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Type IV Hypersensitivity

Cell mediated hypersensitivity

or Delayed hypersensitivity
Type IV Hypersensitivity
It is mediated by cells; circulating
antibody and complement are not
involved. Many reactions to
immunologic insult involve both
cellular and humoral components.
It is mediated by soluble factors
(lymphokines) released by the
sensitized T lymphocytes. The
lymphokines have biological
activities affecting various cell
Type IV Hypersensitivity
Those that may be used as examples of
delayed type hypersensitivity
response includes:
Tuberculin skin reaction
Contact sensitivity
Granulomatous hypersensitivity
Tuberculin-type Hypersensitivity
This form of hypersensitivity was
originally described by Koch.
The skin reaction is frequently used
to test for sensitivity to the
organisms following previous
This form of hypersensitivity may
also be induced by non-microbial
antigens, such as beryllium and
Tuberculin-type Hypersensitivity
The tuberculin skin test reaction
principally involves monocytes.
The tuberculin skin test is an
example of the recall response to
soluble antigen previously
encountered during infection.
Tuberculin-type Hypersensitivity
Tuberculin-like delayed type
hypersensitivity (DTH) reactions are
used practically in two ways.
First, reaction to soluble
antigens from a pathogen
demonstrates past infection with
that pathogen. Thus tuberculin
reactivity confirms past
infection with M. tuberculosis,
but not necessarily active
Tuberculin-type Hypersensitivity
Second, DTH responses to frequently
encountered microbes are a general
measure of cell-mediated immunity.
This can be tested with intradermal
injection of single antigens from common
pathogens, or a multipuncture device
which delivers seven common microbial
antigens in a standardized fashion.
Loss of recall responses to specific
antigens occurs in a wide range of
diseases and infections which impair T-
cell function, and during therapy with
corticosteroids or immunosuppressive
Contact hypersensitivity
Contact hypersensitivity is
characterized by an eczematous
reaction at the point of contact
with the allergen.
It is often seen following contact
with agents such as nickel, chromate,
rubber accelerators and
Contact with irritants that damage
skin by toxic mechanisms not
mediated by hypersensitivity can
also produce eczema.
Contact hypersensitivity
The Langerhans’ cell is the principal
antigen-presenting cell
Contact hypersensitivity is primarily
an epidermal reaction, and the
dendritic Langerhans’ cell, located
in the suprabasal epidermis, is the
principal antigen-presenting cell
(APC) involved. Langerhans’ cells are
inactivated by ultraviolet B, which
can thus prevent or alleviate the
effects of contact hypersensitivity.
Contact hypersensitivity
In vitro, Langerhans’ cells act as
APCs and are more potent in this
regard than monocytes. Langerhans’
cells take up hapten-modified
proteins by micropinocytosis and
under the influence of interleukin-1
(IL-1) and tumor necrosis factor (TNF)
from keratinocytes and other cells
undergo maturation, increase the
expression of MHC and co-stimulatory
molecules and migrate to draining
lymph nodes.
Contact hypersensitivity
Keratinocytes produce a range of
cytokines important to the contact
IL-3 can activate Langerhans’ cells,
co-stimulate proliferative responses,
recruit mast cells and induce the
secretion of immunosuppressive
cytokines. These latter dampen the
immune response and induce the
clonal anergy in TH1 cells.
Contact hypersensitivity
Keratinocytes can be activated by a
number of stimuli, including
allergens and irritants. Activated
keratinocytes produce
immunostimulatory cytokines such as
TNFα and granulocyte- macrophage-
colony-stimulating factor (GM-CSF)
which activate Langerhans’ cells.
Contact hypersensitivity
A contact hypersensitivity reaction
has two stages: sensitization and
Sensitization produces a
population of memory T cells
Elicitation involves recruitment
of CD4+ lymphocytes and
Sensitization takes 10 – 14 days in
humans. Once absorbed, the hapten
with a protein and is internalized
by epidermal Langerhans’ cells, which
leave the epidermis and migrates as
veiled cells through the afferent
lymphatics to the paraoctical areas
of regional lymph nodes. Here they
present hapten-protien conjugates to
CD4+ lymphocytes, producing a
population of memory CD4+ T cells.
Langerhans”cells carrying the hapten
carrier complex (1)move from the
epidermis to the dermis, where they
present the hapten-carrier complex to
memory CD4+ T cells (2) Activated
CD4+ T cells released IFNγ, which
induces expression of ICAM-1 (3) and
later MHC class II molecules (4) on
the surface of keratinocytes and on
the endothelial cells of dermal
capillaries and activates
keratinocytes such as IL-,1 IL-6 and
(5) Non antigen specific CD4+ T cells
are attracted to the site by
cytokinesis (6) and may bind to
keratinocytes via ICAM-1 and class II
molecules. Activates macrophages are
also attracted to the skin, but this
occurs later. Thereafter the reaction
stars to downregulate. This
doenregulation may be influenced by
eicosanoids such as PGE, produced by
activated keratinocytes and
macrophages (7) has been shown to
induce a specific inhibitor of IL-1
Granulomatous hypersensitivity is
clinically the most important form of
TYPE IV hypersensitivity, and causes
many of the pathological effects in
disease that involves T cells mediated
It usually results from the persistence
within macrophages of intracellular
microorganisms or other particles that
the cells is unable to destroy. This
process results in epithelioid cell
granuloma formation. This histological
appearance of the granuloma reaction is
quite different from that of the
However, they often result from
sensitization to similar microbial
antigens. Immunological granuloma
formation also occurs in the sensitivity
reactions to zirconium and beryllium, and
in sarcoidosis, although in the latter the
antigen is unknown.
Foreign body granuloma formation occur with
talc, silica and a variety of other
particulate agents. In this case
macrophages are unable to digest the
inorganic matter. These non immunological
granulomas may be distinguished by the
absence of lymphocytes in the lesion.

