1. TYPE IV
HYPERSENSITIVITY
REACTIONS
BY:
Dr. DINA RASHEED
Assistant Prof.
Immunology
2012

2. TYPE IV HYPERSENSITIVITY
REACTIONS
 Immune responses are themselves capable
of causing tissue injury and disease.
Injurious, or pathologic, immune reactions
are called hypersensitivity reactions.
 This term is derived from the idea that an
immune response to an antigen may result
in sensitivity to challenge with that antigen
and, therefore, hypersensitivity is a reflection
of excessive or aberrant immune responses.

3. TYPE IV HYPERSENSITIVITY
REACTIONS
Hypersensitivity reactions may occur in two
situations:
 First,responses to foreign antigens may be
dysregulated or uncontrolled, resulting in tissue
injury.
 Second, the immune responses may be directed
against self (autologous) antigens, as a result of the
failure of self-tolerance. Responses against self
antigens are termed autoimmunity, and disorders
caused by such responses are called autoimmune
diseases.

4. TYPE IV HYPERSENSITIVITY
REACTIONS
Immediate
hypersensitivity,
or type I hypersensitivity,
is a type of pathologic
reaction that is caused
by the release of
mediators from mast
cells. This reaction most
commonly is triggered
by the production of IgE
antibody against
environmental antigens
and the binding of IgE to
mast cells in various
tissues.

5. TYPE IV HYPERSENSITIVITY
REACTIONS
Antibodies directed against
cell or tissue antigens can
damage these cells or tissues
or impair their functions. These
diseases are said to be
antibody-mediated and
represent type II
hypersensitivity.
Sometimes, antibodies against
soluble antigens may form
complexes with the antigens,
and the immune complexes
may deposit in blood vessels in
various tissues, causing
inflammation and tissue injury.
Such diseases are called
immune complex diseases and
represent type III
hypersensitivity.

6. TYPE IV HYPERSENSITIVITY
REACTIONS
 Finally, some diseases result from the reactions of
T-lymphocytes and not antibodies, as in the previous three
hypersensitivity reactions. These T cell-mediated diseases
represent type IV hypersensitivity.
These type IV reactions result from T cell-initiated
inflammation.
Inflammatory responses result from the manner in which T
cells encounter and respond to antigen.
The hypersensitivity reactions usually are directed against
cellular antigens with restricted tissue distribution.
Therefore, T cell-mediated autoimmune diseases tend to
be limited to a few organs and usually are not systemic.

7. TYPE IV HYPERSENSITIVITY
REACTIONS
Figure 3: Mechanisms of T cell-mediated tissue injury. T cells may cause tissue
injury and disease by two mechanisms: (1) delayed-type hypersensitivity
reactions (A), which may be triggered by CD4+ and CD8+ T cells and in which
tissue injury is caused by activated macrophages and inflammatory cells, and
(2) direct killing of target cells (B), which is mediated by CD8+ CTLs.

8. TYPE IV HYPERSENSITIVITY
REACTIONS

9. TYPE IV HYPERSENSITIVITY
REACTIONS
 Tissue injury is caused by a delayed-type hypersensitivity
reaction mediated by CD4+ T cells or by killing of host cells by
CD8+ CTLs.
 The mechanisms of tissue injury are the same as the
mechanisms used by T cells to eliminate cell-associated
microbes.
 CD4+ T cells may react against cell or tissue antigens and
secrete cytokines that induce local inflammation and
activate macrophages. Different diseases may be associated
with activation of TH1 and TH17 cells.
 TH1 cells are the source of IFN-γ, the principal macrophage-
activating cytokine, and TH17 cells are thought to be
responsible for recruitment of leukocytes, including neutrophils.

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REACTIONS

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REACTIONS
MQ activation and its effector mechanisms

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REACTIONS

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REACTIONS

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REACTIONS

15. TYPE IV HYPERSENSITIVITY
REACTIONS
 The actual tissue injury in these diseases is caused by the macrophages
and neutrophils.
 CD8+ T cells specific for antigens on host cells may directly kill these cells.
In many T cell-mediated autoimmune diseases, both CD4+ T cells and
CD8+ T cells specific for self antigens are present, and both contribute to
tissue injury.
 Also, tissue injury with release and alteration of self proteins may result in
reactions against these proteins, a phenomenon that has been called
"epitope spreading" to indicate that the initial immune response against
one or a few self antigen epitopes may expand to include responses
against many more self antigens.
 Chronic inflammatory diseases that are initiated by immune reactions are
called immune-mediated inflammatory diseases.

16. TYPE IV HYPERSENSITIVITY
REACTIONS
CLINICAL EXAMPLES:
 Contact dermatitis, is a form of sensitivity to chemicals (e.g.,
those found in poison ivy) is a T cell-mediated reaction.
 Tissue injury also may accompany T cell responses to
microbes. For instance, in tuberculosis, a T cell-mediated
immune response is raised against Mycobacterium
tuberculosis, and the response becomes chronic because the
infection is difficult to eradicate. The resultant granulomatous
inflammation causes injury to normal tissues at the site of
infection.
 Injecting a microbial protein into the skin of an individual who
has been immunized against the microbe by prior infection or
vaccination, leads to another form of type IV hypersensitivity
reaction (DTH), as seen in PPD skin test (Tuberculin test).

17. This reaction is called delayed-type hypersensitivity (DTH), because it
occurs 24 to 48 hours after an immunized individual is challenged
with a microbial protein (i.e., the reaction is delayed), and because it
reflects an increased sensitivity to antigen challenge.
The delay occurs because it takes 24 to 48 hours for circulating
effector T lymphocytes to home to the site of antigen challenge,
respond to the antigen at this site, and induce a detectable
reaction.
DTH reactions are manifested by infiltrates of T cells and blood
monocytes into the tissues, edema and fibrin deposition caused by
increased vascular permeability in response to cytokines produced
by CD4+ T cells, and tissue damage induced by the products of
macrophages activated by T cells.
DTH reactions often are used to determine if people have
been
previously exposed to and have responded to an antigen. For
instance, a DTH reaction to a mycobacterial antigen, PPD
(purified protein derivative), is an indicator of a T cell response
to the mycobacteria. This is the basis for the PPD skin test,
which frequently is used to detect past or active
mycobacterial infection

18. TYPE IV HYPERSENSITIVITY
REACTIONS
 Excessive polyclonal T cell activation by certain
microbial toxins produced by some bacteria and
viruses can lead to production of large amounts of
inflammatory cytokines, causing a syndrome similar to
septic shock. These toxins are called superantigens
because they stimulate large numbers of T cells.
 Superantigens bind to invariant parts of T cell
receptors on many different clones of T cells,
regardless of antigen specificity, thereby activating
these cells.

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REACTIONS

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REACTIONS
 The therapy for T cell-mediated hypersensitivity disorders
is designed to reduce inflammation, using: corticosteroids
and antagonists against cytokines such as TNF, and to
inhibit T cell responses with immunosuppressive drugs
such as cyclosporine.
 Antagonists of TNF have proved to be beneficial in
patients with rheumatoid arthritis and inflammatory
bowel disease.
 Many newer agents are being developed to inhibit T
cell responses. These include: agents that block
costimulators such as B7 and antagonists against
receptors for cytokines such as IL-2. There also is great
hope for inducing tolerance in pathogenic T cells, but
no successful clinical trials have been reported yet.

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REACTIONS
Thank you for your attention