgG and IgE and thus bind directly
to antibody-coated allergens. This in turn causes release
of toxic granules from eosinophils which contribute to
the chronic inflammation of the bronchial mucosa that
characterizes persistent asthma
™™ Neutrophil infiltration: It is induced by NCF (neutrophil
chemotactic factor), and other cytokines such as IL-8.
Activated neutrophils release various mediators which
further potentiate inflammatory tissue damage and
thickening of basement membrane.
™™ There are several gene loci identified which encode
proteins that are involved in the regulation of immune
responses towards the allergens
™™ It is also observed that if both the parents are allergic
there is 50% chance that the child will be allergic and
when only one parent is allergic, the chance of the child
being allergic drops down to 30%.
2. Allergen Dose
The dose of the allergen has a definite impact on the type
of immune response produced. It is observed that repeated
small doses of allergen induce a persistent IgE response in
mice; while higher dosage leads to transient IgE response
with a shift towards IgG response.
3. TH1 vs TH2 Response
The balance between TH1 and TH2 response determines the
response of an individual towards an allergen.
™™ TH1 response produces cytokine interferon-γ, which
is inhibitory to type I hypersensitivity; whereas TH2
response induced cytokine IL-3, IL-4 and IL-5 promotes
IgE-mediated allergic response
™™ Hence, accordingly atopic and non-atopic individuals
would demonstrate a predominant TH2 and TH1 response
to an allergen respectively.
Detection of Type I Hypersensitivity
Skin Prick Test
Small amounts of suspected potential allergens are
introduced at different skin sites either by intradermal
injection or by superficial scratching.
™™ If a person is already sensitized to the allergen, a local
wheal and flare response develops within 30 minutes at
the inoculation sites (Fig. 16.2)
™™ Advantage: Skin test is relatively inexpensive and allows
screening of a large number of allergens at one go
™™ Disadvantage: It may occasionally sensitize the individual to new allergens and in some rare cases may induce late-phase reaction or even systemic anaphylactic
shock.
Factors Influencing Type I Hypersensitivity
1. Genetic Makeup
Host genetic factors play an important role in mounting an
immune response against an allergen.
™™ Some individuals mount a normal response where
as some mount an exaggerated immune response.
Allergen to one individual may not be allergic to other
individual
Fig. 16.2: Skin testing by intradermal testing of allergens into
forearm.
Chapter 16  Hypersensitivity
Total Serum IgE Antibody
TYPE II HYPERSENSITIVITY REACTION
Quantitative detection of total serum IgE is performed
by various formats such as enzyme immunoassay or
radiometric assay called radioimmunosorbent test (RIST,
now not in use).
In type II reactions, the host injury is mediated by
antibodies (IgG or rarely IgM) which interact with various
types of antigens, such as:
™™ Host cell surface antigens (e.g. RBC membrane antigens
like blood group and Rh antigens)
™™ Extracellular matrix antigens or
™™ Exogenous antigens absorbed on host cells (e.g. a drug
coating on RBC membrane).
After Ag-Ab binding occurs, the Fc region of antibody
initiates the type II reactions by the following three broad
mechanisms (Figs 16.3A and B).
Allergen-specific IgE
Detection of allergen-specific IgE is more specific than
total IgE detection. Various test formats are available.
™™ Multiplex immunoblot assay: Uses a nitrocellulose strip
coated with 54 allergens
™™ Fluoro-enzyme immunoassay (FEIA): Commercially
available as ImmunoCAP assay
™™ Automated immunoassay system (Hytec 288 Plus
system)
™™ Anti-CCD absorbent IgE assay: Detects IgE after absorbing (removing) the nonspecific anti-CCD IgE which
are produced against the cross-reactive carbohydrate
determinants (CCD) present on the allergens
™™ RAST: Earlier, a radiometric assay called RAST
(Radioallergosorbent test) was in use.
T Reatment
‰‰
‰‰
‰‰
‰‰
Type I hypersensitivity reaction
Avoidance of contact with known allergens: The first and
foremost step is identification and avoidance of contact with
known allergens such as dusts, house pets, allergic food, etc.
