Immunology

Allergy and Hypersensitivity

 Introduction
• Generally the immune system is protective
• Protective mechanisms may result in severe
damages to tissues and may lead to death

When?
Severe damages may occur when the immune
system responded in exaggerated or
inappropriate form.
 Classification
Coombs and Gell Type Alternative names Mediators
classification I Allergy (immediate) IgE
• Type I – IgM or IgG
immediate (atopic, or Cytotoxic, antibody-
II Complement
anaphylactic) dependent
MAC
• Type II - IgG
antibody- Immune complex
III Complement
dependent disease
Neutrophils
• Type III - Delayed-type
immune complex hypersensitivity, cell-
• Type IV - cell- IV mediated immune T-cells
mediated or memory response,
antibody-independent
delayed
 Type I - immediate (or atopic, or
anaphylactic)

• Type I hypersensitivity is an allergic reaction provoked by re-

exposure to a specific antigen.
• Exposure may be by ingestion, inhalation, injection, or direct
contact.
• The reaction is mediated by IgE, antibodies and produced by
the immediate release of histamine, typtase, arachidonate and
derivatives by basophils and mast cells..
• This causes an inflammatory response leading
to an immediate (within seconds to minutes)
reaction.

• The reaction may be either local or systemic.

Symptoms vary from mild irritation to sudden
death from anaphylactic shock.

• Treatment usually involves epinephrine,

antihistamines, and corticosteroids
• The reaction may cause a range of symptoms
from minor inconvenience to death.

• The reaction usually takes 15 - 30 minutes

from the time of exposure to the antigen.
– sometimes it may have a delayed onset (10 - 12
hours).
• Immediate hypersensitivity is mediated by IgE.
• The primary cellular component in this
hypersensitivity is the mast cell or basophil.
• The reaction is amplified and/or modified by
platelets, neutrophils and eosinophils.
• A biopsy of the reaction site demonstrates
mainly mast cells and eosinophils.
 Mechanism:
• The mechanism of reaction involves preferential production of
IgE, in response to certain antigens (allergens).
• IgE has very high affinity for its receptor on mast cells and
basophils.
• A subsequent exposure to the same allergen cross links the cell-
bound IgE and triggers the release of various pharmacologically
active substances
• Cross-linking of IgE Fc-receptor is important in mast cell
triggering. Mast cell degranulation is preceded by increased
Ca++ influx, which is a crucial process; ionophores which
increase cytoplasmic Ca++ also promote degranulation, whereas,
agents which deplete cytoplasmic Ca++ suppress degranulation.
• Mast cells may be triggered by other stimuli such
as
-Exercise,
-Emotional stress
-Chemicals (e.g., photographic developing medium,
calcium ionophores, codeine, etc.),
-Anaphylotoxins (e.g., C4a, C3a, C5a, etc.).
• These reactions are not hypersensitivity
reactions although they produce the same
symptoms.
Some examples:
• Allergic asthma
• Allergic rhinitis ("hay fever")
• Allergic conjunctivitis
• Anaphylaxis
• Angioedema
• Urticaria (hives)
 Type II - antibody-dependent

• 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
• Type II hypersensitivity is also known as cytotoxic
hypersensitivity and may affect a variety of organs and tissues.
• The antigens are normally endogenous, although exogenous
chemicals (haptens) which can attach to cell membranes can also
lead to type II hypersensitivity.

Examples:
- Drug-induced hemolytic anemia
-Granulocytopenia
-Thrombocytopenia
• The reaction time is minutes to hours.

• Type II hypersensitivity is primarily mediated by

antibodies of the IgM or IgG classes and
complement

• Phagocytes and K cells may also play a role

(ADCC).
• IgG and IgM antibodies bind to these antigens to form
complexes that activate the classical pathway of
complement activation for eliminating cells presenting
foreign antigens (which are usually, but not in this case,
pathogens).

