Hypersensitivity Reactions

Hypersensitivity
Exaggerated or inappropriate immune
responses
damaging to the host vs. protective
Caused by: Autoimmunity, Reactions against
microbes or environmental antigens.

Hypersensitivity diseases are

commonly classified according to the
type of immune response and the
effector mechanism responsible for cell
and tissue injury.

Gell & Coombs Classification of

Hypersensitivity
1960s:Philip Gell and Robin Coombs
Type I - IgE mediated reactions
Type II - Cytolytic or cytotoxic reactions
Type III - Immune Complex reactions
Type IV - Cell mediated Immunity reactions

Type I Hypersensitivity
Anaphylaxis
Away from protection
Prophylaxis - toward protection

Immediate type hypersensitivity

Occurs within minutes
Types:
Allergic rhinitis - Hayfever
Food allergies
Atopic dermatitis
Asthma

Mast Cell Degranulation

around blood vessels in
connective tissue (skin)
mucosal surfaces (gut &
respiratory tracts)

Characterization of Type I
Hypersensitivity
3 phases
Sensitization phase
IgE produced in response to antigenic stimulus &
binds to receptors on mast cells and basophils

Activation phase
Re-exposure to antigen triggers mast cells and
basophils to respond by release of their granules

Effector phase
Complex response occurs as a result of histamine
& other pharmacologically active agents released
by mast cells & basophils

Sensitization Phase
Repeated exposure to low dose of allergens
About 50% of population makes IgE in response to
allergens
About 20% of population develops clinical symptoms

T cell dependent
TH2 response:
IL-4 induces isotype switching to IgE
IFN- (TH1) downregulates IgE production

Allergic responses:
Balance between TH1 & TH 2 responses
Viruses & other events may disturb this balance
Hygiene Hypothesis

FEATURES OF IgE-DEPENDENT
IMMUNE REACTIONS
The hallmarks of allergic diseases are the
activation of TH2 cells and the production
of IgE antibody.
sequence of events includes: First exposure
to allergen
Activation of TH2 cells and
stimulation of IgE class switching in B cells
Production of IgE
Binding of IgE to
FcRI on mast cells
Repeated exposure to
allergen
Activation of mast cell: release of
mediators: Early and Late phase.

PRODUCTION OF IgE
Atopic individuals produce high levels of
IgE in response to environmental allergens,
whereas normal individuals generally
synthesize other Ig isotypes, such as IgM
and IgG, and only small amounts of IgE.
IgE antibody is responsible for sensitizing
mast cells and provides recognition of
antigen for immediate hypersensitivity
reactions.

The Nature of Allergens

Antigens that elicit immediate hypersensitivity
reactions (allergens) are proteins or
chemicals bound to proteins to which the
atopic individual is chronically exposed.
Allergens features: low to medium molecular
weight (5 to 70 kD), stability, glycosylation, and
high solubility in body fluids.
Chronic or repeated T cell activation in the
absence of strong innate immunity may drive
CD4+ T cells toward the TH2 pathway.

Activation of TH2 Cells

Differentiated TH1, TH2, and TH17 cells all develop from
naive CD4+ T lymphocytes, mainly in response to
cytokines present early during immune responses,
and differentiation involves transcriptional activation
and epigenetic modification of cytokine genes.
IgE synthesis is dependent on the activation of CD4+
helper T cells of the TH2 subset and their secretion of
IL-4 and IL-13.
major factors driving differentiation of TH2:
follicular helper T (TFH) cells that secrete TH2 cytokines.
the cytokine thymic stromal lymphopoietin, secreted by epithelial
cells in the skin, gut, and lungs, enhances the ability of tissue
dendritic cells to promote TH2 differentiation.

Development of
TH2 cells.

Role of TH2 Cells

TH2 and TFH cells induces B cell switching to IgE through
the actions of CD40 ligand and the cytokines IL-4 and IL13.
IL-5 secreted by TH2 cells activates eosinophils.
IL-13 stimulates epithelial cells (e.g., in the airways) to
secrete increased amounts of mucus.
TH2 cells also contribute to the inflammation of the latephase reaction.
Allergen-specific IgE produced by plasmablasts and plasma
cells enters the circulation and binds to Fc receptors on
tissue mast cells, also at lesser degree with basophils.