However, it is not practically possible to avoid all allergens
especially airborne allergens, such as pollens
Hyposensitization: Repeated exposure to increased
subcutaneous doses of allergens can reduce or eliminate the
allergic response to the same allergen
¾¾ This occurs probably due to either (1) a shift of IgE response
towards IgG or (2) a shift of TH2 response towards TH1
response, which secrete IFN-γ that in turn can suppress
the IgE response
¾¾ Here, the IgG acts as blocking antibody because it competes
with IgE for binding to the allergen. The IgG-allergen
immunocomplex can be removed later by phagocytosis.
Monoclonal anti-IgE: Humanized monoclonal anti-IgE can
bind and block the IgE; but useful only if the IgE is not already
bound to high affinity Fc receptors
Drugs: Several drugs are useful in suppressing type 1 response
through various mechanisms (Table 16.4).
Table 16.4: Drugs used in type I hypersensitivity.
Drugs
Mechanism of action
Antihistamines
Block H1 receptors on target cells; hence
antagonize the effects of histamine released
Epinephrine
(adrenaline)
Stimulates cAMP production in mast cells;
thereby prevents mast cell degranulation
Also it causes bronchial smooth muscle
relaxation and ionotropic effect
Cortisone
Blocks conversion of histidine to histamine
and stimulates cAMP levels in mast cells
Theophylline
Prolongs high cAMP levels in mast cells
Cromolyn sodium
Blocks Ca2+ influx into mast cells
Abbreviation: cAMP, cyclic adenosine monophosphate.
Complement-dependent Reactions
The Fc region of antibody (bound with antigen) can activate
the classical pathway of complement system. Activation of
classical pathway leads to host cell injury which is mediated
by the following three mechanisms (Fig. 16.3A).
1. Complement-dependent cytolysis: The membrane
attack complex (C5-C9) formed by the activation of
classical pathway can produce pores which lead to lysis
of the target cells
2. Complement-dependent inflammation: The byproducts of complement pathways such as C3a and C5a
are chemoattractants; hence can induce inflammatory
response leading to tissue injury
3. Opsonization: By-products of complement pathway,
such as C3b and C4b act as opsonins. They deposit on
the target cells. Phagocytes, such as macrophage and
neutrophil can engulf such C3b and C4b coated target
cells via complement receptors.
Complement Mediated Type II Reactions
Antibody-dependent complement mediated type II hyper­
sensitivity is observed in various clinical conditions such as:
‰‰ Transfusion reaction (ABO incompatibility): RBCs from
an incompatible donor are destroyed after being coated
with recipient antibodies directed against the donor’s
blood group antigens (Fig. 16.3A)
‰‰ Erythroblastosis fetalis (Rh incompatibility): Rh negative
mother having anti-Rh antibodies due to prior exposure
to Rh positive blood (due to previous pregnancy or blood
transfusion), can cross the placenta and cause destruction
of Rh-positive fetal RBCs
‰‰ Autoimmune hemolytic anemia, agranulocytosis, or
thrombocytopenia: All these result due to production of
autoantibodies to individual’s own membrane antigens of
RBCs/granulocytes/platelets respectively
‰‰ Drug-induced hemolytic anemia: Drug or its metabolic
products may get adsorbed onto RBC membrane. If
antibodies are formed against the drug, these antibodies
will bind with the adsorbed drug on RBC surface and lead
to complement activation and lysis of RBCs. For example,
following quinine therapy used for malaria (resulting in
black water fever) and penicillin therapy (Fig. 16.3A)
‰‰ Pemphigus vulgaris (autoantibodies against desmosomal
proteins that lead to disruption of epidermal intercellular
junctions).
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A
B
Figs 16.3A and B: Different mechanisms of antibody mediated type II hypersensitivity reactions:
A. Complement-dependent reactions; B. Antibody-dependent cellular cytotoxicity (ADCC).
Abbreviations: RBC, red blood cell; NK, natural killer.
