INTRODUCTION TO

HYPERSENSITIVITY REACTIONS

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 Introduction
• Hypersentivity Reactions (HSR) Allergies
Greek = altered reactivity 1906 – von Pirquet
coined term: Hypersensitivity reactions – ‘over
reaction’ of the immune system to harmless
environmental antigens
• Definition : Hypersensitivity is defined as an
abnormal, exaggerated immune reaction to a
foreign agent, with resulting injury to host
tissues
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 General features of HSR
• HSR may be elicited by both exogenous and
endogenous antigens
• Examples of exogenous antigens include dust, pollens,
foods, drugs, microbes, chemicals, and some blood
• The immune responses against such antigens may take
the form discomforts, such as itching of the skin, to
potentially fatal diseases, such as bronchial asthma and
anaphylaxis.
• Immune responses against self, or autologous, antigens
is the cause of autoimmune diseases.
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 CT
• Certain susceptibility genes have implicated
in the development of hypersensitivity
diseases.
• These genes include HLA genes and many
non-HLA genes

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 CT
• hypersensitivity reflects an imbalance
between the effector mechanisms of immune
responses and the control mechanisms that
serve to normally limit such responses.

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 CLASSIFICATIONS OF HSR
• Classification is based on the immunologic
mechanism that mediates the disease
• This is of value in distinguishing the manner in
which the immune response causes tissue
injury and disease, and the accompanying
pathologic and clinical manifestations.
However multiple mechanisms may be
operative in any one hypersensitivity disease

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 Classification
• Coombs and Gell classification

1-Type I - immediate ( atopic, or anaphylactic)

2-Type II - antibody-dependent
3-Type III - immune complex
4-Type IV - cell-mediated or delayed

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Types of Immune Hypersensitivity Reactions

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 CT
• Type I, II, and III hypersensitivity reactions all
require formation of a specific antibody
against an exogenous (foreign) or an
endogenous (self) antigen
• The antibody class is a critical determinant of
the mechanism by which tissue injury occurs.

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 CT
• Type IV reactions (cell-mediated, or delayed-
type hypersensitivity reactions) do not involve
antibodies
• Rather, antigen activation of T lymphocytes,
usually with the help of macrophages leading
to tissue injury

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 CT
• Many immunologic diseases are mediated by
more than one type of hypersensitivity
reaction

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 Type I (Anaphylactic Type)
• This is a rapid immunologic reaction occurring
within minutes after the combination of an
antigen with antibody bound to mast cells in
individuals previously sensitized to the
antigen.
• Reaction can occur within minutes - may be
systemic or localized
• Local form (atopy) often hereditary

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 CT
• Local reactions are diverse and vary
depending on the portal of entry of the allergen
• They may take the form of localized cutaneous
swellings (skin allergy, hives)
• nasal and conjunctival discharge (allergic
rhinitis and conjunctivitis)
• hay fever, bronchial asthma, or allergic
gastroenteritis (food allergy).

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 CT
• Many local type I hypersensitivity reactions have
two well-defined phases
• The immediate or initial reaction
– Xtrised by vasodilation, increased vascular permiability
• These become evident within 5 to 30 minutes after
exposure to an allergen and subside in 60 minutes.
• Second, late-phase reaction sets in 2 to 24 hours
later without additional exposure to antigen and
may last for several days.
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 CT
• Type I hypersensitivity reactions involves IgE
antibodies, which are formed by a CD4+, Th2,
T-cell dependent mechanism and which bind
avidly to Fc receptors on mast cells and
basophils.
• The high avidity of binding of IgE accounts
for the term cytophilic antibody

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 CT
• Once exposed to a specific allergen that elicits
IgE, a person is sensitized, and subsequent
exposures to that allergen induce immediate
hypersensitivity reactions
• After IgE is elicited, repeat exposure to
antigens typically induces additional IgE
antibodies, rather than antibodies of other
classes, such as IgM or IgG.

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Antigen binding to IgE on mast cells leads to amplification
of IgE production

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 CT
• mast cells (and basophils) are activated by the
cross-linking of high-affinity IgE Fc receptors
• Some factors can directly induce degranulation
independent of IgE: C3a, C5a, codeine,
morphine, mellitin (in bee venom), trauma,
heat, cold

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 CT
• Activated T cells, specifically the Th2 type,
produce cytokines that have important roles in
allergic responses
• Activated Th2 T-cell subsets produce IL-4, IL-
5, and IL-13, leading to IgE production and
increased numbers of mast cells and
eosinophils.

