hypersensitivity type iv
TRANSCRIPT
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Type IV or Delayed-TypeHypersensitivity (DTH)
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When some subpopulations of activated TH
cells encounter certain types of antigens, they
secrete cytokines that induce a localized
inflammatory reaction called delayed-type
hypersensitivity (DTH).
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The reaction is characterized by large influxes of
nonspecific inflammatory cells, in particular,macrophages.
This type of reaction was first described in 1890 by
Robert Koch, who observed that individuals infectedwith Mycobacterium tuberculosis developed a
localized inflammatory response when injected
intradermally with a filtrate derived from a
mycobacterial culture.
He called this localized skin reaction a tuberculin
reaction.
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Later, as it became apparent that a variety of
other antigens could induce this response its
name was changed to delayed-type or type IV
hypersensitivity in reference to the delayed
onset of the reaction and to the tissue
damage (hypersensitivity) that is often
associated with it
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The term hypersensitivity is somewhat
misleading, for it suggests that a DTH
response is always detrimental.
Although in some cases a DTH response does
cause extensive tissue damage and is in itself
pathologic, in many cases tissue damage is
limited, and the response plays an importantrole in defense against intracellular pathogens
and contact antigens.
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The hallmarks of a type IV reaction are the
delay in time required for the reaction todevelop and the recruitment of macrophages
as opposed to neutrophils, as found in a type
III reaction.
Macroph
ages are th
e major component of th
einfiltrate that surrounds the site of
inflammation.
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There Are Several Phasesof the DTH Response
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The development of the DTH response begins
with
an initial sensitization ph
ase of 12weeks after primary contact with an antigen.
During this period, TH cells are activated and
clonally expanded by antigen presented
together with the requisite class II MHC
molecule on an appropriate antigen
presenting cell
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A variety of antigen-presenting cells have
been shown to be involved in the activation of
a DTH response, including Langerhans cells
and macrophages.
Langerhans cells are dendritic cells found in
the epidermis
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These cells are thought to pick up antigen that enters
th
rough
th
e skin and transport it to regional lymph
nodes, where T cells are activated by the antigen
Generally, the T cells activated during the
sensitization phase are CD4+, but in a few casesCD8+ cells have also been shown to induce a DTH
response.
The activated T cells previously were called TDTH
cells to denote their function in the DTH response
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A subsequent exposure to the antigen induces the
effector ph
ase of th
e DTH response
In the effector phase, TH1 cells secrete a variety of
cytokines that recruit and activate macrophages and
other nonspecific inflammatory cells.
A DTH response normally does not become apparent
until an average of 24h
after th
e second contact with
the antigen; the response generally peaks 4872 h
after second contact.
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The delayed onset of this response reflects the time
required for th
e cytokines to induce localized influxesof macrophages and their activation
Once a DTH response begins, a complex interplay of
nonspecific cells and mediators is set in motion thatcan result in tremendous amplification.
Macroph
ages are th
e principal effector cells of th
eDTH response
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The influx and activation of macrophages in the DTH
response is important inh
ost defense againstparasites and bacteria that live within cells, where
circulating antibodies cannot reach them.
The heightened phagocytic activity and the buildup
of lytic enzymes from macroph
ages in th
e area ofinfection lead to nonspecific destruction of cells, and
thus of the intracellular pathogen.
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Generally, the pathogen is cleared rapidly with
little tissue damage.
However, in some cases, especially if the
antigen is not easily cleared, a prolonged DTH
response can itself become destructive to the
host as the intense inflammatory response
develops into a visible granulomatous
reaction.
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A granuloma develops when continuous activation of
macrophages induces the macrophages to adhere
closely to one another, assuming an epithelioid
shape and sometimes fusing to form multinucleated
giant cells
These giant cells displace the normal tissue cells,
forming palpable nodules, and release high
concentrations of lytic enzymes, which destroysurrounding tissue
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N
umerous Cytokines Participatein the DTH Reaction
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IL-3 and GM-CSF
IFN- and TNF- (together with macrophage-
derived TN
F- and IL-1)
Migration-inhibition factor (MIF)
MCP- Monocyte chemo tactic protein
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The DTH Reaction Is Detectedwith a Skin Test
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The presence of a DTH reaction can be measured
experimentally by injecting antigen intradermally
into an animal and observing whether a
characteristic skin lesion develops at the injectionsite.
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For example, to determine whether an individual has
been exposed to M.tuberculosis, a protein derived
from the cell wall of this mycobacterium, is injectedintradermally.
Development of a red, slightly swollen, firm lesion at
the site between 48 and 72 h later indicates previous
exposure.
The skin lesion results from intense infiltration ofcells to the site of injection during a DTH reaction;
80%90% of these cells are macrophages
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Contact Dermatitis Is a Typeof DTH Response
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Many contact-dermatitis reactions, including the
responses to -
formaldehyde,
trinitrophenol,
nickel,
turpentine, Active agents in various cosmetics and
hair dyes,
poison oak,
poison ivy, are mediated by TH1 cells.
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Most of these substances are small molecules that
can complex with
skin proteins.
This complex is internalized by antigen-presenting
cells in the skin (e.g., Langerhans cells), then
processed and presented together with class II MHCmolecules, causing activation of sensitized TH1 cells
In the reaction to poison oak, for example, a
pentadecacatechol compound from the leaves of the
plant forms a complex with skin proteins
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When TH cells react with this compound
appropriately displayed by local antigen-presenting
cells, they differentiate into sensitized TH1 cells.
A subsequent exposure to pentadecacatechol will
elicit activation of TH1 cells and induce cytokine
production
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Approximately 4872 h after the second exposure,
the secreted cytokines cause macrophages to
accumulate at the site.
Activation of these macrophages and release of lyticenzymes result in the redness and pustules that
characterize a reaction to poison oak.
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