Antibody-dependent Cellular Cytotoxicity (ADCC)
IgG antibodies can coat on the target cells by interacting
with the surface antigens through Fab region. The Fc
portion of IgG in turn binds to Fc receptors on various
effector cells such as NK cells which result in destruction
of the target cells (Fig. 16.3B).
™™ ADCC is involved in destruction of the targets that are
too large to be phagocytozed, e.g. parasites, tumors or
graft rejection
™™ Although ADCC is typically mediated by IgG antibodies,
in certain instances (e.g. eosinophil-mediated killing of
parasites) IgE antibodies are used.
Autoantibody Mediated (Antibody-dependent
Cellular Dysfunction or ADCD)
In this condition, the host produces certain autoantibodies
which bind and disturb the normal function of human selfantigens.
™™ Anti-receptor Ab: Antibodies may be directed against
human receptors, resulting in either inhibition or
excessive activation of the receptors leading to host injury
„„ Activation of receptor, e.g. Graves’ disease: Here,
the autoantibodies produced are called LATS (longacting thyroid stimulators), which stimulate the
thyroid cells to upregulate the production of thyroid
hormones
„„ Inhibition of receptor, e.g. myasthenia gravis: In
this condition, anti-acetylcholine (ACh) receptor
antibodies are produced; which block the ACh
receptors, leading to profound muscular weakness.
™™ Other examples of ADCD:
„„
„„
„„
„„
Goodpasture syndrome (antibody produced against
type IV collagen)
Pernicious anemia (antibody directed against
intrinsic factor)
Rheumatic fever (antibody against streptococcal
antigens cross reacting with heart)
Myocarditis in Chagas disease.
TYPE III HYPERSENSITIVITY REACTION
Type III hypersensitivity reactions develop as a result
of excess formation of immune complexes (Ag-Ab
complexes) which initiate an inflammatory response
through activation of complement system leading to tissue
injury (Fig. 16.4).
™™ Antigen involved: Immune complexes can involve
exogenous antigens such as bacteria and viruses or
endogenous antigens such as DNA
™™ Removal of immune complexes: Mere formation
of immune complexes does not result in type III
hypersensitivity reaction
„„ Under normal circumstances, the immune complexes
are rapidly cleared by activation of complement system
„„ Immune complexes coated with complements
are either directly phagocytosed by macrophages/
monocytes or are bound to RBCs and carried to liver
and spleen where they are phagocytosed.
™™ However, in some situations, the immune system may
be exposed to excess dose of antigen over long period of
time such as in chronic infection, autoimmune diseases,
Chapter 16  Hypersensitivity
secretory granules (through frustrated phagocytosis)
which causes extensive tissue damage.
Platelet Activation
Immune complexes bind to the Fc receptors on platelets
leading to their activation. Platelet aggregation (leads to
microthrombi formation) and vasoactive amines released
from activated platelets, both together cause tissue
ischemia leading to further tissue damage.
Activation of Hageman Factor
Activation of Hageman factor leads to activation of kinin,
which in turn causes vasodilatation and edema.
Types of Type III Hypersensitivity Reaction
Type III reactions are either localized or generalized.
Localized or Arthus Reaction
Fig. 16.4: Mechanism of systemic type III hypersensitivity reaction.
and repeated exposure to environmental pollutants. This
leads to formation of excessive immune complexes.
Soluble vs Insoluble Immune Complexes
Balance between level of antigen and antibody decides the
nature of immune complex that is going to be formed.
™™ In case of antibody excess or antigen-antibody
equivalence, immune complexes formed are large and
insoluble; which tend to localize near the site of antigen
administration to produce a localized type III reaction
™™ However, in situations when the antigen is in excess
(particularly monovalent antigens), small soluble
complexes are formed which tend to travel through
blood and get deposited in various sites producing a
generalized type III reaction.
Mechanism of Tissue Injury
Classical Complement Activation
The Ag-Ab-immune complexes stimulate the classical
pathway of complement; the products of which mediate
the tissue injury in type III reaction.
