Learning objectives:

BIG QUESTION:
What happens when immune system overreacts?
Differentiate between the mechanisms of the four hypersensitivity reactions.
1. Mechanism of Type I hypersensitivity
2. Understand the principle of chronic desensitization
3. Examples of Type I
4. Know the role of ADCC in Type II hypersensitivity
5. Foreign antigen versus selfantigen in Type II hypersensitivity
6. Druginduced hypersensitivity
7. Examples of Type II
8. Mechanism of Type III
9. Foreign antigen verses self antigen in Type III hypersensitivity
10. Examples of Type III
11. Mechanism of Type IV
12. Foreign antigen verses self antigen in Type IV hypersensitivity
13. Examples of Type IV

Although immune responses may cause some damage

to the body during antigen removal (such as swelling
and pain), the damage is usually mild.

However, when the damage is too great,

the injury can become very serious, even lifethreatening.
This undesirable reaction done to the body by an
immune response is called a hypersensitivity
reaction.
Hypersensitivities are classified into four types based
on the mechanism of tissue damage.

Hypersensitivities

Type I Hypersensitivity
Most of what we call "allergy" is Type I hypersensitivity, in which
mast cells are activated by IgE produced in response to an allergen
ONE IN 5 PEOPLE HAVE ATOPY - a predisposition towards Type
I hypersensitivity
The risk of developing a Type I hypersensitivity is linked to family
history and IgE levels.
People with higher IgE levels tend to be atopic more often than
people with lower IgE levels, although the linkage is not absolute.
Allergens for Type I fall into groups of molecules, such as grasses,
pollens, animal, and foods that usually reach mucosal surfaces at
very low doses.
They are protein, since only protein molecules can be presented
to T cells and elicit T cell help.

Mast cells
Mast cells are common at sites in the
body exposed to the external
environment, such as the skin.

Found in close proximity to

blood vessels, where they can
regulate vascular permeability
and effector-cell recruitment.
No direct cellcell contact with
local populations of APCs,
such as the Langerhans cells
in the skin.
Modulate the behavior of
neighboring effector cells
through the release of
mediators.

Mast cells

Type I examples

Asthma- thick mucous

plug, inflammatory cells,
hypertrophy of smooth
muscle, thickened basal
membrane, increased
number of eosonophils

TYPE I mechanism:
Has two distinct phases:
1. Sensitization phase (the synthesis of IgE
upon initial exposure to Ag)

2. Activation phase (the stimulation of mast

cells upon re-exposure)

Sensitization phase
Low Ag dose
Low M.W, soluble

mucosal membranes

Activation phase

Mast cell

ACTIVATION PHASE: detailed

Initial/Early response can occur immediately
1. Preformed molecules stored in cytoplasmic granules of mast cell are
rapidly released

Histamine - causes smooth muscle contraction, mucus release,

vasodilatation, sensory nerve stimulation and increased capillary
permeability

Proteolytic enzymes - break down tissue matrix proteins

2. Rresult: Increased blood flow and fluid released at the mucus membranes
and at the tissues washes away antigen

Late-phase response usually occurs hours after initial binding

Further tissue damage

The chemokines released in early phase attract more leukocytes, such as eosinophils
to the inflammation.

Cytokines from early and late phase stimulate white blood cell production in the marrow,

Skin test

Chronic desensitization allergy immunotherapy

Injected administration of allergen beginning with very low doses that are
increased over many months.
Current hypotheses is that the immune response is switched from IgE
to IgG, which binds allergen before it can trigger mast cells
Desensitization is not effective for every allergen or for every individual, and
its mechanism of action is unresolved.

Type II Hypersensitivity Disease

Antibody binds to a cell-surface antigen.
The ensuing reaction causes damage by:

1. Activation of complement
Classical complement activation by IgG releases
inflammation-promoting anaphylatoxins and leads to
formation of membrane attack complex (MAC) and lysis
of the antibody-coated cell.

2. Antibody-dependent cell-mediated cytotoxicity

(ADCC)
The binding of Ab-cell complex to FcgRI on cells such as NK
cells and macrophages.

Both processes can result in lysis of the target cell.

Activate complement and ADCC

If a cell is part of an organ, the result is inflammation

Clinical examples of Type II hypersensitivities:

Foreign antigen induced

Blood transfusion reaction

Drug induced reaction
(Hyperacute graft rejection)

Autoantigen induced

Myasthenia gravis
Graves disease
Hemolytic anemia

Foreign antigen-induced:
1. Blood transfusion can also result in Type II
Hypersensitivity to blood group antigens such as A, B
and Rh.

Foreign antigen-induced:
2. Drugs like aspirin and penicillin, which often complex with
erythrocyte membrane proteins, may induce synthesis of IgG antibodies
which then bind drug-coated erythrocytes and damage them.