An immunological granuloma typically
has a core of epithelioid cells and
macrophages, sometimes with giant
cells. In some diseases, such as
tuberculosis, this central area may
have a zone of necrosis, with
complete destruction of all cellular
architecture. The
macrophage/epithelioid core is
surrounded by a cuff of lymphocytes,
and there may also be considerable
fibrosis caused by proliferation of
fibroblasts and increased collagen
Type Reaction Clinical Histology Antigen
time appearance

contact 48-72 hr Eczema Lymphocytes, Epidermal e.g.

later nickel, rubber,
macrophages, poison ivy
oedema of
tuberculin 48-72 hr Local induration Lymphocytes, Intradermal e.g.
monocytes, tuberculin
granuloma 21-28 days Hardening e.g. Macrophages, Persistent Ag or
skin or lungs epithelioid cells, Ag/Ab
giant cells, complexes or
fibrosis non-
e.g. talc
Type V Hypersensitivity
Receptor mediated hypersensitivity
Type V Hypersensitivity
This reaction occur when IgG
class antibodies directed
towards cell surfaces antigens
have either a stimulating or
inhibitory effect on their
Cells are signaled by agents such
as hormones, mainly amino acid-
based hormones:
These hormones cannot pass through
plasma membranes because they are
Type V Hypersensitivity
Type V hypersensitivity has been
added as a distinction from Type
This additional class of reaction
refers to stimulatory
hypersensitivity where, instead
of binding to cell surface
components and destroying the
cells, IgG receptors thus either
prevents ligand binding, or
mimics the effect of the
endogenous ligand, thus impairing
Type V Hypersensitivity
This is a useful distinction to Type
II reactions where the cytotoxic
binding of antibody causes cell
Stimulatory hypersensitivity occurs
when the autoantibodies cause
inappropriate stimulation of the
Allergic Contact Dermatitis
from a Henna Tattoo
Colby C. Evans, M.D.
John D. Fleming, M.B., B.S
New England Journal of Medicine
August 2008
Allergic Contact Dermatitis from a Henna

Temporary henna tattooing is a custom

at weddings in much of the world. The
dyeing agent (hennotannic acid)
rarely leads to skin sensitization.
However, tattoo henna is often mixed
with paraphenylenediamine (PPD) to
hasten drying and darken the color.
PPD is a common allergen that is
also found in permanent hair dyes.

Allergic Contact Dermatitis from a
Henna Tattoo

Allergens that cause reactions in

patients who are sensitive to PPD
include sunscreens containing
aminobenzoic acid, certain local
anesthetics, and sulfonamides.
The patient was treated high-potency
topical corticosteroids, and the
lesions resolved, although with
extensive postinflammatory
Allergic Contact Dermatitis from a
Henna Tattoo