• As a result mediators of acute inflammation are

generated at the site and membrane attack complexes
cause cell lysis and death. The reaction takes hours to a
day.
 Examples
• Autoimmune haemolytic anemia
• Pernicious anemia
• Immune thrombocytopenia
• Transfusion reactions
• Hashimoto's thyroiditis
• Graves' disease
• Myasthenia gravis
• Farmer's Lung
• Hemolytic disease of the newborn
Type II
in
Asthma
 Type III - immune complex
In type III hypersensitivity:
• Soluble immune complexes (aggregations of antigens and
IgG and IgM antibodies) form in the blood and are
deposited in various tissues (typically the skin, kidney and
joints)

• This may trigger an immune response according

to the classical pathway of complement
activation.
• The reaction takes hours to days to develop
• Also known as immune complex disease
• Occurs when immune complex (Ag-Ab) are not
removed from circulation
• These complexes are deposited in various tissues
and organs such as:
- Kidneys
- Joints
- Lung
- Skin
• Immune complex formation may occur as a
result of :
Autoimmune diseases (RA)
Persistence infection (Hepatitis virus)
Repeated inhalation of antigenic materials
MECHANISM
Step 1

Large quantities of
soluble antigen-antibody
complexes form in the
blood and are not
completely removed by
macrophages.
Step 2

These antigen-antibody
complexes lodge in the
capillaries between the
endothelial cells and the
basement membrane.
Step 3

These antigen-antibody
complexes activate the
classical complement
pathway leading to
vasodilatation.
Step 4

The complement
proteins and
antigen-antibody
complexes attract
leukocytes to the
area.
Step 5
The leukocytes
discharge their killing
agents and promote
massive
inflammation. This
can lead to tissue
death and
hemorrhage.
Size of the immune complex, time, and place
determine if this reaction will occur or not
Localized depositions of immune complexes
within a tissue cause type III hypersensitivity
Examples:
• Immune complex glomerulonephritis
• Rheumatoid arthritis
• Serum sickness
• Subacute bacterial endocarditis
• Symptoms of malaria
• Systemic lupus erythematosus
• Arthus reaction
 Systemic Lupus Erythematosus
• The disease is characterized
by the presence of
autoantibodies , which form
immune complexes with
autoantigens and are
deposited within the kidney
glomeruli
• The resulting type III
hypersensitivity is responsible
for the glomerulonephritis
(Inflammation of blood
capillary vessels in the
glomeruli)
 Type IV Hypersensitivity

• Type IV hypersensitivity is often called

delayed type as the reaction takes two to three
days to develop.
• Unlike the other types, it is not antibody
mediated but rather is a type of cell-mediated
response.
• Type IV hypersensitivity is also known as cell
mediated or delayed type hypersensitivity.

• The classical example of this hypersensitivity is

tuberculin (Montoux) reaction

• Reaction peaks 48 hours after the injection of

antigen (PPD or old tuberculin). The lesion is
characterized by induration and erythema
• Another form of delayed hypersensitivity is
contact dermatitis (poison ivy (figure 6),
chemicals, heavy metals, etc.) in which the lesions
are more papular

• Type IV hypersensitivity can be classified into

three categories depending on the time of onset
and clinical and histological presentation
 Diagnosis
• Diagnostic tests in vivo include delayed cutaneous
reaction (e.g. Montoux test )

• In vitro tests for delayed hypersensitivity include

mitogenic response, lympho-cytotoxicity and IL-2
production.

• Corticosteroids & other immunosuppressive agents

are used in treatment.
Some clinical examples:
• Contact dermatitis (E.g: poison ivy rash)
• Temporal arteritis
• Symptoms of leprosy
• Symptoms of tuberculosis
• Transplant rejection
Hypersensitivity
reactions
Figure 12-2
Hypersensitivity
reactions
 Type Reaction Clinical Histology Antigen and site
time Appearance

Contact 48-72 hr Eczema Lymphocytes, Epidermal ( organic

followed by chemicals, poison ivy,
macrophages; heavy metals, etc.)
edema of
epidermis
Tuberculin 48-72 hr Local induratio Lymphocytes, Intradermal
monocytes, (tuberculin, lepromin,
macrophages etc.)
Granuloma 21-28 days Hardening Macrophages, Persistent antigen or
epitheloid and giant foreign body presence
cells, fibrosis (tuberculosis, leprosy,
etc.)
Thank you~ 