ACTIVATION PHASE

ROLE OF MAST CELLS, BASOPHILS, AND

EOSINOPHILS IN IMMEDIATE HYPERSENSITIVITY

Mast cells, basophils, and eosinophils

are the effector cells of immediate
hypersensitivity reactions and allergic
disease.
Mature mast cells are found throughout
the body, predominantly near blood
vessels and nerves and beneath epithelia,
containing acidic proteoglycans granules.

 Mast cells, basophils, and eosinophils are the effector cells of immediate
hypersensitivity reactions and allergic disease..
Basophils are blood granulocytes with structural and functional
similarities to mast cells.

 Mast cells and basophils express a high-affinity

Fc receptor specific for heavy chains, called
FcRI, which binds IgE.
Each FcRI molecule is composed of an chain
that binds the Fc region of IgE and a chain and
two chains that are responsible for signaling.

Mast cells are activated by cross-linking of FcRI molecules, which occurs by

binding of multivalent antigens to the IgE molecules that are attached to the Fc
receptors.
cross-linking leads to rapid degranulation (60-300 secs) of the mast cells

 Activation of mast cells results in three types of biologic

response: secretion of the preformed granule contents by
exocytosis (degranulation), synthesis and secretion of lipid
mediators, and synthesis and secretion of cytokines.
Mast cells can be directly activated by a variety of biologic
substances independent of allergen-mediated cross-linking
of FcRI, including polybasic compounds, peptides ,
neuropaptide (substance P, somatostatin, and vasoactive
intestinal peptide), chemokines, and complement-derived
anaphylatoxins.
Cold temperatures and intense exercise may also trigger
mast cell degranulation.
Different mast cell populations exist that are distinguished
by their anatomic locations, granule contents, and activities

Mast Cell Subsets

Characteristic

Connective Tissue
Mast Cells

Mucosal Mast Cells

Location

Skin, intestinal
submucosa

Alveoli, intestinal
mucosa

T cell dependence for

development of
phenotype
in tissues

No

Yes

Granule contents

Major neutral
proteases: tryptase,
chymase,
carboxypeptidase,
cathepsin G

Major neutral
protease:
tryptase

EFFECTOR PHASE

Mediators Derived from Mast Cells

The effector functions of mast cells are mediated by
soluble molecules released from the cells on activation
Biogenic Amines: low-molecular weight compounds that contain an
amine group eg. Histamine.
Granule Enzymes and Proteoglycans: Neutral serine proteasestryptase and chymase, carboxypeptidase A, cathepsin G, heparin,
chondroitin sulfate.
Lipid Mediators: Mast cell activation results in the rapid de novo
synthesis and release of lipid-derived mediators that have a variety of
effects on blood vessels, bronchial smooth muscle, and leukocytes.
prostaglandin D2, leukotrienes (slow-reacting substance of
anaphylaxis :SRS-A), platelet-activating factor (PAF).

Cytokines: (the late-phase reaction) TNF, IL-1, IL-4, IL-5, IL6, IL-13, CCL3, CCL4, and various colony-stimulating factors
such as IL-3 and granulocyte monocyte colony-stimulating
factor (GM-CSF).

Mediators Produced by Mast Cells &

Basophils

Mediators Produced by Eosinophils

IgE- AND MAST CELLDEPENDENT REACTIONS

The Immediate Reaction

The early vascular changes that occur

during immediate hypersensitivity
reactions are demonstrated by the wheal
and flare reaction to the intradermal
injection of an allergen.
Passive cutaneous anaphylaxis: immediate
hypersensitivity reactions against an allergen
can be elicited in unresponsive individuals if
the local skin site is first injected with IgE
(reagin)from an allergic individual.

cross-linking of the IgE by the antigen

mast cells activation
release of mediators (histamine)
Histamine binds to histamine receptors on venular endothelial
cells
endothelial cells synthesize and release PGI2, nitric oxide, and
PAF
Vasodilation and vascular leak
leukotrienes

 The Late-Phase Reaction: The

immediate wheal and flare reaction is
followed 2 to 4 hours later by a latephase reaction consisting of the
accumulation of inflammatory
leukocytes, including neutrophils,
eosinophils, basophils, and TH2 cells.
The late-phase reaction may occur
without a detectable preceding
immediate hypersensitivity reaction.