™™ Anaphylatoxin: Complement by-products C3a and
C5a being anaphylatoxins, induce localized mast cell
degranulation with consequent increase in vascular
permeability
™™ Chemoattractant: C3a and C5a also act as chemo­
attractants, causing recruitment of neutrophils to the
site of immune complex deposition
™™ Role of neutrophils: Neutrophils attempt to phagocytose
the large immune complexes, but fail in doing so. Instead,
they release large number of lytic enzymes from the
Arthus reaction is defined as localized area of tissue
necrosis due to vasculitis resulting from acute
immune complex deposition at the site of inoculation
of antigen.
The reaction is produced experimentally (NM Arthus,
1903) by injecting an antigen into the skin of a previously
immunized animal, e.g. rabbit (i.e. excess of preformed
antibodies against the injected antigen are already present
in the circulation). The circulating antibodies bind with
the antigen in the dermis and form immune complexes.
These immune complexes fix the complement, resulting
in localized immune complex mediated inflammatory
response called Arthus reaction.
In humans, localized Arthus reaction is seen in some
situations, such as:
™™ In skin: (1) following insect bites or (2) during allergic
desensitization treatment wherein repeated injections
of the same antigen is given for long periods
™™ In lungs, following inhalation of bacteria, fungi, spores or
proteins may produce intrapulmonary lesions. Examples
include conditions causing extrinsic allergic alveolitis,
such as:
„„ Farmer’s lung: It develops following inhalation of
actinomycetes (Saccharopolyspora species) from
mouldy hay
„„ Bird-Fancier’s disease: This develops following inhalation of serum proteins in dust derived from dried
pigeon’s feces.
Generalized or Systemic Type III Reactions
The pathogenesis of systemic immune complex disease
can be divided into two phases:
1. Formation of small sized soluble Ag-Ab complexes
in the circulation, which occurs following the entry of a
large dose of antigen into the body
2. Induces inflammatory reaction: Deposition of the
immune complexes in various tissues, thus initiating
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Section 2  Immunology
Table 16.5: Diseases associated with generalized type III
hypersensitivity reactions.
Connective tissue disorders: Result due to autoantibodies
forming immune complexes with self-antigens
•• SLE (systemic lupus erythematosus): Anti-DNA Ab
•• Rheumatoid arthritis: Ab against human immunoglobulin
•• PAN (polyarteritis nodosa)
Parasitic diseases: Resulting from immune complex deposition
•• Nephrotic syndrome in Plasmodium malariae
•• Katayama fever in schistosomiasis
•• African trypanosomiasis
Bacterial diseases: Resulting from immune complex deposition
•• Streptococcus pyogenes: Post-streptococcal glomerulonephritis
•• Mycobacterium leprae (Lepra reaction type 2)
Viral diseases: With immune complex deposition
•• Hepatitis B (arthritis)
•• Hepatitis C (arthritis)
•• Infectious mononucleosis (Epstein-Barr virus)
•• Dengue (arthritis)
Others:
•• Hyperacute graft rejection
•• Subacute bacterial endocarditis
•• Serum sickness
Mechanism of Type IV Reactions
Type IV hypersensitivity reactions occur through two
phases—(1) sensitization and (2) effector phases (Figs
16.5A and B).
Sensitization Phase
This is the initial phase of 1–2 weeks occurring following
antigenic exposure (Fig. 16.5A).
™™ During this period, the antigen presenting cells (APCs)
process and present the antigenic peptides along with
MHC-II to the helper T cells. TH cells are differentiated
to form TDTH cells
™™ Most TDTH cells are derived from TH1 cells; but occasionally
other T cells, such as CD8+ T cells and CD4+ TH17 can also
act as TDTH cells.
Effector Phase
The TDTH cells, on subsequent contact with the antigen,
secrete variety of cytokines which attract and recruit
various inflammatory cells (e.g. macrophages) at the site
of DTH reaction (Fig. 16.5B).
an inflammatory reaction in various sites throughout
the body such as; blood vessels (vasculitis), glomerular
basement membrane (glomerulonephritis), and synovial
membrane (arthritis). This has been linked to the pathogenesis of various diseases (Table 16.5).
