Hypersensitivity Reactions
Dr.
Aws
Alshamsan
Department
of
Pharmaceu5cs
Office:
AA87
Tel:
4677363
aalshamsan@[Link]
Learning Objectives
By the end of this lecture you will be able
to:
① List the four types of hypersensitivity reactions
② Describe the mechanism of each hypersensitivity
reaction
③ Understand the clinical manifestations and
managements of some hypersensitivity reactions
Hypersensitivity reactions
• Excessive or inappropriate
reaction of the immune
system
• Resulting from repeated
or prolonged exposure to
antigens
• Sometimes lead to host
tissue damage
Hypersensitivity reactions
• They cause injury by the release of substances
that attract and activate cells and molecules of
inflammation
• The reactions are classified into four types
depending upon the mechanism that underline
the tissue damage
Type I
• Is an Immediate
Hypersensitivity Reaction
• Also called Allergic
reaction
• Characterized by
production if IgE against
proteins commonly
present in the
environment
Immediate Hypersensitivity Reaction
• Occurs within minutes
to hours of Ag
exposure
• Allergens are
relatively harmless
antigens commonly
found in the
environment
First
exposure
6
1
Second
Cytokines
exposure
and
4
5
2
3
+ Basophils
Immediate Hypersensitivity Mediators
Mediator
Effects
Histamine
Vascular permeability and bronchospasm
AUTACOIDS
Leukotrienes
Vascular permeability and bronchospasm
Prostaglandins
Vascular permeability and bronchospasm
Vascular permeability and bronchospasm
Bradykinins
CYTOKINES
IL-1 & TNF-α
Systemic anaphylaxis and increase of CAMs expression
IL-4 & IL-13
Increase IgE production
Localized Type I reactions
• Mast cells accumulate
in tissues such as
respiratory passages,
intestinal walls, and
skin
• Inhaled allergens
cause allergic asthma
Immediate and Late responses
PEFR
Due to
the other
mediators
Due to
histamine
release
Acute and chronic asthma
Localized Type I reactions
• Skin allergens cause
inflammatory response
Immediate and Late responses
Wheal and flare Edema (late-
(early-phase) phase) after 6
within 15 minutes hours of allergen
of allergen challenge
challenge
Systemic Type I reactions ANAPHYLAXIS
• Dissemination of some antigens by the
bloodstream can result in systemic inflammation
(anaphylaxis)
• Mediated by systemic release of basophilic and
mast cell mediators
• Management: Epinephrine (life saving), H1 and
H2 antagonists, Corticosteroids, and Salbutamol
Anaphylactic vs. Anaphylactoid
• An anaphylactoid (“allergic-like”) reaction is an
immediate, systemic reaction that mimics anaphylaxis
(release of identical mediators from mast cells and
basophils), but differs in that it is NOT an IgE mediated
response
Can be Can be
caused by caused by
drugs e.g. drugs e.g.
penicillin
morphine
Anaphylactic
Anaphylactoid
Anaphylactic vs. Anaphylactoid
Anaphylactic Anaphylactoid
Reaction
Reaction
Is sensitization required?
Yes
No
Can reaction occur in first
No
Yes
exposure?
How much exposure is
Little
Much
needed to start reaction?
Is reaction predicted by
Yes
No
allergy skin test?
Can be caused by drugs?
Yes
Yes
Atopy and Hygiene Hypothesis
• Exposure to some infectious
agents in childhood drives the
immune system towards TH1
response and non-atopy.
