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TYPE III & IV
HYPERSENSITIVITY
REACTION
Hypersensitivity reaction
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Outline
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Introduction.
Type III hypersensitivity reaction.
- General mechanisem of action
1-Systemic Immune Complex Disease
2-Local Immune Complex Disease
- Summary
TypeVI hypersensitivity reaction.
- Variants of type IV hypersensitivity reactions
- Mechanisem of action
Hypersensitivity reaction
Type III hypersensitivity reaction
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Sensitization phase
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IgM and IgG bind to soluble Ag which lead to
immune comlex formation
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Soluble Ag-Ab complex that are large in size are
cleared from circulation by phagocyte cell (liver and
spleen)
Hypersensitivity reaction
Type III hypersensitivity reaction
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However
Circulation Ag-Ab immune complexe formed in excess
(chronic infection) and are Small in size
escape clearance
Hypersensitivity reaction
Title
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Larger aggregates fix complement and are readily cleared from
the circulation by the mononuclear phagocytic system. The small
complexes that form at antigen excess, however, tend to deposit in
blood vessel walls. There they can ligate Fc receptors on leukocytes,
leading to leukocyte activation and tissue injury.
Hypersensitivity reaction
Type III hypersensitivity reaction
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Effectors phase
They are then deposited in capillary walls either:
 Locally at site Ag entry
 Systematically in blood vessels and various tissue.
Ag-Ab complex stimulate complement activation causing
tissue damage (Type III)
Hypersensitivity reaction
Type III hypersensitivity reaction
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Factors that determine whether immune complex formation will
lead to tissue deposition and disease:
*Size of immune complexes and functional status of the
mononuclear phagocyte system
1. large complexes in antibody excess are rapidly
removed from circulation by mononuclear phagocyte
system (harmless)
2.Pathogenic complexes are small or intermediate
(formed in antigen excess), which bind less avidly to
phagocytic cells  circulate longer
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Type III hypersensitivity reaction
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Antigen-Antibody complex
Complement activation
Macrophage activation
Attract polymorphs
Release TNF-α ,IL1
Rlease of proteolytic enzyme
Hypersensitivity reaction
Type III hypersensitivity reaction
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Immune complex-mediated diseases can be
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generalized  immune complexes are formed in
circulation and deposited in many organs
localized  deposited to particular organs, such as
kidney (glomerulonephritis), joints (arthritis), or small
blood vessels of skin
Hypersensitivity reaction
Type III hypersensitivity reaction
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Systemic Immune Complex Disease
Hypersensitivity reaction
Type III hypersensitivity reaction
Systemic Immune Complex Disease
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Pathogenesis of systemic immune complex disease divided into
three phases:
1.) formation of antigen-antibody complexes in circulation
- initiated by introduction of an antigen, a protein, and
interaction with immunocompetent cells formation of
antibodies which are secreted into blood  they react with
antigen still present in the circulation to form antigen-antibody
complexes
2.) deposition of the immune complexes in various tissues
3.) an inflammatory reaction at the sites of immune complex
deposition
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Type III hypersensitivity reaction
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Two types of antigens cause immune complex –
mediated injury
1) antigen may be exogenous (foreign protein,
bacterium, or virus)
2) individual can produce antibody against selfcomponents (endogenous antigens); antigen
compounds of one’s own cells/tissues such as nuclear
antigens, immunoglobulin
or tumour antigens.
Hypersensitivity reaction
Type III hypersensitivity reaction
Systemic Immune Complex Disease
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serum sickness
- patients with diphtheria infection treated with serum from
horses immunized with diphtheria toxin
- patients develop arthritis, skin rash, fever
- patients made antibodies to horse serum proteins 
antibodies formed complexes with injected proteins, and
disease was due to antibodies or immune complexes
Hypersensitivity reaction
hypersensitivity Reactions
Type IV
(T-Cell Mediated)
Type IV hypersensitivity Reactions (T-Cell
Mediated)
It is also known as cell mediated or delayed type hypersensitivity.
Type IV hypersensitivity reactions are mediated by immune cells (T
cell), not antibodies that develops in response to antigen challenge in
a previously sensitized individual.
In contrast with immediate hypersensitivity, the DTH reaction is
delayed for 48-72 hours, which is the time it takes for effector T cells
to be recruited to the site of antigen challenge and to be activated to
secrete cytokines.
The delayed hypersensitivity reactions lesions mainly contain
monocytes and T cells
Type IV hypersensitivity Reactions
Two types of T cell reactions are capable of causing tissue
injury and disease:
(1) Cytokine-mediated inflammation:
-In which the cytokines are produced mainly by CD4+ T cells .