Autoantigens induced: antibodies are produced to

membrane proteins
1. Myasthenia gravis
2. Graves' disease
3. Autoimmune hemolytic anemia

Autoantigens induced
1. Myasthenia gravis Ab against the acetylcholine receptor

Myasthenia gravis is a neuromuscular

disorder.
It effects skeletal muscles and is caused
by antibody binding to the ACh receptor
on skeletal muscle.
ACh Ab

The symptoms include:

Weakness in muscles that control
eye movement
Weakness in arms and legs,
Difficulty swallowing

2. Graves' disease - thyroid hormone receptor Ab

Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients

Caused by agonistic autoantibodies to the TSH receptor

Ab activates the TSH receptor, thereby stimulating thyroid hormones T3 and T4
synthesis and secretion
Ab also stimulates thyroid growth (causing a diffuse goiter)
People with Graves disease often have swelling around the eyes, redness, and bulging
eyes. This is due to an infiltration of the orbital connective tissue because it also contains
TSH receptor.

3. Autoimmune hemolytic anemia

Ab against erythrocyte membrane protein

Type III hypersensitivity

Type III is caused by Immune complex deposition in the tissues, where the
complement cascade results in tissue damage.
When antigen persists in the body for long period or if high levels of antigen are
encountered at one time, immune complexes reach high levels and cause damage.
Common sites of deposition and tissue damage are blood vessel walls, kidney, and
joints.

Clinical examples of Type III hypersensitivities:

Foreign antigen induced

Arthus reaction

Serum sickness

Autoantigen induced

Lupus

Rheumatoid arthritis

Foreign antigen local:

1. Arthus reaction

Foreign antigen: systemic

1. Serum sickness: A response to passive

immunization with foreign antiserum
Example: A person is bitten by Malayan pit viper

Antisnake venom (ASV) immunoglobulins

are administered as therapy

The person will develop a primary response to

the horse anti-venom IgG.

After 7-10 days, enough anti-horse IgG antibody

has been produced to form immune complexes
that deposit in small vessels and activate
complement and macrophages.

On second exposure to ASV, the patient would

begin experiencing serum sickness within hours
or days since isotype switching to IgG had
already occurred.

Symptoms of serum sickness include fever,

chills, rash, arthritis, and sometimes kidney
damage.

Autoimmune diseases:
1. Rheumatoid arthritis
Patients develop an auto-IgM antibody against their own IgG that
is thought to contribute to arthritic joint inflammation.

Autoimmune diseases:
2. Systemic Lupus Erythematosis autoantibodies are produced against the
patients own DNA and histones.

Events
required
to trigger
lupus

Type III flow chart

Infection
Environment
Auto-Ag

Ab

Ag

Clearance by
complement

Immune complex

Immune
complex disease
localized

systemic

SLE
Serum sickness

Arthus rxn

Glomerulonephritis
Rheumatoid arthritis

Type IV hypersensitivity
Delayed-type hypersensitivity (DTH)

Occurs 48-72 hours after antigen contact

Mediated by antigen-specific Th1 cells and activated

macrophages or by CD8 T cells

Initial response is called sensitization and may not result

in symptoms but generated memory Th1 and CD8 cells

Second contact with antigen results in activation of

memory T cells which often causes the development of
the characteristic itchy rash.

Clinical examples of Type IV hypersensitivities:

Foreign antigen induced

Poison Ivy, nickel (and other

contact dermatitis)

PPD test

Acute and Chronic Graft vs Host

Autoantigen induced

Diabetes Type I
Multiple Sclerosis
Celiac disease

Foreign antigen induced

1. Poison ivy reaction.

Foreign antigen induced

2. Mycobacterial proteins used in TB skin testing (PPD test)
Sensitization during prior exposure to Mycobacterium tuberculosis
results in production of memory Th1 cells to Mycobacterial proteins.
When purified tuberculin is injected into intradermally into the skin,
memory Th1 cells secrete cytokines to attract macrophages and
granulocytes and visa versa and cause induration and erythema.

Foreign antigen induced

3. Acute and Chronic Allograft rejection
(NOT hyperacute)

Autoimmune reactions:

Type I diabetes
Multiple sclerosis
Celiac disease

Autoimmune reactions

1. Type I diabetes
In type 1,
pancreatic beta
cells in the islets
of Langerhans
are destroyed,
decreasing
endogenous
insulin
production.

Autoimmune reactions
2. Multiple sclerosis
Demyelination of nerves in CNS, including the optic nerves
which control vision, so vision is affected, but the closure of
eyelid is fine.

Autoimmune reactions

3. Celiac disease

Hapten

Binds cell

Type II

Binds
cytoplasmic
protein

Binds soluble
protein

Stimulate IgG

Stimulate IgE

Type III

Type I

Activates T
cells
(Type IV)