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 CT
• Mast cells and basophils express a high-
affinity receptor, called FcεRI, that is specific
for the Fc portion of IgE, and therefore avidly
binds IgE antibodies.
• When a mast cell, armed with IgE antibodies,
is exposed to the specific allergen, a series of
reactions takes place, leading to the release of
powerful mediators.

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 CT
• In the first step in this sequence, antigen
(allergen) binds to the IgE antibodies
previously attached to the mast cells.
• Multivalent antigens bind to and cross-link
adjacent IgE antibodies and the underlying IgE
Fc receptors.

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Molecules released upon activation of mast cells

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 CT
• The bridging of the Fcε receptors activates
signal transduction pathways from the
cytoplasmic portion of the receptors.
• These signals lead to mast cell degranulation
with the discharge of preformed (primary)
mediators that are stored in the granules, and de
novo synthesis and release of secondary
mediators, including lipid products and
cytokines
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 CT
• These mediators are responsible for the initial,
sometimes explosive, symptoms of immediate
hypersensitivity, and they also set into motion
the events that lead to the late-phase reaction

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 CT
• Primary (rapidly acting) factors:
• histamine: bronchial smooth muscle
contraction, increased vascular permeability
• eosinophil and neutrophil chemotactic factors
• granule matrix derived factors: heparin,
proteases

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 CT
• Secondary (slow reacting substances of
anaphylaxis):
• Leukotrienes C4, D4: most potent
vasodilators known
• Prostaglandin D2: bronchospasm and
vasodilation
• Leukotriene B4: chemotactic for neutrophils
• Platelet activating factor

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Molecules released upon activation of mast cells

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Toxic granule proteins and inflammatory substances
released upon activation of eosinophils

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 Cytokines
• Mast cells are sources of many cytokines, which may
play an important role at several stages of immediate
hypersensitivity reactions.
• The cytokines include: TNF, IL-1, and chemokines,
which promote leukocyte recruitment (typical of the late-
phase reaction); IL-4, which amplifies the TH2 response
• The inflammatory cells that are recruited by mast cell–
derived TNF and chemokines are additional sources of
cytokines and of histamine-releasing factors that cause
further mast cell degranulation.

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Toxic granule proteins and inflammatory substances
released upon activation of eosinophils

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 Disorders resulting from Type 1 HSR

• Localized Type I Hypersensitivity

• Localized expression of a type I HSR is
termed atopy.
• Atopy represents an inherited predisposition to
an abnormal response against allergens
• Tendency to develop this form of
hypersensitivity is familial

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 CT
• Skin
• In the skin, contact with allergen causes immediate
reddening, swelling, and itching (urticaria, hives);
in other instances, acute dermatitis or eczema
results
• The antigen may come in contact with skin directly
or by injection (some insect bites or stings)
• It may be ingested, as occurs in some food or drug
allergies that produce cutaneous reactions.

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 CT
• Nose
• In the nasal mucosa, inhalation of the allergen
(eg, pollen, animal danders) causes
vasodilation and secretion of mucus (hay
fever, or allergic rhinitis).

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 CT
• Lung
• Inhalation of allergens (pollen, dust) leads to
contraction of bronchial smooth muscle,
resulting in acute airway obstruction and
wheezing (allergic bronchial asthma).

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 CT
• Intestine
• Ingestion of the allergen (eg, nuts, seafood)
causes muscle contraction and fluid secretion
that produce abdominal cramps and diarrhea
(allergic gastroenteritis).