Early vs. Late Response

Eosinophils
&
neutrophils

 Primary mediators

Histamine :Vascular permeability, sm contraction

Serotonin : vascular permeability, sm contraction
ECF-A : eosinophil chaemotaxis
NCF-A : neutrophil chaemotaxis
Proteases : mucus secretion, connective tissue
degradation

Secondary mediators
Leukotrienes : vascular permeability, sm contraction
Prostaglandins : vasodilation, sm contraction, platelet
activation
Bradykinin : vascular permeability, sm contraction
Cytokines : numerous effects inc. activation of vascular
endothelium, eosinophil recruitment and activation

Type of Anaphylaxis
SchultzDale Phenomenon: Isolated
sensitized tissue shows contraction in
presence of specific Ag.
Cutaneous Anaphylaxis: Local wheal and
flare reaction in SPT.

Atopy
Recurrent nonfatal localized reaction.
Genetical
Localised: at the site of entry.
IgE mediated.

PrausnitzKustner (PK) reaction.: Special

affinity of IgE (Reaginic Ab) for skin cells is
demonstrated.

GENETIC SUSCEPTIBILITY TO IMMEDIATE

HYPERSENSITIVITY

The propensity to develop allergies is

influenced by the inheritance of several
genes.

Systemic Anaphylaxis
Anaphylaxis is a systemic immediate
hypersensitivity reaction characterized by
edema in many tissues and a fall in blood
pressure, secondary to vasodilation.
Allergen
mast cell activation mediators gain
access to vascular beds in body decrease in
vascular tone and leakage of plasma fall in
blood pressure (anaphylactic shock)
systemic epinephrine & Antihistamines &PAF
receptor antagonists.

Bronchial Asthma
Asthma is an inflammatory disease caused by
repeated immediate-phase hypersensitivity and
late-phase allergic reactions in the lung leading to
the clinicopathologic triad of intermittent and
reversible airway obstruction, chronic bronchial
inflammation with eosinophils, and bronchial
smooth muscle cell hypertrophy and hyper
reactivity to bronchoconstrictors.
Respiratory viral and bacterial infections are a
predisposing factor in the development of asthma
or exacerbations of preexisting asthma.

Detection of Allergies
Skin Test
Blood Test
Elevated IgE (ELISA)
RIST Test - radioimmunosorbant test
RAST Test - radioallergosorbent test

 Hygiene Hypothesis
Exposure to infections early in childhood protect
against allergic Rxs
Correlation with increasing allergic Rxs & advanced
societies
Younger Children in large families are protected against
atopy & asthma
Exposure to gut pathogens like Toxoplasma gondii protect
Conclusion: Exposure to TH1 responses protect

Exposure to Helminth Infections

Inverse correlation between exposure to worm
infections & allergic Rxs
Exposure to ALL types of infections protects against atopy
b/c infections stimulate regulatory cytokines which down
regulate both TH1 & TH2

Treatment for inflammatory bowel disease:

Ingest eggs of a Pig Whipworm

Type II Hypersensitivity
Mediated by IgG & IgM
Cytotoxic reactions
Complement
Antibody dependent cell mediated cytoxicity
(ADCC)
3 types:
Blood transfusion Rxs (ABO)
Hemolytic Disease of the newborn
Drug-induced hemolytic anemia

Type III Hypersensitivity

Due to large amounts of
immune complexes (IgG)
Localized inflammatory
response
Influx of neutrophils
Immune complex
deposition
Blood vessel walls
Synovial membrane of
joints
Glomerular basement
membranes of kidney
Choroid plexus of the brain
Arthus Rx (4-8 hrs)

