10/10/2023

Hypersensitivity

Hypersensitivity

• Hypersensitivity refers to undesirable reactions produced by the

normal immune system.
• Hypersensitivity in general include 2 stages:
Sensitization stage: the individual is pre-sensitized to that particular
antigen.
Effector stage: on the second exposure to the same antigen, immune
system becomes overactive and is capable of launching excessive,
inappropriate immune response against this harmless antigen.

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Hypersensitivity reactions classifications

• Type I - IgE mediated immediate reaction

• Type II- Antibody-mediated cytotoxic reaction (IgG or IgM antibodies)
• Type III- Immune complex-mediated reaction
• Type IV- Cell-mediated, delayed hypersensitivity reaction

• The first three types are considered immediate hypersensitivity reactions

because they occur within 24 hours.
• The fourth type is considered a delayed hypersensitivity reaction because
it usually occurs more than 12 hours after exposure to the allergen, with a
maximal reaction time between 48 and 72 hours.

Type I hypersensitivity (Allergy)

• Also known as Atopy (atopic reactions) or IgE mediated

hypersensitivity.
• Example: drug allergy, food allergy, skin allergy, dust allergy, animal
allergy, etc.
• Antigens that stimulate allergy are known as Allergens (mostly
proteins)
• These are environmental Ag (e.g pollens, dust mites, latex, …), Food
(milk, nuts, fruits, eggs,….), Animal (bee, cats, insects,..), drugs
• Atopic diseases: allergic asthma, allergic rhinitis, conjunctivitis,
dermatitis, etc.

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Atopy or Atopic reaction

Localized Systematic
Confined to organ system, affect Affects whole body
a specific target tissue
Anaphylaxis
Allergic asthma (airways)
Life-threatening reactions

Venom (bee, wasp, insect stings)

Eczema (skin)
Drugs (penicillin)
Hay Fever (Nose) Food (seafood, nuts)

Mechanism of Hypersensitivity I
I-Sensitization Stage
1. Exposure to antigen (inhalation, ingestion, injection)
Ag is taken up by APCs (dendritic cells) and presented it (MHC cpx)>>> At site of entry
2. Nearby Lymph node:
These cells will travel to near lymph node and activate naïve T helper to Th2 cells which
activate B-cells
B cells also activated by binding Ag
3. Th2 cells migrate to the site of entry , secrete cytokines (IL-4, IL-5, IL-13) which will
switch activated B-cells to proliferate into IgE producing plasma cells specific for this
antigen.
IgE will bind directly Ag and some free IgE bind to mast cell in tissue, excess IgE reach
circulation and bind to basophils and mast cells in different tissues>>>>>>>> sensitized
cells
Sensitization of mast cells and basophils
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Mechanism of Hypersensitivity I
2-Effector stage

Second Exposure to same allergen

➢The allergen cross-links bound IgE molecules on the sensitized cells
➢Resulting in degranulation of mast cells and the secretion of
inflammatory mediators:
Histamine (vasodilatation, vaso permeability, s.m. contraction, mucus),
leukotriene and prostaglandin that act on the surrounding tissues.
The effects of such products are vasodilation and smooth- muscle
contraction that may result in the classical allergic symptoms of
bronchoconstriction with mucous secretion and rhinitis.
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Mechanism of
Hypersensitivity I

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Diagnosis

• Diagnostic tests for immediate hypersensitivity include skin (prick and

intradermal) tests resulting in wheal and flare reaction (ch. local cutaneous
reaction, developing within 10 to 15 minutes of injecting an allergen)
• Measurement of total IgE and specific IgE antibodies against the suspected
allergens by ELISA, Radioallergosorbent test (RAST)

Control of Type 1 hypersensitivity

• Avoiding contact
• Immunotherapy Subcutaneous injections of
allergens(Hyposensitization) causes shift to Ig G production instead of
Ig E (repeated injection of allergen)
• Monoclonal anti-human Ig E (Though expensive and difficult
administer).
• Drug therapies
Can treated with pharmacological inhibitors of cellular and tissue
responses and inflammation (antihistamines, leukotriene inhibitors and
corticosteroids)
Epinephrine -which inhibits degranulation (severe Type I hypersensitivity
reactions are treated with epinephrine first, often followed by corticosteroids)
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Type II hypersensitivity
• An antibody-mediated immune reaction in which antibodies
(IgG or IgM) are directed against Ag present on cells or tissues
• Examples: hemolytic anemia (if RBCs are involved), leukopenia
(WBCs), thrombocytopenia (platelets), blood transfusion reactions,
Rh incompatibility, ….
• Mechanism:
Ab-mediated cytotoxicity
• Complement activation
• Opsonization or opsonized phagocytosis
• ADCC

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Hemolytic disease of the

newborn
Erythroblastosis Fetalis

To prevent HDN,
human Rho(D)
immune globulin
(e.g., RhoGAM) is
injected IV or IM into
the mother during the
28th week of
pregnancy and within
72 hrs after delivery.