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Systemic Type I Hypersensitivity Reactions

• Anaphylaxis is a rare life-threatening systemic

type I hypersensitivity reaction
• Release of vasoactive amines into the circulation
causes smooth muscle contraction, generalized
vasodilation, and increased vascular permeability
with leakage of intravascular fluids
• The resulting peripheral circulatory failure and
shock can lead to death within minutes
(anaphylactic shock).
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 CT
• In less severe cases, the increased vascular
permeability leads to allergic edema, which
affects the larynx particularly and may cause
fatal asphyxia
• Systemic anaphylaxis typically results from
injected allergens (eg, penicillin, foreign
serum, local anesthetics, radiographic contrast
dyes)

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 CT
• More rarely, anaphylaxis may result from
ingested allergens (seafood, egg, berries) or
cutaneous allergens (bee and wasp stings)
• In sensitized individuals, only a small amount
of allergen may be required to produce fatal
anaphylaxis.

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Type II - antibody-dependent (AKA: Cytotoxic
Type (although not always cytotoxic)

• In type II hypersensitivity, the antibodies produced by the

immune response bind to antigens on the patient's own cell
surfaces.

• The antigens recognized in this way may either be intrinsic

("self" antigen, innately part of the patient's cells) or extrinsic
(absorbed onto the cells during exposure to some foreign
antigen, possibly as part of infection with a pathogen

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 CT
• Antibodies react with antigens present on cell
surfaces or in the extracellular matrix and
cause disease by
– destroying these cells
– triggering inflammation
– or interfering with normal functions.

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 CT
• An important characteristic of these antibodies
is their ability to activate complement through
the immunoglobulin Fc domain.

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 CT
• At sufficient density, bound immunoglobulin
leads to complement fixation via C1q and the
classic pathway
• Once activated, complement can destroy
target cells by several methods.

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 Opsonization and Phagocytosis
• Cells opsonized by IgG antibodies are recognized by
phagocyte Fc receptors, which are specific for the Fc
portions of some IgG subclasses
• In addition,when IgM or IgG antibodies are deposited
on the surfaces of cells, they may activate the
complement system by the classical pathway
• Complement activation generates by-products, mainly
C3b and C4b, which are deposited on the surfaces of
the cells and recognized by phagocytes that express
receptors for these proteins.
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 CT
• Complement activation on cells also leads to
the formation of the membrane attack complex
• This disrupts membrane integrity by “drilling
holes” through the lipid bilayer, thereby
causing osmotic lysis of the cells

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 ADCC

• This involves cytolytic leukocytes that attack antibody-coated

target cells after binding via Fc receptors
• Phagocytic cells and NK cells can function as effector cells in
ADCC
• The mechanisms by which target cells are destroyed in these
reactions are not entirely understood
• ADCC may also be involved in the pathogenesis of some
autoimmune diseases (e.g., autoimmune thyroiditis).
• The contribution of ADCC to common hypersensitivity
diseases is uncertain.

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 Inflammation
• Inflammation results when antibodies deposit in fixed tissues, such
as basement membranes and extracellular matrix
• The deposited antibodies activate complement, generating by-
products, including chemotactic agents (mainly C5a)
• The leukocytes are activated by engagement of their C3b and Fc
receptors
• This results in the production of other substances that damage
tissues, such as lysosomal enzymes, including proteases capable of
digesting basement membrane, collagen, elastin, and cartilage,
• Antibody-mediated inflammation is the mechanism responsible for
tissue injury in some forms of glomerulonephritis,
• vascular rejection in organ grafts, and other disorders

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 Change in Cellular Function
• In some type II reactions, antibody binding to
a specific target cell receptor does not lead to
cell death but rather to a change in function
• Autoimmune diseases such as Graves disease
and myasthenia gravis feature autoantibodies
against cell-surface hormone receptors

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 Examples
• Autoimmune haemolytic anaemia
• Pernicious anemia
• Immune thrombocytopenia
• Transfusion reactions
• Hashimoto's thyroiditis
• Graves' disease
• Myasthenia gravis
• Farmer's Lung
• Hemolytic disease of the newborn
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 Type III (Immune Complex Mediated)
• In this type of HSR, antigen-antibody complexes
produce tissue damage mainly by eliciting
inflammation at the sites of deposition.
• The pathologic reaction is usually initiated when
antigen combines with antibody in the circulation,
creating immune complexes that typically deposit in
vessel walls.
• Less frequently, the complexes may be formed at
sites where antigen has been “planted” previously
(called in situ immune complexes)
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 CT
• Immune complex formation may occur as a
result of :
 Autoimmune diseases (RA)
 Persistence infection (Hepatitis virus)
 Repeated inhalation of antigenic materials