-CD4+ T cells of the TH1 and TH17 subsets secrete cytokines,
which recruit and activate other cells, especially macrophages,
and these are the major effector cells of injury.
(2) Direct cell cytotoxicity:
-Mediated by CD8+ T cells
-In which cytotoxic CD8+ T cells are responsible for tissue damage.
Type IV hypersensitivity Reactions
1) Cytokine-mediated inflammation :
1-Naive CD4+ T lymphocytes recognize peptide antigens of self or microbial
proteins in association with class II MHC molecules on the surface of
DCs or macrophages that have processed the antigens.
2-Then CD4+ T cells are activated and differentiate into TH1 and TH17
effector cells.
(If the DCs produce IL-12, the naive T cells differentiate into effector cells of
the TH1 type, If the APCs produce IL-1, IL-6, or IL-23 instead of IL-12, the
CD4+ cells develop into TH17 effectors)
Type IV hypersensitivity Reactions
3-Subsequent exposure to the antigen the previously generated effector cells
are recruited to the site of antigen exposure and results in the secretion of
cytokines.
4-The TH1 cells secrete IFN-γ, which is the most potent macrophageactivating cytokine known.
5-Macrophages produce substances that cause tissue damage and promote
fibrosis, and TH17 secrete IL-17 and other cytokines recruit leukocytes
especially macrophages , thus promoting inflammation.
Cytokine-mediated inflammation
Type IV hypersensitivity Reactions
2)T cell–mediated cytotoxicity :
1- CD8+ CTLs specific for an antigen recognize cells expressing the target antigen and kill these cells.
2- Class I MHC molecules bind to intracellular peptide antigens and present the peptides to CD8+ T
lymphocytes, stimulating the differentiation of these T cells into effector cells called CTLs.
3-The principal mechanism of killing by CTLs is dependent on the perforin–granzyme system.
4-These enzymes induce apoptotic death of the target cells.
5-CD8+ T cells may also secrete IFN-γ and contribute to cytokine-mediated inflammation, but less so than
CD4+ cells
T cell–mediated cytotoxicity
T cell–mediated cytotoxicity
Sensitization phase
Type IV hypersensitivity Reactions
Cont. phases :
2- Effector phase:
This occurs following re-exposure to antigen and activation of the
memory Th1 cells
IFN γ, from activated Th1 cells, promotes differentiation of
monocytes to
macrophages, and activates mature macrophages to kill
intracellular organisms. In addition, activated macrophages
secrete products including IL-1
and TNF, that stimulate processes producing inflammatory
mediators that
cause bystander tissue injury.
Effector phase:
IFNγ, secreted by
activated Th1 cells, is a potent
activator of tissue
macrophages
Activated macrophages secrete cytokines
(e.g., IL-1 and TNF) and
chemokines that activate adhesion molecules
on the endothelium
and circulating leukocytes
Neutrophils phagocytose antigen and secrete
inflammatory mediators that cause local tissue damage
Type IV hypersensitivity Reactions
 Examples :
1. Contact hypersensitivity
2. Granulomatous hypersensitivity
3. The tuberculin test
Contact Hypersensitivity
is usually caused by haptens that combine with proteins
(particularly the amino acid lysine) in the skin of some people to
produce an immune response .
Reactions to poison ivy , cosmetics, and the metals in jewelry
(especially nickel ) are familiar examples of these allergies.
Contact Hypersensitivity
Granulomatous hypersensitivity
It usually results from the persistence within macrophages of
intracellular microorganisms, which are able to resist macrophage
killing or particles that the cell is unable to destroy.
This leads to chronic stimulation of T cells and the release of
cytokines. The process results in the formation of epithelioid cell
granulomas with a central collection of epithelioid cells,giant
cells and macrophages surrounded by lymphocytes.
Granulomas occur with chronic infections such as tuberculosis
or with foreign particulate agents such as talc and silica .
Granulomatous hypersensitivity
The tuberculin test
The test is used to determine whether an individual has been
infected with the causative agent of tuberculosis,
Mycobacterium tuberculosis. (A previously infected individual
would harbor reactive T cells in the blood.)
The Mechanism of Tuberculin Test
small amounts of protein extracted from the mycobacterium are injected
into the skin.
If reactive T cells are present
redness and swelling appear at the injection site 24-72 hours
If a tissue sample is examined, it will show :
**infiltration by lymphocytes and monocytes,
** increased fluid between the fibrous structures of the skin,
**some cell death
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Hypersensitivity reaction