Serum Sickness
This is another historical example of type III reaction. This
condition is not seen nowadays, it was seen in the past,
following serum therapy, i.e. administration of foreign
serum, e.g. horse anti-tetanus serum, to treat tetanus cases.
™™ The horse serum proteins being foreign can induce
antibody formation in the host, leading to generation of
large number of immune complexes
™™ Typically, after 7–8 days, the individuals begin to show
various manifestations which are collectively called
serum sickness. The symptoms include fever, weakness,
vasculitis, edema, erythema and rarely lymphadenopathy
and glomerulonephritis
™™ It subsides gradually once the immune complexes are
cleared and free antibodies accumulate.
TYPE IV HYPERSENSITIVITY REACTION
Type IV hypersensitivity reactions differ from other types
in various ways:
™™ It is delayed type (occurs after 48–72 hours of antigen
exposure)
™™ It is cell-mediated; characteristic cells called TDTH cells
(delayed type of hypersensitivity T cells) are the principal
mediators of type IV reactions
™™ Tissue injury occurs predominantly due to activated
macrophages.
Figs 16.5A and B: Mechanism of delayed type hypersensitivity:
A. Sensitization phase; B. Effector phase.
Abbreviations: APCs, antigen presenting cells; MHC, major histocompatibility
complex; TNF, tumor necrosis factor; IFN, interferons; DTH, delayed type
hypersensitivity; MCAF, monocyte chemotactic and activating factor; MIF
migration inhibitory factor; GM-CSF, granulocyte monocyte colony stimulating
factor.
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Chapter 16  Hypersensitivity
Cytokines Secreted from TDTH Cells
‰‰ Interferon-γ: It is the key cytokine of type IV reaction.
It activates the resting macrophages into activated
macrophages which are highly competent for microbial
killing; mediated through several mechanisms such as:
¾¾ ↑ Expression of MHC-II molecules so that they can act
as efficient APCs
¾¾ ↑ TNF receptors
¾¾ ↑ Levels of oxygen radicals and nitric oxide.
‰‰ Interleukin-2 (IL-2): It acts in autocrine manner; stimulates
the proliferation of TDTHcells
‰‰ MCAF (Monocyte chemotactic and activating factor) and
TNF β–Help in migration of monocytes from blood to
the site of DTH and transforming them into tissue macrophages
‰‰ MIF (migration inhibitory factor): It further inhibits
migration of macrophages from the site of DTH
‰‰ IL-3 and GM-CSF (granulocyte-monocyte colony
stimulating factor)-help in local synthesis of monocytes.
Role of DTH: Protective vs Tissue Damage Response
Through type IV hypersensitivity reactions, host attempts to
provide defense against many intracellular microorganisms
such as M. tuberculosis as well as several chemicals and
nickel salts (Table 16.6). Always, the attempts do not result
in protection.
Protective Response
Under normal circumstances, the pathogens are usually cleared with little tissue damage; mediated by
the enhanced microbicidal potency of activated macrophages.
Tissue Damage Response
However, in conditions, when the intracellular
microbes escape the macrophage killing mechanisms;
the enhanced phagocytic activity and release of various
lytic enzymes by the activated macrophages in an
attempt to kill the pathogen leads to nonspecific tissue
destruction.
Table 16.6: Examples of delayed-type hypersensitivity (DTH).
Intracellular pathogens inducing DTH
Intracellular bacteria
•• Mycobacterium leprae
•• M. tuberculosis
•• Listeria monocytogenes
•• Brucella abortus
Intracellular fungi
•• Pneumocystis jirovecii
•• Candida albicans
•• Histoplasma capsulatum
•• Cryptococcus neoformans
Intracellular viruses
•• Herpes simplex virus
•• Variola (smallpox)
•• Measles virus
Skin test to demonstrate DTH
•• Tuberculin test (Mantoux test)
•• Lepromin test
•• Montenegro test
(leishmaniasis)
•• Frei test—done in LGV
Contact dermatitis
Following exposure to contact antigens:
Nickel, poison ivy, poison oak, picryl chloride
Other examples of DTH
Noninfectious conditions
•• Diabetes mellitus type 1
•• Multiple sclerosis
•• Peripheral neuropathies
•• Hashimoto’s thyroiditis
Granuloma formation seen in
Tuberculosis, sarcoidosis,
schistosomiasis and other
trematode infections
•• Crohn’s disease
•• Chronic transplant rejection
•• Graft-versus-host disease
Other example
Lepra reaction type I
Abbreviation: LGV, lymphogranuloma venereum.