• Immune complex may be systemic or localised

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Systemic Immune Complex Disease
• Acute serum sickness is the prototype of a
systemic immune complex disease
• it was once a frequent sequela to the
administration of large amounts of foreign
serum (e.g serum from immunized horses used
for protection against diphtheria)
• In modern times the disease is infrequent, and
usually seen in individuals who receive
antibodies from other individuals or species.
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 Pathogenesis
• The pathogenesis of systemic immune
complex disease is divided into three phases

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 Formation of immune complexes
• The introduction of a protein antigen triggers an
immune response that results in the formation of
antibodies
• This occurs about a week after the injection of
the protein
• These antibodies are secreted into the blood,
where they react with the antigen still present in
the circulation and form antigen-antibody
complexes.
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 Deposition of immune complexes
• In this phase, the circulating antigen-antibody
complexes are deposited in various tissues.
• The factors that determine whether immune complex
formation will lead to tissue deposition and disease are
not fully understood
• The major influences seem to be the characteristics of
the complexes and local vascular alterations
• In general,complexes that are of medium size, formed
in slight antigen excess, are the most pathogenic

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 CT
• Organs where blood is filtered at high pressure
to form other fluids, like urine and synovial
fluid, are sites where immune complexes
become concentrated and tend to deposit
• Therefore, immune complex disease often
affects glomeruli and joints.

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 Inflammation and tissue injury.
• On deposition of immune complexes in the tissues,
they initiate an acute inflammatory reaction
• During this phase (approximately 10 days after antigen
administration), clinical features such as fever,
urticaria, joint pains (arthralgias), lymph node
enlargement, and proteinuria
• The resultant inflammatory lesion is
• termed vasculitis if it occurs in blood vessels,
glomerulonephritis if it occurs in renal glomeruli,
arthritis if it occurs in the joints etc.
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 CT
• The pathology of this lesion is induced by complement-
fixing antibodies (i.e., IgG and IgM) and antibodies that
bind to leukocyte Fc receptors
• The role of complement in the pathogenesis of the tissue
injury is supported by the observations that complement
proteins can be detected at the site of injury and, during
the active phase of the disease, consumption of
complement leads to a decrease in serum levels of C3
• Serum C3 levels can, in some cases, be used to monitor
disease activity.

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 Morphology
• The main manifestation of immune complex injury is acute
vasculitis, associated with necrosis of the vessel wall and intense
neutrophilic infiltration
• The necrotic tissue and deposits of immune complexes,
complement, and plasma protein appear as a smudgy eosinophilic
area of tissue destruction, this is knonwn as fibrinoid necrosis
• If it isdeposited in the kidney, the complexes can be seen on
immunofluorescence microscopy as granular lumpy deposits of
immunoglobulin and complement
• On electron microscopy it appears as electron-dense deposits
along the glomerular basement membrane

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 Localized Form (Arthus Reaction)

• This occurs as a result of Introduction of antigen

to which patient has been sensitized
• It manifest as localized tissue necrosis resulting
from acute immune complex vasculitis, usually in
the skin
• Lesion develops over 4-10 hrs; may ulcerate
• Histology shows fibrinoid necrosis of vessels,
platelet thromboses, edema, hemorrhage, and
numerous neutrophils
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Local Immune Complex Disease (Arthus Reaction)

• The Arthus reaction is a localized area of

tissue necrosis
• It results from acute immune complex
vasculitis, usually elicited in the skin.

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 Examples of type 111 HSR
• Immune complex glomerulonephritis
• Rheumatoid arthritis
• Serum sickness
• Subacute bacterial endocarditis
• Symptoms of malaria
• Systemic lupus erythematosus
• Arthus reaction

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 TYPE IV HSR
• Included among these reactions are delayed-
type cellular inflammatory responses and cell-
mediated cytotoxic effects.
• Type IV reactions often occur together with
antibody-dependent reactions, which can make
it difficult to distinguish these processes.

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 CT
• The clinical and experimental studies suggest
that the type of tissue response is largely
determined by the nature of the inciting agent.