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Type III hypersensitivity

• Abnormal immune response is mediated by the formation of antigen-

antibody aggregates called "immune complexes."
• It involves soluble antigens that are not bound to cell surfaces
• 2 types of antigens cause immune complex-mediated injuries
• Exogenous antigens: Microbial proteins or proteins produced by
pathogen
• Endogenous antigens: (self protein, glycoprotein, DNA )An individual
can produce antibody against self components
(auto-immune diseases)

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Mechanism of Type III hypersensitivity

Ag binds Abs in the circulation and
forms immune complex
These complex in normal cases are
small and cleared by phagocytosis
When immune cpx attain large size
(insoluble), can’t be phagocytosed
They start deposit in the tissues
(kidney, joints, small blood vessels)
Once Immune complexes deposited
(Attach to the walls of small blood
vessels) activate complement
cascade
Polymorphonuclear cells (like
neutrophils) are attracted to the site
Release of cytotoxic granules &
reactive oxygen that damage body
tissues

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Diseases involving a type III hypersensitivity reaction

The most common:
• Serum sickness
• Post-streptococcal glomerulonephritis
• Systemic lupus erythematosus
• Farmers' lung (hypersensitivity pneumonitis)
• Rheumatoid arthritis
• Arthus reactions

The principle feature that separates type III reactions from other
hypersensitivity reactions is that in type III reaction, the antigen-antibody
complexes are pre-formed in the circulation before their deposition in
tissues
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Diseases involving a type III hypersensitivity

reaction
• Scientific evidence that in COVID-19 vasculitis a life-
threatening escalation from type 2 T-helper immune
response (humoral immunity) to type 3
hypersensitivity (immune complex disease) takes
place.
• The subsequent deposition of immune complexes
inside the vascular walls is supposed to induce a
severe inflammatory state and a cytokine release
syndrome, whose interleukin-6 is the key myokine,
from the smooth muscle cells of blood vessels.

Roncati,et al. Clin Immunol ; 217: 108487, 2020 08.

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Type IV hypersensitivity

• Delayed hypersensitivity reaction (DTH) because of its delayed

appearance (i.e., after 24–48 h)
• This is the only type of hypersensitivity reaction which is not
mediated by antibody (Cell mediated hypersensitivity)
• Ag may be:
Foreign Ag that alter self Ag e.g. Poison ivy (bind self Ag & create new
Ag), Auto Ag, or Ag derived from intracellular pathogen e.g.
Mycobacterium (escape immunity), viruses, protozoa, fungi and some
metazoan parasites.

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Mechanism of type IV
hypersensitivity
T-cell mediated
a. Sensitization stage:

1st exposure Ag is captured by

dendritic (APC) which takes it to
the nearest lymph node and
presents the antigen as peptide
nestled to class II MHC* which
will be recognized by CD4 T
cells (naïve T cells). These cells
will proliferate to TH1 helper
(This stage will take 1-2 weeks)

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Mechanism of type IV hypersensitivity

T-cell mediated
2. The effector stage:
On 2nd exposure to same Ag
TH1 releases IL-2, TNF-B, INF-γ which
activates phagocytes like macrophages
and creates more TH1 cells.
The activated macrophages release proinflammatory cytokines causing leaky
endothelial barrier and attracting more immune cells to the area leading to
edema, redness, local swelling and systemic symptoms like fever.
Those activated macrophages also secrete lysosomal enzymes and reactive
oxygen species to the exposed area which damage tissue.
(This stage will takes 1-2 days)
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Contact dermatitis
• The response to
poison (oak or ivy) is
a classic Type IV.
• Small molecules on
poison ivy (urushiol)
form a complex with
skin proteins that is
taken up by APCs
and presented to
CD4 T cells

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DTH is a type of immune

response classified by (T-cell
mediated) Th1 and
macrophage activation that
results in tissue damage.

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