• Children with genetic
susceptibility to atopy and living
in an environment with low
exposure to infectious disease
tent to mount TH2 responses,
and will be more susceptible to
develop atopic allergic diseases
Type II
• Is an Antibody-Mediated
Cytotoxic Reaction
• Mediated by IgG and
IgM binding to specific
cells or tissues surface
• The damage is restricted
to the cells and tissues
bearing this antigen
Antibody-Mediated Cytotoxic Reaction
• Antibody directed against cell
surface or tissue antigens
• also interacts with the Fc
receptor (FcR) on a variety of
effector immune cells (e.g. NK,
MΦ, PMN)
• or can activate complement
cascade where MAC is formed
and C3b can deposit on target
cells
FcR-Mediated Mechanism
① Antibodies (may also be auto-
reactive) generated against
surface antigens
② They also bind to FcR on
effector cells
③ Effector cells include NK cell,
Macrophage, Neutrophil
④ NK cell will kill target cells
by ADCC
⑤ Macrophages and neutrophils
will undergo phagocytosis or
frustrated phagocytosis
Complement Pathway-Mediated
① Auto-reactive antibodies
generated against surface
antigens
② C1 binds to auto-reactive IgG
and IgM on target cell or
tissue
③ Classical complement pathway
is initiated on target cell or
tissue
④ MAC formation
CR-Mediated Mechanism
① C3b deposit on target cell surface
② Recognized by CR on macrophages and neutrophils
(recruited by C3a and C5a “Chemotaxis”)
③ Phagocytosis or frustrated phagocytosis
C3b
Frustrated
Phagocytosis
Damage mechanisms
Frustrated
Phagocytosis
Transfusion Reaction
Hemolytic disease of the newborn (HDN)
Also known as: Erythroblastosis Fetalis
Rh- mother
bearing an
Rh+ fetus
Second fetus Rhogam shot
dies
throughout
the pregnancy
Type II-like Autoimmune diseases
Graves disease
Myasthenia gravis
Type III
• Is an Immune Complex
Reaction to prolonged Ag
exposure
• Mediated by large
amounts of immune
complexes (Ab-soluble
antigens)
• The damage depends Or MΦ
upon the site of complex
deposition
Clearing Immune Complexes
• Immune complexes can damage
tissues
• C3b coats immune complexes
• RBC have capability of binding
C3b coated complexes and
carrying them to liver and
spleen to be cleared
Clearing Immune Complexes
Virus Particle
Bacterial Toxin
Self Antigen
Systemic Immune
Complex Reaction
• Presence of large amount of
antibodies in the serum against
soluble antigen
• Serum sickness
• HAMA response
• Autoimmune diseases (SLE, RA)
• Drug reactions (penicillin, sulfonamides)
• Infectious disease
systemic
• Recruitment of
vasculitis
neutrophils and Mϕ
• Frustrated phagocytosis (IL-1, TNF-α)
• Platelets aggregation
fever
rashes
itching
joint pain
lymphadenopathy
malaise
Hypotension
Splenomegaly
glomerulonephritis
proteinuria
hematuria
shock
Local Immune Complex Reaction
• Injection of antigen intradermally or subcutaneously into
a body that has high level of antibody for that antigen
(e.g. Arthus reation, Bug bites)
local
vasculitis
C3a
Type IV
• Is a Delayed-Type
Hypersensitivity (DTH)
Reaction
• It is a T-cell mediated
inflammatory response (no
Ab involved)
• Ag-specific effector T cells
lead to MΦ activation
Delayed-Type Hypersensitivity
• Can be elicited against exogenous or endogenous
antigens (autoimmune T cells)
Delayed-Type Hypersensitivity
• Three variants of Type-IV reactions:
• Contact hypersensitivity (48-72 hours)
• Tuberculin-type hypersensitivity (48-72 hours)
• Granulomatous hypersensitivity (21-28 days)
• The local response is also accompanied by a
variety of systemic immune responses, such as T
cell proliferation and synthesis of cytokines
including (IFN-γ)
Contact hypersensitivity
• Reaction at the point of contact
with allergen
• Seen following contact with
agents such as nickel, chromate,
rubber, and pentadecacatechol
Tuberculin-type hypersensitivity
• Induced by injection of soluble Ag from
intracellular organisms such as Mycobacterium
tuberculosis e.g. Tuberculin test (PPD test)
Granulomatous hypersensitivity
• The most important form of Type-IV reactions
• Persistence of intracellular organism within MΦ
• Particles cannot be destroyed by MΦ
• Chronic stimulation of T cells and release of
cytokines lead to the formation of epithelioid cell
granuloma (central collection of epithelioid cells
and MΦ surrounded by T cells)
You are now able to:
ü List the four types of hypersensitivity reactions
ü Describe the mechanism of each hypersensitivity
reaction
ü Understand the clinical manifestations and
managements of some hypersensitivity reactions