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 CT
• It is caused by inflammation resulting from cytokines
produced by CD4+ T cells and cell killing by CD8+ T cells
• CD4+ T cell–mediated hypersensitivity induced by
environmental and self antigens is the cause of many
chronic inflammatory diseases, including autoimmune
diseases
• CD8+ cells may also be involved in some of these
autoimmune diseases
• CD8+ cells may be the dominant effector cells in certain
reactions, especially those that follow viral infections.

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 CD4+ T Cell–Mediated Inflammation
• In CD4+ T cell–mediated hypersensitivity reactions, cytokines produced
by the T cells induce inflammation that may be chronic and destructive
• The prototype of T cell–mediated inflammation is delayed-type
hypersensitivity (DTH)
• In this reaction, an antigen administered into the skin of a previously
immunized individual results in a detectable cutaneous reaction within
24 to 48 hours
• Both TH1 and TH17 cells contribute to organ-specific diseases in which
inflammation is a prominent aspect of the pathology
• The inflammatory reaction associated with TH1 cells is dominated by
activated macrophages, and that triggered by TH17 cells has a greater
neutrophil component

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 CT
• Naïve CD4+ T cells recognize peptides
displayed by dendritic cells
• It secretes IL-2, which functions as an autocrine
growth factor to stimulate proliferation of the
antigen responsive T cells
• The subsequent differentiation of antigen-
stimulated T cells to TH1 or TH17 cells is
driven by the cytokines produced by APCs at
the time of T-cell activation.
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 CT
• In some situations the APCs (dendritic cells and
macrophages) produce IL-12, which induces differentiation
of CD4+ T cells to the TH1 subset
• IFN-γ produced by these effector cells promotes further
TH1 development, thus amplifying the reaction
• If the APCs produce inflammatory cytokines such as IL-1,
IL-6, and IL-23, these stimulate differentiation of T cells to
the TH17 subset
• Some of the differentiated effector cells enter the
circulation and may remain in the memory pool of T cells
for long periods, sometimes years.
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Responses of Differentiated Effector T Cells

• Upon repeat exposure to an antigen, TH1 cells secrete

cytokines, mainly IFN-γ, which are responsible for many of
the manifestations of delayed-type hypersensitivity
• IFN-γ-activated(“classically activated”) macrophages are
altered in several ways:
– Their ability to phagocytose and kill microorganisms is markedly
augmented
– they express more class II MHC molecules on the surface, thus
facilitating further antigen presentation
– They secrete TNF, IL-1, and chemokines, which promote
inflammation
– they produce more IL-12, thereby amplifying the TH1 response.

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 CT

• Activated TH17 cells secrete IL-17, IL-22,

chemokines and several other cytokines
• These cytokines recruit neutrophils and
monocytes to the reaction, thus promoting
inflammation.
• TH17 cells also produce IL-21, which
amplifies the TH17 response.

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• Type IV hypersensitivity is involved in the pathogenesis of many
autoimmune and infectious diseases:
 Tuberculosis
 Leprosy
 Blastomycosis
 Histoplasmosis
 Toxoplasmosis
 Leishmaniasis
 Granulomas due to infections and foreign antigens
 Graft rejection
 Contact dermatitis

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 CD8+ T Cell–Mediated Cytotoxicity
• CD8+ cytotoxic T-Cells kill cells via pore
formation; recognize modified self- MHC Class I
antigens
• These immune mechanisms are important in
destroying and eliminating cells infected by viruses
• Also possibly play roles in eliminating tumor cells
that express neoantigens
• Cytotoxic T cells also play an important role in
transplant graft rejection.

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 CT
• The principal mechanism of T cell–mediated killing of targets
involves perforins and granzymes
• CTLs that recognize the target cells secrete a complex consisting
of perforin, granzymes, and other proteins which enters target cells
by endocytosis
• In the target cell cytoplasm, perforin facilitates the release of the
granzymes from the complex
• Granzymes are proteases that cleave and activate caspases, which
induce apoptosis of the target cells
• Activated CTLs also express Fas ligand, a molecule with
homology to TNF, which can bind to Fas expressed on target cells
and trigger apoptosis.

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 CT
• CD8+ T cells also produce cytokines, notably
IFN-γ, and are involved in inflammatory
reactions resembling DTH, especially
following virus infections
• exposure to some contact sensitizing agents.

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