and a peripheral rim of fibroblasts and connective tissue
(Fig. 16.6).
Tuberculin Test
Tuberculin test is the prototype of delayed hypersensitivity.
In sensitized individuals, (i.e. who possess sensitized TDTH
cells due to prior contact with M. tuberculosis); when a
preparation of tuberculin antigen (glycerol extract of the
tubercle bacillus) is injected intradermally, a local reaction
develops after 48–72 hours consisting of induration
surrounded by erythema.
Pathology of DTH Reaction (Granuloma Formation)
Continuous DTH reaction for killing the intracellular
microbes (especially persistent and/or nondegradable
antigens) leads to formation of granuloma (e.g. tubercles
in leprosy and tuberculosis).
™™ The initial TH cell infiltrate is progressively replaced by
macrophages in 2–3 weeks. Macrophages transform into
two type of cells:
1. They become large, flat, and eosinophilic; denoted as
epithelioid cells
2. The epithelioid cells occasionally fuse (induced by
IFN-γ) to form multinucleated giant cells.
Granuloma consists of an inner zone of epithelioid
cells, typically surrounded by a collar of lymphocytes
Fig. 16.6: Structure of granuloma.
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Section 2  Immunology
Contact Dermatitis
™™ This hapten-skin protein complex is internalized by skin
Many antigens such as nickel, poison oak, etc. (Table 16.6)
act by producing DTH response:
™™ Most of these substances are haptens; they complex with
skin proteins, which act as carrier to make the haptens
immunogenic
APCs (e.g. Langerhans cells), then presented to TH cells
to induce a TDH reaction
™™ Activated macrophages release lytic enzymes which
result in skin lesions (e.g. redness and pustule seen
following contact with poison oak).
EXPECTED QUESTIONS
I.Write essay on:
1. Define and classify hypersensitivity reactions. Write
in detail about type IV hypersensitivity reaction.
2. Neha, a 17-year student who has recently joined
MBBS, has come back to the hostel after the first
vacation. After entering to her hostel room, she
suddenly developed an episode of severe sneezing,
and dyspnea. She had to be admitted to the casualty
and when asked, she told that she has faced similar
episodes since her childhood.
a. What type of immune reaction is this?
b. Describe the pathogenesis of this condition and
management.
II.Write short notes on:
1. Type II hypersensitivity reaction.
2. Immune complex mediated hypersensitivity reaction.
III. Multiple Choice Questions (MCQs):
1. Type I hypersensitivity is mediated by which of
the following immunoglobulins?
a. IgA
b. IgG
c. IgM
d. IgE
2. The type of hypersensitivity reaction in
myasthenia gravis is:
Answers
1. d
2. b
3. d
4. a
5. d
a. Type I
b. Type II
c. Type III
d. Type IV
3. A positive tuberculin test is an example of:
a. Type I hypersensitivity
b. Type II hypersensitivity
c. Type III hypersensitivity
d. Type IV hypersensitivity
4. Example
of
antibody-dependent
cellular
dysfunction or ADCD:
a. Graves’ disease
b. Hemolytic anemia
c. Pemphigus vulgaris d. Transfusion reaction
5.Which of the following statement is wrong about
type III hypersensitivity reaction?
a. Antibody excess—produce a localized type III
reaction
b. Antigen excess—produce a systemic type III
reaction
c. Antigen-antibody equivalence—produce a
localized type III reaction
d. Soluble
immunocomplexes—produce
a
localized type III reaction