Arthus Reaction

Ag-Ab complexes diffuse into vessel walls

Activate complements

Chemotactic C-factors releases> attract neutrophils

and induce intravascular clumping of platlets
Neutophils ingest complexes and releases\
lysosomal enzymes, which damage neighboring
cells and cause necrosis and inflammatory reaction
Aggregation of platelets causes vascular occlusion
leading to ischemic necrosis of blood vessels

Detection of Type III Reactions

Immunofluorescence detection of tissues

Goodpasteurs Syndrome; staining of basement membranes

Type III Hypersensitivity Rxs

Generalized Type III
Rxs
Autoimmune diseases
Systemic lupus
Rhematoid arthritis

Drug reactions
Pencillin, sulfonamides

Infectious diseases
Mononucleosis,
malaria,
menigitis, Hepatitis

Localized Type III

Rxs ( Arthus Rxs)
Insect bites (4-8 hrs)
Pulmonary rxs:
bacterial spores, fungi,
dried fecal proteins
Farmers Lung
Pigeon Fanciers
disease
Aspergillosis

Type IV Hypersensitivity or Delayed

Type Hypersensitivity (DTH)
DTH response:
Localized inflammatory response induced by
TH cells
Characterized by large influx of inflammatory
cells and especially macrophages
Delayed : 24-72 hrs
Hypersensitivity:
DTH is often helpful & plays important role in
intracellular pathogens & contact antigens
DTH can cause tissue damage & be pathological

Pathogens & Antigens associated with

Type IV Hypersensitivity

Detection of DTH Rxs

Inject antigen intradermally (96 spots)
Wait 48-72 hrs
Positive rx:
Red, swollen, firm lesion
Lesion results from infiltration of cells to site of
injection
Most will be macrophages

Mantoux skin test

PPD = purified protein derivative

Granulomas
Prolonged DTH response
Continuous activation of
macrophages
Macs adhere to one another
Fuse to form multinucleated
giant cells
Form palpable nodules
Release lytic enzymes
Tissue damage
Ex: Mycobacterium
tuberculosis in the lung:
Tubercles
Lung damage

cells organized within the granuloma structure

CD4+ T cell
CD8+ T cell
B cell
Eosinophil
Neutrophil
Macrophage
Dendritic
cell
Giant cell
Fibroblast
Collagen

Type I: necrotizing
granuloma in the lung of
Mycobacterium
tuberculosis-

Type II: fibrotic granuloma

surrounding parasite egg in the
liver of
Schistosoma mansoni-infected
patient

Immediate Vs. delayed

Immediate Hypersensitivity

Delayed Hypersensitivity

Appears and recedes rapidly

Appears slowly lost longer

Induced by Antigens or haptens by

any route

Antigen or hapten intradermally or

with Freunds adjuvant or by skin
contact.

Circulating antibodies present and

responsible for reaction; Ab
Mediated reaction.

Circulating antibodies may be absent

and not responsible for reaction;
cell mediated reaction.

Passive transfer possible with serum

Can not be transferred with serum;

but possible with T cells or transfer
factor.

Desensitization easy, but short-lived

Difficult , but long-lasting.

TYPE

II

III

IV

DESCRIPTIVE

INI.

NAME

TIM
E

MECHANISM

IgE-mediated
hypersensitivity

230
min

Ag induces cross-linking of
IgE bound to mast cells
with release of vasoactive
mediators

Systemic anaphylaxis,
Local anaphylaxis,
Hay fever,
Asthma, Eczema

5-8
hrs

Ab directed against cellsurface antigens mediates

cell destruction via ADCC
or complement

Blood transfusion
reactions,
Haemolytic disease of
the newborn,
Autoimmune Haemolytic
anaemia

Immunecomplex
mediated
hypersensitivity

2-8
hrs

Ag-Ab complexes
deposited at various sites
induces mast cell
degranulation via
FcgammaRIII, PMN
degranulation damages
tissue

Arthus reaction
(Localised);
Systemic reactions
disseminated rash,
arthritis,
glomerulonephritis

cell-mediated
hypersensitivity

2472
hr

Antibodymediated
cytotoxic
hypersensitivity

Memory TH1 cells release

cytokines that recruit and
activate macrophages

EXAMPLES

Contact dermatitis,
Tubercular lesions